MBS Reviews VITAMIN D TESTING REPORT...February 2014 MBS Reviews – Vitamin D Testing Review Report...

MBS Reviews

VITAMIN D TESTING

REPORT

February 2014

February 2014

MBS Reviews

Vitamin D Testing Review Report

Table of Contents

Section Page

LIST OF ABBREVIATIONS ............................................................................................................ 4

EXECUTIVE SUMMARY ..................................................................................................................................... 7

PURPOSE OF THE REVIEW ......................................................................................................................................... 7

VITAMIN D TESTING ................................................................................................................................................. 7

CONCERNS ABOUT VITAMIN D TESTING ................................................................................................................... 7

REVIEW METHODOLOGY .......................................................................................................................................... 8

STAKEHOLDER CONSULTATION ................................................................................................................................ 8

SUMMARY OF FINDINGS ........................................................................................................................................... 8

CONCLUSIONS ........................................................................................................................................................ 14

1 BACKGROUND ON VITAMIN D TESTING ......................................................................... 15

1.1 DESCRIPTION OF CURRENT SERVICES ........................................................................................................ 15

1.2 THE CLINICAL FLOWCHARTS ..................................................................................................................... 23

2 REVIEW METHODOLOGY ..................................................................................................... 24

2.1 SECONDARY DATA ANALYSIS .................................................................................................................... 24

2.2 GUIDELINE CONCORDANCE ....................................................................................................................... 24

2.3 SYSTEMATIC LITERATURE REVIEW FOR CLINICAL EVIDENCE ..................................................................... 25

2.4 SYSTEMATIC LITERATURE REVIEW FOR ECONOMIC EVIDENCE .................................................................. 28

3 SECONDARY DATA ANALYSIS ............................................................................................. 29

3.1 MBS ITEM NUMBER USAGE AND EXPENDITURE ......................................................................................... 29

3.2 AGE AND GENDER PROFILE OF PATIENTS ................................................................................................... 32

3.3 FREQUENCY OF TESTING BY PATIENT ........................................................................................................ 33

3.4 PROFILE OF PROVIDERS REQUESTING VITAMIN D TESTING SERVICES ........................................................ 34

3.5 FREQUENCY OF REQUESTS FOR TESTING BY PROVIDER .............................................................................. 35

4 REVIEW OF GUIDELINES RELEVANT TO VITAMIN D TESTING ............................. 37

4.1 AUSTRALIAN GUIDELINES ......................................................................................................................... 37

4.2 INTERNATIONAL GUIDELINES .................................................................................................................... 45

5 REVIEW OF THE CLINICAL EVIDENCE FOR VITAMIN D TESTING ....................... 51

5.1 EVIDENCE BASE ........................................................................................................................................ 51

5.2 PREVIOUS HEALTH TECHNOLOGY ASSESSMENTS OF VITAMIN D TESTING .................................................. 53

5.3 RELATIONSHIP BETWEEN VITAMIN D AND HEALTH OUTCOMES ................................................................. 54

5.4 RELATIONSHIP BETWEEN TESTING FOR VITAMIN D LEVELS AND HEALTH OUTCOMES ............................... 56

5.5 EVIDENCE OF THE DIFFERENTIAL CLINICAL UTILITY OF VITAMIN D TESTING ............................................ 56

February 2014

MBS Reviews

Vitamin D Testing Review Report

5.6 HARMS ASSOCIATED WITH VITAMIN D TESTING OR SUPPLEMENTATION .................................................... 56

5.7 EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION IN HEALTHY POPULATIONS ........................................ 57

5.8 EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION IN PATIENTS WITH CHRONIC DISEASE ......................... 58

5.9 OVERALL SUMMARY FROM THE CLINICAL EVIDENCE ................................................................................ 59

6 REVIEW OF THE ECONOMIC EVIDENCE RELATING TO VITAMIN D TESTING 61

6.1 EVIDENCE BASE ........................................................................................................................................ 61

6.2 COST IMPLICATIONS OF VITAMIN D TESTING ............................................................................................. 61

6.3 COST-EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION ......................................................................... 62

7 FINDINGS AND CONCLUSIONS ............................................................................................ 63

7.1 CURRENT USAGE OF VITAMIN D TESTING SERVICES IN AUSTRALIA ........................................................... 63

7.2 CLINICAL GUIDANCE ON VITAMIN D TESTING ........................................................................................... 64

7.3 RELATIONSHIP BETWEEN VITAMIN D AND HEALTH OUTCOMES ................................................................. 67

7.4 RELATIONSHIP BETWEEN TESTING FOR VITAMIN D LEVELS AND HEALTH OUTCOMES ............................... 67

7.5 EFFECTIVENESS OF VITAMIN D SUPPLEMENTATION................................................................................... 68

7.6 HARMS ASSOCIATED WITH VITAMIN D TESTING OR SUPPLEMENTATION .................................................... 69

7.7 COST IMPLICATIONS OF VITAMIN D TESTING ............................................................................................. 69

7.8 CONCLUSIONS ........................................................................................................................................... 69

APPENDIX 1 – REFERENCES ............................................................................................................ 71

APPENDIX 2 – REVIEW CONSULTATION COMMITTEE MEMBERS ............................................... 86

APPENDIX 3 – MBS INFORMATION ................................................................................................ 87

APPENDIX 4 – SEARCH TERM STRATEGY ...................................................................................... 88

APPENDIX 5 – TOOLS FOR ASSESSING THE EVIDENCE IN THE SYSTEMATIC REVIEW ................ 92

APPENDIX 6 – QUOROM FLOWCHART ........................................................................................ 94

APPENDIX 7 - GRADING OF RECOMMENDATIONS ........................................................................ 95

APPENDIX 8 – SUMMARY OF INCLUDED STUDIES AND SYSTEMATIC REVIEWS ........................... 96

APPENDIX 9 – REVIEW OF THE EFFECTIVENESS OF SUPPLEMENTATION IN HEALTHY PATIENT

POPULATIONS................................................................................................................................. 114

A9.1 EFFECT OF VITAMIN D SUPPLEMENTATION ON MUSCULOSKELETAL HEALTH .......................................... 114

APPENDIX 10 – REVIEW OF THE EFFECTIVENESS OF SUPPLEMENTATION IN PATIENTS WITH

CHRONIC DISEASE.......................................................................................................................... 136

A10.1 EFFECT OF VITAMIN D SUPPLEMENTATION ON OBESITY .......................................................................... 136

February 2014

MBS Reviews – Vitamin D Testing Review Report

LIST OF ABBREVIATIONS

1,25-(OH)2D 1,25 Dihydroxy vitamin D

25-(OH)D 25 Hydroxy vitamin D

µg Microgram (unit of measurement)

ACHI Australian Classification of Health Interventions

AHRQ Agency for Health Research and Quality

AIHW Australian Institute of Health and Welfare

BMC Bone mineral content

BMD Bone mineral density

BMI Body mass index

BP Blood pressure

CAD Coronary artery disease

CHD Coronary heart disease

CI Confidence interval

CKD Chronic kidney disease

CMFM Comprehensive Management Framework for the MBS

CRC Consultation Review Committee

CVD Cardiovascular disease

CWG Clinical Working Group

DBP Diastolic blood pressure

DOES Dubbo Osteoporosis Epidemiology Study

DRG Diagnosis-related group

EAR Estimated average requirements

EDSS Expanded Disability Status Scale

ESC Evaluation Sub-Committee (of MSAC)

grp Group

February 2014



HTA Health technology assessment

IFN Interferon

IOM Institute of Medicine

IR Insulin resistance

ITT Intention-to-treat

IU International Unit

LC-MS Liquid chromatography-mass spectrometry

MA Meta-analysis

MI Myocardial infarction

mm Hg Millimetre of mercury

mos Months

MS Multiple sclerosis

MSAC Medical Services Advisory Committee

MBS Medicare Benefits Schedule

MESP MSAC Expert Standing Panel

MRI Magnetic Resonance Imaging

NHANES National Health and Nutrition Examination Survey

NHMD National Hospital Morbidity Database

NICE National Institute for Health and Clinical Excellence

NIST National Institute of Standards and Technology

nmol/L Nanomole per litre (unit of measurement

NR Not reported

NS Not (statistically) significant

OHTAC Ontario Health Technology Advisory Committee

OR Odds ratio

PASC Protocol Advisory Sub-Committee (of MSAC)

February 2014



PBS Pharmaceutical Benefits Scheme

PICO Population, intervention, comparator, outcome

PTH Parathyroid Hormone

QUOROM Quality of Reporting of Meta-analyses

RACGP Royal Australian College of General Practitioners

RCPA QAP Royal College of Pathologists of Australasia Quality Assurance Program

RCC Research Consultation Committee

RCT Randomised controlled trials

RDA Recommended dietary allowance

RDI Recommended daily intake

RR Relative risk

SBP Systolic blood pressure

SD Standard deviation

SMD Standard mean difference

SR Systematic review

Subgrp Subgroup

TGA Therapeutics Goods Administration

US United States

USPSTF U.S. Preventive Services Task Force

UVB Ultraviolet B

VA Veterans Administration

VitD Vitamin D

WHI Women’s Health Initiative

Wks Weeks

WMD Weighted mean difference

February 2014


EXECUTIVE SUMMARY

In the 2011-12 Budget, the Australian Government announced a further commitment to the

Comprehensive Management Framework for the Medicare Benefits Schedule [MBS]

(CMFM), to continue the systematic review of MBS items to ensure that they reflect

contemporary evidence, improve health outcomes for patients and represent value for money.

MBS Reviews aim to ensure the clinical and financial sustainability of the MBS. Reviews

assess specific MBS services (i.e. MBS items) and associated policy issues in a focussed, fit-

for-purpose, evidence-based process. Findings recognise that the MBS funding should align

with contemporary evidence, reflecting appropriate patient groups and best clinical practice.

The Reviews have a primary focus on improving health outcomes and the financial

sustainability of the MBS through the following criteria:

assess patient safety risk;

identify services that have limited health benefit and/or are used inappropriately;

be evidence-based and fit-for-purpose;

be conducted in consultation with key stakeholders including, but not limited to, the

medical profession and consumers;

include opportunities for public submission; and

use Government resources efficiently.

Purpose of the review

This Review Report outlines the rationale behind conducting the review of the MBS items

relevant to vitamin D testing and the process undertaken to identify and appraise the available

information on the MBS items to ensure that they reflect contemporary evidence, improve

health outcomes for patients and represent value for money.

Vitamin D testing

Vitamin D is a lipid soluble vitamin that acts as a hormone. It is synthesised in the skin

through exposure to ultraviolet B light (UVB) radiation from sunlight and may also be

obtained from dietary sources and supplements. Vitamin D from sunlight exposure, diet or

supplements first undergoes a hydroxylation reaction in the liver, producing 25-

hydroxyvitamin D (25-(OH)D; also known as calcidiol). This is the major circulating form

and the metabolite routinely used to assess overall vitamin D status. Further hydroxylation

occurs in the kidney (and in other tissues) to form the hormonal and biologically active 1,25-

dihydroxyvitamin D (1,25-(OH)2D), also known as calcitriol.

There are two different assays for measuring serum levels of 25-(OH)D: liquid

chromatography-tandem mass spectrometry (LC-MS), which is referred to as the ‘gold

standard’ test, and commercial immunoassays either using radioactive markers or chemical

markers.

Concerns about vitamin D testing

There has been a significant increase in the number of claims and benefits paid for MBS item

numbers relating to vitamin D testing (increased by 4,600% over the last 10 years). There are

concerns that some patient groups may be tested for vitamin D levels unnecessarily and/or

more frequently than necessary.

February 2014


Review methodology

The review methodology comprised consulting with key stakeholders; developing a review

protocol document, which outlined the detailed review methodology (including specifying the

key clinical/research questions for the systematic review, preparing the clinical flowcharts,

and documenting the economic review strategy); analysing secondary data sources (MBS

data); conducting an evidence-based systematic literature review on vitamin D testing; and

undertaking an assessment and synthesis of all of the evidence to draw conclusions in relation

to the clinical/research questions.

Stakeholder consultation

Stakeholder engagement is a pivotal part of the MBS Reviews process, particularly as

feedback helps inform Review Reports. During the review process, stakeholders were

informed of the progress of the MBS items being considered. This included ensuring that

relevant documents were released for public consultation at the appropriate time and that

comments were incorporated into the review process.

As part of the MBS Review process, the Department established a Review Consultation

Committee (RCC). The RCC is a time-limited committee of nominated representatives,

established to provide advice to the Department. A list of RCC members is found at

Appendix 2.

Summary of findings

Current usage of vitamin D testing services in Australia

The number of MBS claims for vitamin D testing (item 66608 and 66609) has increased each

year over the past ten years, from 117,474 claims in 2003/04 to 4,331,030 claims in 2012/13.

This represents a 3,587% increase in vitamin D testing services. Over the same time period, a

similar increase (3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04

to $151,129,505 in 2012/13.

Over 98% of vitamin D testing services are for MBS item 66608. The proportion of services

bulk billed for this item from 2008/09 to 2012/13 was high (more than 95% of services),

which is consistent with the high proportion of out-of-hospital services for this item (over

98%). MBS item 66609 was listed on the MBS in May 2007. After a peak in services in

2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13). For

item 66609, over 85% of services were bulk billed from 2008/09 to 2012/13.

Between 2008/09 and 2012/13, the majority of all claims for item 66608 were from NSW and

Victoria; the other states and territories together accounted for less than 30% of total claims in

each year. Victoria had the highest rate of claiming per capita (25,267 claims per 100,000

population), followed by the ACT and NSW. The lowest per capita rates of vitamin D testing

services were in the northernmost states and territories (NT and Queensland). Item 66609

showed much more variability over time, and relatively high usage in Queensland as a

proportion of total claims. The highest number of claims per capita in 2012/13 was for

Tasmania and the ACT, while Victoria had the lowest.

Item numbers 66608 and 66609 are claimed by both genders; however, from 2008/09 to

2012/13, 70.2% of claims for MBS item 66608 and 68.9% of claims for item 66609 were for

February 2014


females. The number of claims is particularly significant for females aged between 24 and 84

years. Australian guidelines for general practice recommend that targeted vitamin D testing

should be considered for people who are at risk of osteoporosis and who are at high risk of

vitamin D deficiency. Prevalence estimates from Australia indicate that 31%-36% of adults

are deficient in vitamin D (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to

50%-62% in women during winter-spring or in people residing in southern states. The gender

imbalance and peak in testing for vitamin D levels within the 55-64 year age category is

consistent with epidemiological trends for vitamin D deficiency and osteoporosis. However,

the reason for the high rate of testing in the 45-54 year age category is less clear. An

examination of total services for MBS item 66608 in 2012/13 showed no difference in the

proportion of tests claimed in winter-spring (when the prevalence of vitamin D deficiency is

reported to be at its highest) compared with summer-autumn.

An analysis of vitamin D testing frequency per patient was conducted. The proportion of

patients who received only one test per year increased slightly over time for item 66608

(81.8% in 2008/09 and 83.4% in 2012/13), whereas the proportion of patients who received

two tests per year decreased from 14.8% to 13.9%, and the proportion of patients who

received three or more tests per year decreased from 3.4% to 2.8%. For item 66609, the

proportion of patients who received one or two tests per year was relatively stable over time

whereas the proportion of patients who received three or more tests decreased from 3.1% in

2008/09 to 2.1% in 2012/13. Taken together with the age profile of patients being tested,

these data suggest that the majority of vitamin D testing services are being undertaken for the

purposes of screening/testing rather than monitoring.

From 2008/09 to 2012/13, there were no material changes in the pattern of requesting

providers. GPs and other medical practitioners (OMPs) accounted for nearly two-thirds of all

providers requesting vitamin D testing services for item 66608. Internal medicine consultant

physicians accounted for another 15% of all provider counts, followed by a large variety of

other provider types. For item 66609, GPs and OMPs accounted for over 60% of all

providers requesting vitamin D testing services, followed by internal medicine consultant

physicians (approximately 28%).

An analysis of test requests for item 66608 by frequency from any one provider was

conducted. In 2012/13, the proportion of providers requesting ≤ 10 tests, 11-50 tests, and >

50 tests was 38.7%, 24.5%, and 36.8%, respectively. While the proportion of providers

requesting ≤ 10 tests has decreased since 2008/09, the proportion of providers requesting

more than 50 tests per year has increased. Each year, there is a small number of providers

who request over 400 vitamin D tests per year (682 in 2008/09 rising to 1,867 in 2012/13).

For item 66609, the proportion of providers requesting one test in 2012/13 was 64.1% (up

from 54.5% in 2008/09), whereas the proportion of providers requesting two or more tests per

year was 35.9% (down from 45.5% in 2008/09).

Taken together, these data show that there is a large and increasing number of providers,

primarily GPs and OMPs, who are requesting high volumes of vitamin D tests per year,

presumably for the purposes of screening/testing rather than monitoring.

Clinical guidance on vitamin D testing

The MBS data indicate that the majority of requests for vitamin D testing are initiated by GPs

and OMPs. The relevant College providing practice advice is the Royal Australian College of

General Practitioners (RACGP). Their 2012 guidelines for preventative activities in general

February 2014


practice advise that routine screening for vitamin D deficiency is not recommended in low

risk populations. However, targeted testing of people who are at risk of osteoporosis and who

are at high risk of vitamin D deficiency should be considered. High-risk groups for vitamin D

deficiency in pregnancy may also benefit from vitamin D screening. The guidelines do not

advise on the frequency of testing.

The RACGP has also produced a 2010 clinical guideline for the prevention and treatment of

osteoporosis in postmenopausal women and older men. Serum 25-(OH)D is one of the

recommended laboratory tests for the diagnostic assessment for osteoporotic fractures, but

only under particular conditions (e.g. if secondary osteoporosis is suspected).

The Royal College of Pathologists of Australasia (RCPA) released a Position Statement in

May 2013 for the use and interpretation of vitamin D testing. The Position Statement

recommended testing for vitamin D status in individuals at risk of vitamin D deficiency and

showing the following indications:

signs, symptoms and/or planned treatment of osteoporosis or osteomalacia;

increased alkaline phosphatase with otherwise normal liver function tests;

hyperparathyroidism, hypo- or hypercalcaemia or hypophosphataemia;

malabsorption (e.g. cystic fibrosis, short bowel syndrome, inflammatory bowel disease,

untreated coeliac disease, bariatric surgery);

deeply pigmented skin, or chronic or severe lack of sun exposure for cultural, medical,

occupational or residential reasons;

medications known to decrease vitamin D levels (mainly anticonvulsants); and

chronic renal failure and renal transplant patients.

The Position Statement states that routine testing for vitamin D status in the general

population (including healthy adults, pregnant women, and children) is not currently

recommended. However, it recommended that serum vitamin D levels be retested after three

months following the commencement of vitamin D supplementation. No further testing is

required once desirable 25-(OH)D target levels are achieved. The Position Statement

recommended against high dose annual replacement of cholecalciferol. The Statement

recommended that the target level of serum 25-(OH)D should be >50 nmol/L at the end of

winter.

The Working Group of the Australian and New Zealand Bone and Mineral Society

(ANZBMS), Endocrine Society of Australia and Osteoporosis Australia released a position

statement in 2012 that recommended screening for 25-(OH)D levels in high-risk groups,

defined as:

older or disabled people in low-level and high-level residential care;

dark-skinned people of either sex, particularly migrants and/or if modest dress is worn;

people with a disability of chronic disease (e.g. multiple sclerosis);

fair-skinned people and those at risk of skin cancer who avoid sun exposure;

obese people; and

people working in an enclosed environment.

The position statement advised for retesting of vitamin D levels three months after

commencement of supplementation.

February 2014


In 2013, the Working Group of the ANZBMS and Osteoporosis Australia also released a

position statement on vitamin D and health in pregnancy, infants, children and adolescents.

The position statement advised that universal screening for vitamin D status in pregnant

women, infants, children and adolescents is not supported by the evidence. However, 25-

(OH)D levels should be tested in those with one or more risk factors for low vitamin D,

defined as:

lack of skin exposure to sunlight (due to lifestyle factors, chronic illness or hospitalisation,

covering clothing or southerly latitude);

dark skin;

medical conditions (obesity, end-stage liver disease, renal disease) or medications

affecting vitamin D metabolism and storage; and

in infants, maternal vitamin D deficiency and exclusive breastfeeding combined with at

least one other risk factor.

Infants, children and adolescents with ongoing risk factors require ongoing monitoring of

vitamin D status with annual testing. Pregnant women with risk factors should be tested at

their first antenatal visit and again at 28 weeks’ gestation. For neonates with moderate or

severe deficiency, follow-up testing is recommended at one month after commencement of

vitamin D supplementation; in other groups, follow-up at three months is usually more

practical; and in the long term, annual testing is recommended. Very frequent testing should

be avoided.

In 2012, Kidney Health Australia published CARI (Caring for Australasians with Renal

Impairment) guidelines on vitamin D therapy in early kidney disease. The guidelines

recommend that patients with early chronic kidney disease on vitamin D therapy have their

25-(OH)D levels monitored regularly. Further details on the frequency of testing are not

provided.

The identified Australian guidelines are consistent with international guidelines that

recommend against routine screening for vitamin D status in adults, pregnant women and

children. However, there are guidelines that support screening in high-risk individuals

(although definitions of at-risk were lacking in these guidelines), and testing vitamin D status

in populations with known poor bone health (such as children with skeletal fragility and

adults with osteoporosis). Follow-up testing is also recommended in people being treated

pharmaceutically for osteoporosis (at 3-4 months after commencement of therapy).

Recommendations against routine screening are consistent with the lack of direct evidence

that vitamin D testing improves outcomes, as well as the lack of moderate or high quality

evidence that supplementation improves outcomes in healthy populations. Recommendations

for testing in populations with known poor bone health are weakly supported by evidence of

the effectiveness of supplementation in these populations, but there is no direct evidence

concerning the clinical utility of testing (see below).

Several guidelines mention that measurement of serum 25-(OH)D is the best way of

estimating vitamin D status, due to its relatively long half-life. Immunoassays are often

automated and are therefore cheaper and faster; however, a weakness is the inability to

quantify vitamin D2 and vitamin D3 separately. LC-MS is more sensitive than immunoassay

but is also more labour intensive and requires expensive equipment and skilled staff.

February 2014


The performance of radioimmunoassay is generally considered to be acceptable; however, the

bias and imprecision of many automated methods may be problematic at the lower, clinically

and analytically important range (< 50 nmol/L) of the assay. Prior to the recent introduction

of the standard reference material for 25-(OH)D from the National Institute of Standards and

Technology (NIST), there were numerous publications reporting that different immunoassays

may be yielding different results. However, the introduction of the reference standard has

helped to assess the accuracy of the different immunoassays and provide more reliable results.

All Australian and New Zealand laboratories offering 25-(OH)D testing are required to be

enrolled in external proficiency programs.

Relationship between vitamin D and health outcomes

The evidence suggests a harmful association of serum 25-(OH)D with cancer mortality in

men, but a protective association of serum 25-(OH)D with bone health, cardiovascular health,

type 2 diabetes, colorectal cancer, ovarian cancer and all-cause mortality. The link between

serum 25-(OH)D and cancer (other than colorectal or ovarian) is unclear. There is insufficient

evidence regarding an association of serum 25-(OH)D with obesity, gestational diabetes,

multiple sclerosis, depression and mood disorders.

For disease outcomes where a link has been demonstrated, the evidence does not support

definitive cut-off points at which 25-(OH)D serum levels can be expected to predict optimal

overall health. However, the evidence is consistent with approximately 30 nmol/L as the

level below which there is a risk of deficiency and a threshold ≥ 50 nmol/L, and possibly as

high as 70 nmol/L, for optimal health. Optimal thresholds may vary by the outcome of

interest.

There is very sparse evidence for an association between serum levels of 25-(OH)D and

disease-related outcomes in individuals with chronic disease. Vitamin D screening may have

promise for establishing a prognosis in patients with colon cancer, prostate cancer or

melanoma and for assessing the risk of disease-related events and complications in patients

with hypertension and diabetes; however, the evidence is too sparse to support clinical rules

or cut-off points.

Relationship between testing for vitamin D levels and health outcomes

No trials designed to measure the effect of vitamin D screening or testing on health outcomes,

patient behaviour or clinical decisions were identified. Therefore, trials of vitamin D

supplementation were reviewed as an indication of the potential utility of vitamin D

screening/testing. The rationale was that screening or testing would not improve health

outcomes if there were no effective treatment that could be recommended for individuals with

low serum vitamin D.

Due to a lack of studies directly evaluating the effectiveness of testing, differential

effectiveness and safety by type of assay, frequency of monitoring and time of year that tests

are conducted could not be directly evaluated.

Effectiveness of vitamin D supplementation

A good quality Health Technology Assessment (HTA) published in November 2012 for the

Washington State Health Care Authority evaluated the effect of vitamin D supplementation in

healthy populations (without symptoms or findings of the outcome of interest) and

February 2014


populations with chronic disease that may be linked with, but does not cause, vitamin D

insufficiency.

The effect of vitamin D supplementation on outcomes in healthy populations was evaluated in

six systematic reviews and 14 randomised controlled trials (RCTs). Participants were not

selected on the basis of vitamin D test results. The evidence base was generally considered to

be of low quality, except for moderate-quality evidence regarding prevention of mood

disorders. Common weaknesses included variable vitamin D doses across studies and varied

protocols with respect to the use of non-study vitamin D. Where the evidence suggested a

benefit, the effects were small.

In summary, the evidence suggests positive effects of supplementation on musculoskeletal

health and general mortality in older adults. Evidence regarding the effectiveness of

increased vitamin D intake through supplementation does not, in general, support vitamin D

screening to improve non-skeletal health outcomes other than mortality.

The effect of supplementation on disease-related outcomes in patients with chronic disease

was evaluated in three systematic reviews and 16 RCTs. Participants were not selected on the

basis of vitamin D test results. The evidence was considered to be of low to moderate quality.

Even in the disease populations where the evidence showed a benefit, the effects were

generally small and the clinical relevance was questionable.

An exception was the effect of active vitamin D supplementation on bone health in older

adults with osteoporosis or a history of fracture. On the basis of a moderate body of evidence

showing benefit of supplementation in this population, the HTA concluded that vitamin D

testing in patients who have evidence of osteoporosis has the potential to improve bone-

related outcomes. Given the evidence showing supplementation to modestly improve disease-

related outcomes in individuals with cardiovascular disease or abnormal blood glucose,

vitamin D screening to assess the risk of adverse disease outcomes might also be effective in

these populations. The available evidence regarding the effectiveness of increased vitamin D

intake through supplementation does not, in general, support screening in other disease

populations.

On the basis of the available evidence for supplementation and associations between serum

25-(OH)D and health outcomes, knowledge of vitamin D serum levels might have value:

(1) to demonstrate the need for supplementation in postmenopausal women as a means of

reducing disease and mortality risk (based on low quality evidence); and

(2) to inform treatment for individuals with known or highly suspected osteoporosis (based

on moderate quality evidence).

Harms associated with vitamin D testing or supplementation

Testing for vitamin D status is a relatively safe procedure that relies on a blood draw. The

consequences of inaccurate or inappropriately interpreted test results (false negative and false

positive tests) are relatively small considering that vitamin D supplementation provides

relatively modest effects and is a relatively safe therapy (albeit through low or moderate

quality evidence).

February 2014


Cost implications of vitamin D testing

As no trials have assessed the effectiveness of vitamin D testing itself, a cost-effectiveness

analysis of vitamin D testing is not possible. One poor-quality cost analysis of vitamin D

testing was identified, which was based on a retrospective chart review of Veterans Medical

Centers in the United States. There was no comparison of costs between individuals who had

no vitamin D testing at all and those who had one or more tests.

Three cost-effectiveness studies of vitamin D supplementation were identified, all relating to

the prevention of fractures and/or falls in older adult populations. The studies were generally

well designed and the evidence was considered to be of moderate quality. However, the

selected studies did not consider vitamin D testing to be one of the costs associated with

supplementation. The studies provide consistent evidence that suggests that routine

supplementation in older populations reduces costs associated with hip fracture. In that case,

there is no need for vitamin D screening to identify subpopulations in whom there is a

potential for such cost savings. For other populations and outcomes, there is no evidence

relating to the cost implications of vitamin D testing or screening.

Conclusions

There has been a substantial increase in the number of claims for vitamin D testing over the

past ten years. Analysis of MBS data indicates that the majority of vitamin D testing services

are requested by GPs and OMPs for the purposes of screening or testing, rather than follow-

up monitoring. Australian and international clinical practice guidelines recommend against

routine screening for vitamin D status in adults, pregnant women and children. However,

screening is supported in individuals at high risk of vitamin D deficiency (particularly

pregnant women and paediatric populations) and testing is supported in populations with

known poor bone health (such as children with skeletal fragility and adults with osteoporosis).

Follow-up testing at 3-4 months is also recommended in people with osteoporosis or chronic

kidney disease being treated pharmaceutically. Recommendations for testing in populations

with known poor bone health are weakly supported by evidence of the effectiveness of

supplementation in these populations, but there is no direct evidence concerning the clinical

utility of testing in any population.

February 2014


1 BACKGROUND ON VITAMIN D TESTING

1.1 Description of current services

This section describes vitamin D and vitamin D testing, recommended vitamin D status, and

the population groups and clinical conditions/risk factors in which vitamin D testing is

recommended.

1.1.1 Vitamin D, metabolism and function

Vitamin D is a lipid soluble vitamin that acts as a hormone.(1)

It is synthesised in the skin

through exposure to ultraviolet B light (UVB) radiation from sunlight(2)

and may also be

obtained from dietary sources and supplements.(3)

There are two forms of vitamin D(4)

:

vitamin D2 (also known as ergocalciferol), which is present in plants (e.g. mushrooms);

and

vitamin D3 (also known as cholecalciferol), which is the main form obtained from animal

sources (such as some fish) and exposure to sunlight.(5)

Vitamin D supplements are

composed of the D3 form and are manufactured by the irradiation of 7-dehydrocholesterol

extracted from lanolin found in sheep's wool.(6)

Figure 1.1 shows that cutaneous synthesis of vitamin D is triggered by the skin’s exposure to

UVB (wavelength 290-315 nm), which converts 7-dehydrocholesterol present in the skin into

pre-vitamin D3, which is then converted into vitamin D3.(3)

Experimental data indicates that

exposure of around 15% of the body surface (arms and hands or equivalent) near the middle

of the day will result in the production of about 1000 IU (25 μg) of vitamin D. Achieving this

exposure on most days should generally, though not always, be sufficient to maintain vitamin

D levels in the body.(7)

Factors such as seasons and latitude can play a role in vitamin D

synthesis, for example less vitamin D is synthesised in winter, particularly at latitudes further

from the equator.

February 2014


Figure 1.1: Synthesis of vitamin D

Source: adapted from http://gardenofeaden.blogspot.com.au/2012/02/what-is-vitamin-d-deficiency.html

Vitamin D from diet, supplements, or sunlight exposure first undergoes a hydroxylation

reaction in the liver (Figure 1.1), producing 25-hydroxyvitamin D (25-(OH)D; also known as

calcidiol or calcifediol). This is the major circulating form and the metabolite routinely used

to assess overall vitamin D status. Further hydroxylation occurs in the kidney to form the

hormonal and biologically active 1,25-dihydroxyvitamin D (1,25-(OH)2D), also known as

calcitriol.(5)

This hydroxylation step can also occur in other tissues.(2, 8)

The renal synthesis of

1,25-dihydroxyvitamin D is regulated by plasma parathyroid hormone (PTH), serum calcium

and phosphorus levels.(9)

The active compound of vitamin D promotes intestinal calcium and phosphate absorption and

is important in maintaining adequate calcium levels for bone mineralisation, bone growth and

remodelling, and to prevent hypocalcaemic tetany (i.e. this is an uncommon condition caused

by an abnormally low level of calcium in the blood).(1, 3, 10)

Serum PTH has an inverse

correlation with absorbed calcium.(11)

Vitamin D deficiency reduces the efficiency of calcium

absorption from the intestines and therefore indirectly results in increased serum PTH(11)

,

which may lead to the mobilisation of calcium from the bone.(12)

1.1.2 Vitamin D dietary sources, fortification and supplements

Vitamin D (D3) is naturally present in small quantities in certain foods such as fatty fish

(salmon, herring, tuna, sardines, etc.), egg yolks, fish liver oil, and certain types of

mushrooms (see Table 1.1).(3, 13)

However, most adults are unlikely to obtain more than 5%–

10% of their vitamin D requirement from dietary foods and is therefore insufficient to meet

daily requirements.(14)

Thus, most vitamin D is obtained from exposure to sunlight, some

fortified or unfortified foods, and/or vitamin D supplements.

Vitamin D3 (oily fish, supplements)

Vitamin D2 (mushrooms)

February 2014


Table 1.1: Dietary sources of vitamin D(3)

Type of food Estimated vitamin D content

Salmon (fresh, farmed), 99 grams 100-250 IU vitamin D3

600 – 1,000 IU vitamin D3 (wild)

Mackerel (canned), 99 grams 250 IU vitamin D3

Cod liver oil, 1 teaspoon (also

contains vitamin A)

400-1,000 IU vitamin D3

Tuna (canned), 100 grams 230 IU vitamin D3

Shiitake mushrooms (fresh), 100

grams

100 IU vitamin D2 (fresh)

1,600 IU vitamin D2 (sun-dried)

Egg yolk (1 unit) 20 IU vitamin D3 or D2

Food fortification is defined as the process of adding micronutrients, such as vitamins and

minerals, to food as permitted by the Food Standards Code.(15)

Regulations regarding the

fortification of foods with vitamin D vary between countries. In Australia, mandatory

fortification regulations require the addition of vitamin D to margarines and spreads.(15)

In

Canada, which has similar regulations to the United States, vitamin D fortification of milk

(including evaporated and powdered milk), soy milk and margarine is mandatory.(13)

One

serving (250 mL) of milk contains approximately 44% of the 200 IU adequate daily intake of

vitamin D.(13)

Vitamin D fortification is also permitted for orange juice, meal replacements,

nutritional supplements and formulated liquid diet.(13, 16)

However, a large proportion of the

American and Canadian populations are vitamin D deficient, indicating that limited

fortification has little impact at a population level.(13, 17)

It is acknowledged that the current (2006) guidelines for recommended dietary intakes (i.e.

adequate intakes) of vitamin D in Australia and New Zealand(18)

are out of date.(19)

The

recently revised recommended daily allowances (RDAs) for vitamin D in the US are 600 IU

(15 micrograms) for people aged 1–70 years and 800 IU (20 micrograms) for those aged ≥ 71

years, with an upper limit (that includes a generous safety factor) of 4000 IU (100

micrograms).(20)

Vitamin D synthesis through the skin can be influenced by several factors, such as number of

sunshine hours, time of day, season, latitude and skin colour (due to the amount of melanin in

skin). All these factors determine the amount of UBV that reaches the skin. The season is an

important predictor of serum 25-(OH)D levels.(21, 22)

In an Australian study that looked at

three populations of women in three locations across Australia and covering a broad

latitudinal range (Tasmania, Geelong and Queensland), vitamin D insufficiency was common

in winter and spring regardless of latitude.(22)

However, latitude plays a significant role in

serum 25-(OH)D levels, and higher prevalence of vitamin D deficiencies is reported in people

living at increasing distances from the equator.(23)

Vitamin D toxicity is a rare condition that can be caused by excess oral or intramuscular

administration of vitamin D. The current policy of the Institute of Medicine (IOM) has set the

tolerable upper intake level for vitamin D at 100 micrograms (4000 IU)/day, defining this as

“the highest level of daily nutrient intake that is likely to pose no risks of adverse health

effects to almost all individuals in the general population”.(20)

Vitamin D toxicity cannot be

caused by prolonged exposure of the skin to sunlight, which produces 25-(OH)D amounts

equivalent to daily oral consumption of 250 micrograms (10,000 IU)/day The main

symptoms with hypervitaminosis D are hypercalciuria (i.e. a condition of elevated calcium in

the urine), hypercalcaemia (i.e. a condition of elevated calcium in the blood), and calcification

February 2014


of soft tissues and kidney.(24)

Hypercalcaemia is not seen until serum 25-(OH)D

concentrations have consistently been above 375–500 nmol/L.(25, 26)

1.1.3 Rationale for testing, monitoring and screening

There are a number of clinical factors that suggest the potential for vitamin D insufficiency or

deficiency and thus may be indicators for vitamin D testing.(90(27) Relevant conditions include

poor nutrition, malabsorption due to gastrointestinal disease or malabsorptive bariatric

surgery, hepatic dysfunction, and renal dysfunction or age-related renal changes. Laboratory

findings may also indicate possible vitamin D deficiency, for example low urine calcium

excretion, low serum calcium, low serum phosphorous, elevated parathyroid hormone level,

and elevated alkaline phosphatase. Radiographic findings that might raise suspicion of

deficiency include osteopenia, osteoporosis, nontraumatic fracture and skeletal

pseudofracture.(27) Repeat testing (monitoring) may be undertaken in some patients with a

serious chronic condition, such as chronic renal disease, to assess the impact of replacement

therapy.

In the absence of clinical indicators, vitamin D testing is considered to be screening. The

purpose of screening for vitamin D status is to assess the need to improve the patient’s status

as a preventive measure against health problems.(90(27) When screening is undertaken in

populations defined by the presence of disease (e.g. cancer), the purpose is to assess the need

to improve vitamin D status as a means to improve disease-related outcomes. When

screening is undertaken in healthy populations, it could be universal (routine) or based on

demographic or lifestyle factors associated with low serum vitamin D (i.e. high risk

populations). This review seeks to assess evidence for the utility of vitamin D testing and

screening.

1.1.4 The vitamin D test

A vitamin D test measures 25-(OH)D, the major circulating metabolite to assess vitamin D

status. The 25-(OH)D metabolite has an estimated half-life of approximately two to three

weeks,(5, 28, 29)

and provides a measure of the vitamin D originating from both cutaneous

production and dietary/supplement sources.(5)

Vitamin D stored in other body tissues is,

however, not reflected in the serum 25-(OH)D levels.(5)

1,25-dihydroxyvitamin D has a half-

life of 15 hours and therefore serum levels of this metabolite do not accurately indicate an

individual’s vitamin D status. Since it is closely regulated by PTH and the intake of calcium

and phosphate, serum levels of 1,25-dihydroxyvitamin D(5, 13)

may be normal in individuals

with vitamin D deficiency(30)

and be elevated in vitamin D excess(31)

.

There are two different assays for measuring serum levels of 25-(OH)D(32-34)

:

Liquid chromatography-tandem mass spectrometry (LC-MS): this is a sensitive and

reasonably specific method (with some cross reactivity with the epimer 3-epi 25-

(OH)D3)(35)

for the detection of 25-(OH)D (in its two analyte forms D2 and D3) based on

their respective chemical properties. This method has been referred to as a ‘gold standard’

test, but it is slow and requires expensive equipment and skilled staff.

Commercial immunoassays either using radioactive markers or chemical markers: these are automated immunoassays (e.g. the Abbott Architect, Diasorin Liaison and the

Siemens Centaur) to measure total vitamin D levels. These assays may be cheaper and

quicker to conduct (about half the cost of liquid chromatography). Most are less sensitive

as they do not distinguish between the two metabolites of vitamin D.

February 2014


It is not clear from the literature if the detection of both D2 and D3 metabolites has any clinical

relevance. A systematic review and meta-analysis comparing vitamin D2 and D3

supplementation in raising serum 25-(OH)D status indicated that vitamin D3 is more

efficacious at raising serum 25-(OH)D concentrations than is vitamin D2.(36)

Moreover, some

current automated immunoassays have a limited capacity to detect 25-(OH)D2.(37)

It is

currently accepted in Australia that total 25-(OH)D measurement is appropriate to judge a

patient’s vitamin D status.(38)

1.1.5 Concerns about the accuracy and precision of vitamin D tests

Different immunoassays are readily available for measurement of 25-(OH)D3. Prior to the

recent introduction of the standard reference material for 25-(OH)D, called SRM 972,

introduced from the National Institute of Standards and Technology (NIST)(39)

, there were

numerous publications reporting that different immunoassays may be yielding different

results, with inter-assay variation reaching up to 25% at low serum 25-(OH)D levels (15

nmol/L).(28, 38)

However, the introduction of the reference standard helps to assess the

accuracy of the different immunoassays for the measurement of 25-(OH)D in serum and can

serve as an adjunct to quality assurance programs for vitamin D measurements.(40)

The performance of radioimmunoassay and enzyme-linked assays is acceptable; however, the


and analytically important range (< 50 nmol/L) of the assay.(19)

The new reference standard is

available at four different concentrations (called Level 1 – Level 4 by the manufacturer).(39)

The first SRM 972 concentration (Level 1) is prepared from “normal” human serum and is the

only standard that has not been altered through dilutions or enrichments (59.6 nmol/L). The

second concentration (called Level 2) was prepared by diluting Level 1 with horse serum to

achieve a lower 25-(OH)D concentration, whereas Level 3 and Level 4 had 25-(OH)D3 added

to them.(39)

The development of this reference standard for vitamin D in blood serum has

assisted laboratories to validate the accuracy of their test methods, as well as to validate new

analytical methods as they are developed.(40)

In addition, all Australian and New Zealand laboratories (including those offering 25-(OH)D

testing) are required to be enrolled in external proficiency programs (such as the Royal

College of Pathologists of Australasia Quality Assurance Program (RCPAQAP), which allow

each laboratory to monitor its performance compared with its peers.(19)

These standardisation

efforts are essential to the reliable diagnosis, evaluation and treatment of vitamin D deficiency

in a population and help clinicians to more accurately interpret the results from vitamin D

testing.(41)

1.1.6 Serum vitamin D target values

Some evidence suggests that optimal mineral metabolism, bone density and muscle function

is achieved at serum 25-(OH)D concentrations of greater than 50-60 nmol/L(42-45)

. However,

an optimal serum concentration of vitamin D has not been established and this value may vary

across different stages of life.(5)

Some authors believe that target serum levels should be

above 50 nmol/L(1, 3, 10, 28, 29)

, while others believe that it should be above 75 nmol/L.(2, 3, 5, 29,

46). One study indicated that 25-(OH)D concentrations <75 nmol/L showed increased

unmineralised bone matrix, making this value an appropriate cut-off for optimal bone

health.(47)

This, however, may require vitamin D supplementation.(10)

February 2014


Vitamin D deficiency is defined as serum 25-(OH)D levels below 25 nmol/L(3, 4, 28)

, based

primarily on the risk of rickets in infants and osteomalacia in adults.(48)

Mild vitamin D

deficiency is defined as a serum level below 50 nmol/L.(19)

Severe deficiency has been

defined as a serum level below 12.5 nmol/L.(1, 2, 10)

Table 1.2 summarises serum vitamin D

concentrations and health.

Table 1.2: Serum 25-(OH)D concentrations reflective of vitamin status

(19, 45)

Vitamin D status Serum vitamin D concentrations nmol/L*

Optimal >75

Sufficient 50 – 75

Mild deficiency (49)

25 – 49

Moderate deficiency (50)

12.5 – 24

Severe deficiency < 12.5 *1 nmol/L = 0.4 ng/mL

1.1.7 Prevalence of vitamin D deficiency in Australia

Two publications have attempted to measure the prevalence of vitamin D deficiency in the

Australian population. The first study was conducted by the Baker IDI Heart and Diabetes

Institute.(51)

The population included 11,218 adults aged 25-95 years. The study reported that

4% of the Australian population had severely deficient vitamin D levels (defined as serum 25-

(OH)D levels < 25 nmol/L) and an estimated 31% of adults in Australia have inadequate

vitamin D status (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to 50% in

women during winter-spring and in people residing in southern states. Individuals at greatest

risk for deficiency were identified to be women, the elderly, the obese, people doing less than

2.5 hours of physical activity a week, and people of non-European background.

The second study assessed 24,819 ambulant and inpatient samples taken from a large

reference laboratory in NSW between 1st July 2008 and 30

th July 2010.

(52) This cross-

sectional study reported that 36% of subjects overall were deficient in vitamin D (defined as

serum 25-(OH)D levels < 50 nmol/L), and this increased to 58% in spring. The highest

prevalence of deficiency occurred in female inpatients (42% in summer and 62% in spring).

Factors associated with lower 25-(OH)D included being tested in spring, an inpatient, female,

aged 20–39 years or over 79 years, socioeconomically disadvantaged, and from a major city.

1.1.8 Conditions that may cause vitamin D deficiency

There are several factors reported in the literature that can cause vitamin D deficiency in a

diverse group of individuals. Table 1.3 summarises the risk factors for vitamin D deficiency.

February 2014


Table 1.3: Risk factors for vitamin D deficiency

(5)

Reduced sun

exposure

Dietary intake Age and disease conditions

Elderly(53)

Darker skin

pigmentation(54)

Winter

season(55)

Indoor

workers(19)

People who

habitually wear

long sleeves,

protective

clothing, or

stay in the

shade(56)

Exclusive

breastfeeding

(risk for the

infant)(57)

Obesity(58)

Older age worsened by immobility and aging

kidneys(59)

Chronic kidney disease(60, 61)

Malabsorption syndromes/other conditions :

Crohn’s disease, cystic fibrosis, severe liver

disease(62)

Drug interactions: anticonvulsants, cimetidine,

thiazides, corticosteroids(63, 64)

Drugs that decrease absorption: mineral oil,

laxatives orlistat, cholestiramine, etc(65)

Genetics: Indo-Asians(66)

, individuals with generic

variants influencing vitamin D status (67)

1.1.9 Incidence and prevalence of diseases relevant to the vitamin D testing review

Table 1.4 presents the incidence and prevalence of clinical conditions relevant to vitamin D

testing.

Table 1.4: Incidence and prevalence of conditions relevant to vitamin D testing

Condition Description Prevalence/incidence

Osteoporosis The condition where bone is lost at a higher rate than its

replacement, causing loss of bone mineral density(68)

692,000 cases (3.4% of

the total population);

occurs mainly in people

aged 55 years and over

(84.0%), with women

accounting for the

majority of all cases

(81.9%)(69)

Osteomalacia Softening of bones, inadequate mineralisation of bone

matrix caused by vitamin D deficiency(5, 70)

Data on prevalence is

not available

Rickets Vitamin D deficiency in children resulting in

inadequate bone mineralisation and softening of the

growth plate, leading to soft bones, skeletal

deformities and growth retardation(71)

Australian

Paediatric

Surveillance Unit

(APSU) study

suggests that the

overall incidence in

children ≤ 15 years

of age in Australia

is 4.9/100

000/year(72)

Chronic

kidney

disease

Refers to all conditions of the kidney, lasting at least three

months, where a person has had evidence of kidney

damage and/or reduced kidney function, regardless of the

specific diagnosis of disease or condition causing the

disease. There are five stages depending on the level of

damage(73)

Stages 1-2: 5.6%(73)

Stages 3-5: 7.8%(73)

Crohn’s A form of inflammatory bowel disease, usually affecting 29.3/100,000 (incidence

February 2014


Condition Description Prevalence/incidence

disease the intestines, but may occur anywhere from the mouth to

the end of the rectum(74)

rate)(75)

Coeliac

disease

An autoimmune disease affecting the intestines and

resulting in chronic inflammation of the gastrointestinal

tract(74)

1% prevalence(76)

Cystic

fibrosis

A genetic disease affecting the secretory organs, causing

thick, sticky mucus to build up in the lungs, digestive

tract, and other areas of the body. It is one of the most

common chronic lung diseases in children and young

adults(77)

3,200 cases

(prevalence)(78)

There is an increasing number of medical conditions associated with low vitamin D status.

Prolonged vitamin D deficiency causes rickets in children(48)

and osteomalacia in adults.(5)

Other symptoms associated with vitamin D deficiency include bone pain and muscle

weakness, although the mechanisms are not clear.(79)

Vitamin D deficiency is classified as one of the risk factors for osteoporosis.(69)

Even though

osteoporosis does not cause death, osteoporotic fractures can, however, lead to premature

death among the elderly. In 2007, osteoporosis was listed as the underlying cause of 240

deaths in Australia. Fractures of hip and pelvis (40.5%) and wrist and forearm (17.1%) were

the most common sites of minimal trauma fractures in 2007–08. The total direct health

expenditure for osteoporosis in 2004-05 was $304 million (Table 2.5). Over 70% of this was

spent to cover the cost of pharmaceutical medicines ($215 million). Surgical and non-surgical

procedures to treat fractures in hospitals constitute another large component of this outlay

($35 million, 11.5%).

Table 1.5: Direct health expenditure for osteoporosis, 2000-01 and 2004-05

(69)

Health service area 2000-01 2004-05 Percent growth

Admitted patient services $31.8 m $35.0 m 10.1

Out-of-hospital medical services $29.4 m $47.3 m 60.8

Prescription pharmaceuticals $75.5 m $215.0 m 184.8

Research $2.6 m $7.0 m 169.2

Total $139.3 m $304.3 m 118.5 Source: AIHW 2009. AIHW Disease Expenditure Database

Data collected in the world’s longest running epidemiological study of osteoporotic fractures

in men and women, the Dubbo Osteoporosis Epidemiology Study (DOES), and which

included more than 2,500 men and women aged 60 years or more from the Australian

regional city of Dubbo, showed that osteoporotic fracture affects 44% of women and 25% of

men in Australia.(80)

In addition, re-fractures contributed substantially to overall mortality

associated with fracture. The majority of mortality and re-fractures occurred in the first five

years following the initial fracture. The study reported that 24% of women and 20% of men

with incident fracture had a re-fracture within five years. Of those who had an incident

fracture, 26% of women and 37% of men died without re-fracture. Of those who re-fractured,

a further 50% of women and 75% of men died. Therefore, the total five-year mortality was

39% in women and 51% in men.(80)

February 2014


1.1.10 Service providers claiming MBS benefits for vitamin D testing

Most pathology in Australia is provided in comprehensive laboratories that provide a wide

range of testing services at a single location. Only approved pathology practitioners are

eligible to claim MBS items for vitamin D testing.

1.2 The clinical flowcharts

The clinical decision pathway that determines whether vitamin D testing should be

undertaken is provided in Figure 1.1.

Figure 1.1: Clinical flow chart for vitamin D testing

Patient presents to General Practitioner

Does the patient have any of the following clinical symptoms of

vitamin D deficiency?

• Widespread bone pain or tenderness

• Nonspecific myalgia

• Myalgia on strain

• Proximal muscle weakness

• Non-stress fracture

• Stress fracture e.g. femoral neck, scapula, ribs or vertebrae

• Rickets

• Low serum calcium or high Alkaline Phosphatase

• Low serum phosphate

• Low bone density on DEXA or osteopenia on x ray

No

Does the patient have any of the following risk factors associated with

vitamin D deficiency?

• Housebound or in residential aged care facility

• Patients >65

• Indoor worker

• Long sleeve clothing, staying in the shade

• Dark skinned

• Vegetarians

• Diabetes

• Renal/liver disease

• Pregnancy or breast feeding

• Gastrointestinal disorders e.g. Crohn’s, Coeliac, gastrectomy

• Obesity

No YesYes

Is Vitamin D testing medically

necessary?


necessary?

No


necessary?

No MBS claim for vitamin

D testing

Measure serum Vitamin D

Claim MBS item numbers

66608 or 66609

YesNo


D testing

No


D testing

Measure serum Vitamin D

Claim MBS item numbers

66608 or 66609

Yes

February 2014


2 REVIEW METHODOLOGY

The review methodology comprises an analysis of secondary data (e.g. MBS claims), a

guideline concordance analysis, and a systematic literature review for clinical and economic

evidence. This Chapter presents clinical research questions and the methodology used for

each of these review components.

2.1 Secondary data analysis

Data from Medicare Australia were analysed to determine whether the existing MBS item

numbers for vitamin D testing (66608 and 66609) are appropriate.

2.1.1 The research questions for the MBS analysis

The MBS data were examined to determine:

(1) Whether the existing MBS items for service (66608 and 66609), including the associated

explanatory notes, are appropriate

a. How frequent are the MBS item number under review claimed?

b. Are there any age, sex, temporal or geographic trends associated with usage of these

item numbers?

c. What are the characteristics of patients undergoing vitamin D testing?

d. Are the Medicare claims data consistent with trends in the incidence/prevalence of the

conditions/diseases being addressed by the services?

e. What is the frequency of vitamin D testing by service provider?

2.1.2 Methods for analysis of MBS data

MBS data relates to private medical services (provided in- or out-of-hospital), where the

services are provided to patients regardless of whether or not they have private health cover.

MBS in-hospital services are mainly provided in private hospitals and day surgery clinics, but

patients can elect to be treated as a private patient in a public hospital.

MBS data were analysed by patient gender, age group, patterns of use and discipline of

provider claiming the benefit.

Results of the analysis of the MBS data is presented in Chapter 3.

2.2 Guideline concordance

2.2.1 The research questions for the guideline concordance analysis

The research question addressed as part of the Review using guideline concordance analysis

is:

(1) Is the existing MBS item for service (66608 and 66609) appropriate?

a. Is the descriptor for the MBS item number/service under review consistent with

evidence-based (or in the absence of evidence, consensus-based) recommendations

provided in relevant clinical practice guidelines?

(2) What are the appropriate clinical indications for vitamin D testing?

(3) How frequently should vitamin D levels be tested?

February 2014


2.2.2 Methods for guideline concordance analysis

Searches of guidelines databases1 and relevant discipline websites were undertaken to locate

any existing guidelines relevant to vitamin D testing. Analysis of MBS item numbers 66608

and 66609 was undertaken relative to ‘best practice’, as recommended in relevant Australian

clinical practice guidelines. Where Australian clinical practice guidelines do not exist, other

guidelines in operation in comparable health systems overseas were included. Where

guidelines existed, they were assessed for quality using the AGREE II instrument(81)

.

Differences in the purpose and intended audience of any such guidelines were considered,

documented and acknowledged.

See Chapter 4 for results of the concordance analysis for vitamin D testing.

2.3 Systematic literature review for clinical evidence

2.3.1 The clinical/research questions for the systematic literature review

The clinical/research questions that were the focus of the literature review are:

(1) What are the appropriate clinical indications for medically necessary vitamin D testing?

(2) What is the effectiveness of vitamin D testing in improving outcomes in each target

population?

(3) What are the safety and quality implications (including morbidity, mortality and patient

satisfaction) associated with vitamin D testing in each target population?

(4) How do safety and quality outcomes of vitamin D testing vary according to:

a. the difference in testing methodologies?

b. frequency of testing?

2.3.2 Search strategy

A comprehensive search of peer-reviewed scientific literature was conducted to identify

relevant studies addressing the key questions. Electronic databases were searched for original

research papers, including systematic reviews as shown in Table 2.1. Searches were restricted

to studies published in the English language between January 2002 and December 2012.

Databases maintained by Health Technology Assessment (HTA) agencies were searched to

identify existing assessments of vitamin D testing.

1 The search included: Guidelines International Network (G-I-N) at http://www.g-i-n.net/library/international-

guidelines-library/; National Guidelines Clearinghouse at www.guidelines.gov; National Health and Medical

Research Council (NHMRC) at http://www.nhmrc.gov.au/guidelines-publications

http://www.g-i-n.net/library/international-guidelines-library/

http://www.g-i-n.net/library/international-guidelines-library/

http://www.guidelines.gov/

February 2014


Table 2.1: Databases searched

Database Search period

MEDLINE Jan 2002 – Dec 2012

PubMed Jan 2002 – Dec 2012

The Cochrane Library (includes Cochrane Database of Systematic

Reviews, Database of Abstracts of Reviews of Effects, Cochrane

Central Register of Controlled Trials, NHS Economic Evaluation

Database, Health Technology Assessment, Cochrane Methodology

Register)

2002 – May 2013

Relevant HTA websites and databases2 Up to May 2013

Reference lists of systematic, semi-systematic and selected narrative reviews were also

reviewed. In addition, during the consultation process clinicians were asked if they were

aware of any relevant clinical guidelines, unpublished studies or reviews relevant to this

review of vitamin D testing.

2.3.3 Eligibility criteria for studies

The PICO (Population, Intervention, Comparator, Outcomes) criteria(82)

was used to develop

well-defined questions for the search of published literature. This involved focusing the

question on four elements:

the target population for the intervention;

the intervention being considered;

the comparator for the existing MBS service (where relevant); and

the clinical outcomes that are most relevant to assess safety and effectiveness.

The PICO criteria were determined on the basis of information provided in the literature, as

well as clinical advice. The PICO criteria for the review of vitamin D testing is shown in

Table 2.2.

2 The following HTA websites were searched: Agency for Healthcare Research and Quality (AHRQ) at

www.ahrq.gov; Canadian Agency for Drugs and Technologies in Health (CADTH) at http://www.cadth.ca/en;

National Institute for Health and Care Excellence (NICE) at www.nice.org.uk; Australasian College of Surgeons

(ASERNIP-S) at http://www.surgeons.org/for-health-professionals/audits-and-surgical-research/asernip-s/

http://www.surgeons.org/for-health-professionals/audits-and-surgical-research/asernip-s/

February 2014


Table 2.2: PICO criteria for the vitamin D testing items under review

Population Intervention Comparator Outcomes

Patients at risk of vitamin D

deficiency, including (but not

limited to):

(1) Postmenopausal women and

elderly men with bone

disease (e.g. osteoporosis,

osteomalacia)

(2) Patients with chronic

disease (cancer, CVD,

kidney disease, diabetes)

(3) Patients with multiple

sclerosis

(4) General population

(includes pregnant women,

overweight or obese

individuals, dark-skinned

people etc)

(5) Children with rickets

Serum

vitamin D

testing

No testing Effectiveness

Physical health outcomes (e.g.

improved physical

performance or bone health,

reduction in falls or fractures,

osteomalacia, reduction in all-

cause mortality, CVD,

diabetes, multiple sclerosis,

depression).

Safety

Complications associated with

vitamin D testing (e.g.

infection, needle injuries)

The detailed search strategy and terms used are presented in Appendix 4. Separate searches

were undertaken for each of the PICO populations. A search was also undertaken without the

population terms in the search string.

Studies were excluded on the basis of citation information and/or abstract, where it was

obvious that they did not meet the inclusion criteria. Where there was any doubt about any

reference based on the title and/or abstract, the full paper was retrieved and evaluated. Table

2.3 lists the pre-specified inclusion and exclusion criteria.

Table 2.3: Inclusion/exclusion criteria for identification of relevant studies

Characteristic Criteria

Search period 2000 – Dec 2012

Should there be limited data available during this period, the search will be extended

back in five year increments until sufficient data are sourced.

Publication

type

Clinical studies included. Non-systematic reviews, letters, editorials, animal, in

vitro and laboratory studies were excluded.

Systematic reviews

Systematic reviews that have been superseded were excluded

Primary studies

Primary studies published during the search period of included systematic reviews

were excluded

Effectiveness studies included if:

prospective, comparative trial

>20 patients

Safety studies included if:

>50 patients.

Intervention Vitamin D testing

Comparator No vitamin D testing

Outcome Studies must report on at least one of the following outcomes:

Change in patient management

February 2014


Characteristic Criteria

Patient outcomes: morbidity, mortality, quality of life

Safety: adverse physical health outcomes or complications associated with testing

or subsequent patient management

Language Non-English language articles excluded

2.3.4 Process for classifying the evidence

All eligible studies were assessed according to the National Health and Medical Research

Council (NHMRC) Dimensions of Evidence (refer to Appendix 5). There are three main

domains: strength of the evidence, size of the effect, and relevance of the evidence. One

aspect of the ‘strength of the evidence’ domain is the level of evidence, which is assigned

using the NHMRC Levels of Evidence (Appendix 5). For any eligible publications, study

quality was evaluated and reported using the NHMRC Quality Criteria (Appendix 5) for

randomised controlled trials (RCTs), cohort studies, case-control studies and systematic

reviews.

The results of the review of clinical evidence for vitamin D testing are presented in Chapter 5.

2.4 Systematic literature review for economic evidence

The research question for the review of economic literature is:

(1) What is the evidence regarding the cost implications associated with vitamin D testing

services in each target population

Consistent with the terms of reference, a formal modelled economic evaluation of vitamin D

testing was not in-scope. The review relied on published costing studies and economic

analyses identified through a systematic literature search of the databases shown in Table 2.1.

The detailed search strategy and terms used are presented in Appendix 4. Citations were

reviewed to identify acceptable evidence including: trial-based costing studies, cost analyses

and economic modelling studies. Acceptable outcomes were limited to: cost, incremental

cost-effectiveness ratio (e.g. cost per event avoided, cost per life year gained, cost per quality

adjusted life year or disability adjusted life year).

The results of the search for economic evaluations of vitamin D testing are presented in

Chapter 6.

February 2014


3 SECONDARY DATA ANALYSIS

This Chapter presents an analysis of the available secondary data (including MBS data) that

describes the use of vitamin D testing in Australia.

3.1 MBS item number usage and expenditure

Figure 3.1 shows that the number of MBS claims for vitamin D testing has increased each year

over the past ten years (2003/04 to 2012/13), from 117,474 claims in 2003/04 to 4,331,030

claims in 2012/13. Over 98% of vitamin D testing services are for MBS item 66608.

Figure 3.1: Claims for MBS items 66608 and 66609, 2003/04 to 2012/13

Source: Department of Human Services – Medicare Australia

As shown in Table 3.1, there has been a 3,587% increase in vitamin D testing services (item

66608 and 66609) from 2003/04 to 2012/13. Over the same time period, a similar increase

(3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04 to $151,129,505 in

2012/13.

Table 3.1: Claims and benefits paid for MBS items 66608 and 66609, 2003/04 to 2012/13


MBS item 66609 was listed on the MBS in May 2007. After a peak in services for item 66609

in 2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13)

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

4,000,000

4,500,000

5,000,000

2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013

Nu

mb

er o

f cl

aim

s

66608 66609

February 2014


(Table 3.1). Over the past five years (2008/09 to 2012/13), the number of claims for item

66609 decreased by 26%, while the number of claims for item 66608 increased by 190%.

Table 3.2 shows that the average fee per service for MBS item 66608 has decreased by 5%

from $37.16 in 2008/09 to $35.19 in 2012/13. There has also been a decrease of similar

magnitude in the average benefits paid per service. For item 66608, the proportion of services

bulk billed was high (more than 95% of services) from 2008/09 to 2012/13, which is consistent

with the high proportion of out-of-hospital services for item 66608 (over 98%). For item

66609, over 85% of services were bulk billed from 2008/09 to 2012/13.

Table 3.2: Fees charged and benefits paid for MBS items 66608 and 66609, 2008/09 to 2012/13

Source: Department of Human Services – Medicare Australia *Average out-of-pocket cost is equal to ‘fees charged for patient-billed out-of-hospital services’ minus ‘benefits paid for patient-billed out-of-

hospital services’ divided by ‘number of patient-billed out-of-hospital services’

The claiming pattern for vitamin D services over the past five years is further analysed by state

and territory (Figure 3.2). Between 2008/09 and 2012/13, 36%-38% of all claims for item

66608 were from New South Wales (NSW), while 34%-41% were from Victoria (VIC). The

other states and territories together accounted for less than 30% of total claims in each year.

Item 66609 showed much more variability over time, and relatively high usage in Queensland

(QLD) as a proportion of total claims.

February 2014


Figure 3.2: Relative proportion of total claims for MBS items 66608 and 66609 by state and

territory, 2008/09 to 2012/13


Table 3.3 shows vitamin D testing services per capita (i.e. per 100,000 population), according

to the address at the time of claiming by the patient to whom the service was rendered. In

2012/13, there were 18,629 claims for item 66608 per 100,000 people enrolled in Medicare

across Australia. VIC had the highest rate of claiming of item 66608 per capita (25,267 claims

per 100,000 population), followed by the Australian Capital Territory (ACT) and NSW. The

lowest per capita rates of vitamin D testing services were in the northernmost states and

territories (Northern Territory and QLD). For item 66609, the highest number of claims per

capita in 2012/13 was for Tasmania (TAS) and the ACT, while VIC had the lowest.

0%

20%

40%

60%

80%

100%

2008/2009 2009/2010 2010/2011 2011/2012 2012/2013

Pro

po

rtio

n o

f to

tal

clai

ms

Item 66608

NSW VIC QLD SA WA TAS ACT NT

0%

20%

40%

60%

80%

100%

2008/2009 2009/2010 2010/2011 2011/2012 2012/2013

Pro

po

rtio

n o

f to

tal

clai

ms

Item 66609

NSW VIC QLD SA WA TAS ACT NT

February 2014


Table 3.3: Claims for MBS items 66608 and 66609 per capita (100,000 population)*, 2008/09 to

2012/13

Source: Department of Human Services – Medicare Australia * Services per capita (i.e. per 100,000 population) is calculated by dividing the number of services processed in a month by the number of

people enrolled in Medicare at the end of that month.

An epidemiological study from Australia reported that the proportion of adults with vitamin D

deficiency (defined as serum 25-(OH)D levels < 25 nmol/L) was approximately 50% in women

during winter-spring and in people residing in southern states.(51)

An examination of total

services in 2012/13 for MBS item 66608 showed no difference in the proportion of tests

claimed in winter-spring compared with summer-autumn (48% versus 52%, respectively).

3.2 Age and gender profile of patients

The patterns of usage of items 66608 and 66609 were examined by age and gender for the five-

year time period from July 2008 to June 2013. There were no material changes in the age and

gender profile over time, except for a slight shift towards higher usage in the in female 25-34

year age category relative to the 35-44 year age category. As shown in Figure 3.3, vitamin D

testing claimed under MBS item numbers 66608 and 66609 is performed for both genders;

however, the number of claims is particularly significant for females aged between 24 and 84

years. Over the five-year period from 2008/09 to 2012/13, 70.2% of claims for MBS item

66608 were for females and 68.9% of claims for item 66609 were for females.

Australian guidelines for general practice recommend that targeted vitamin D testing should be

considered for people who are at risk of osteoporosis and who are at high risk of vitamin D

deficiency (see Chapter 4). As discussed in Chapter 1.1.7, an epidemiological study from

Australia has reported that vitamin D deficiency (defined as serum 25-(OH)D levels < 50

nmol/L) is more prevalent in females, particularly those aged 20–39 years or over 79 years.(52)

According to the AIHW, there were 692,000 reported cases of osteoporosis in 2007/08, with

84.0% of cases in people aged 55 years and over, and women accounting for 81.9% of all cases

(Chapter 1.1.9). The gender imbalance and peak in testing for vitamin D levels within the 55-

64 year age category is therefore consistent with epidemiological trends for vitamin D

deficiency and osteoporosis. However, the reason for the high rate of testing in the 45-54 year

age category is less clear.

February 2014


Figure 3.3: Usage of MBS items 66608 and 66609 by age category and gender, July 2008 to June

2013


3.3 Frequency of testing by patient

An analysis of vitamin D testing frequency per patient was conducted. For item 66608, there

was an increase over the period 2008/09 to 2012/133 in the overall number of patients tested for

vitamin D, from 1,248,566 in 2008/09 to 3,193,278 in 2012/13. As shown in Figure 3.4, the

proportion of patients who received only one test per year increased slightly over time (81.8%

in 2008/09 and 83.4% in 2012/13). The proportion of patients who received two tests per year

decreased from 14.8% in 2008/09 to 13.9% in 2012/13, while the proportion of patients who

received three or more tests per year decreased from 3.4% in 2008/09 to 2.8% in 2012/13. In

patients receiving three or more tests, the average number of services was 4.6 in 2008/09 and

3.7 in 2012/13.

For item 66609, there was a decrease over the period 2008/09 to 2012/13 in the overall number

of patients tested for vitamin D, from 7,413 in 2008/09 to 4,716 in 2012/13. The proportion of

patients who received only one test per year was relatively stable over time (89.7% in 2008/09

3 Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

2,000,000

0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

To

tal

nu

mb

er o

f M

BS

cla

ims

Item 66608

female male

0

1000

2000

3000

4000

5000

6000

7000

8000

0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

To

tal

nu

mb

er o

f M

BS

cla

ims

Item 66609

female male

February 2014


and 90.6% in 2012/13). Similarly, the proportion of patients who received two tests per year

did not change significantly over time (7.2% of patients received two vitamin D testing services

in 2008/09 and 2012/13). The proportion of patients who received three or more tests

decreased from 3.1% in 2008/09 to 2.1% in 2012/13.

Taken together with the age profile of patients being tested, these data suggest that the majority

of vitamin D testing services are being undertaken for the purposes of screening/testing rather

than monitoring.

Figure 3.4: Frequency of claiming MBS items 66608 and 66609 per year by patient, 2008/09 to

2012/13*


* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.

3.4 Profile of providers requesting vitamin D testing services

The profile of providers requesting vitamin D services was examined over time from 2008/09

to 2012/13 (Table 3.4). Over the five-year time period, there were no material changes in the

pattern of requesting providers. General practitioners (GPs) and other medical practitioners

(OMPs) accounted for nearly two-thirds of all providers requesting vitamin D testing services

for item 66608. Internal medicine consultant physicians accounted for nearly 15% of all

provider counts over the five-year time period, followed by general surgeons (specialist –

subspecialties) (3.5%), interns (3.3%), psychiatrists (2.6%), obstetricians/gynaecologists

(2.1%), general surgeons (specialist) (1.9%), other temporary resident doctors (1.4%), and non-

specialist surgeons (1.0%). There was a large variety of other providers requesting services,

but they each accounted for less than 1% of provider counts. For item 66609, GPs and OMPs

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

2008/09 2009/10 2010/11 2011/12 2012/13

Per

cen

tage

of

pat

ien

ts

Item 66608

1 test 2 tests 3+ tests

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

2008/09 2009/10 2010/11 2011/12 2012/13

Per

cen

tage

of

pat

ien

ts

Item 66609

1 test 2 tests 3+ tests

February 2014


accounted for over 60% of all providers requesting vitamin D testing services, followed by

internal medicine consultant physicians (approximately 28%).

Chapter 4 summarises recent clinical practice guidelines relating to vitamin D testing. None of

the guidelines recommend screening in low risk populations. However, as mentioned in

Section 3.2, Australian guidelines for general practice recommend that targeted vitamin D

testing should be considered in people who are at risk of osteoporosis and who are at high risk

of vitamin D deficiency.

Table 3.4: Number of providers requesting MBS items 66608 and 66609, 2008/09 to 2012/13

Source: Department of Human Services – Medicare Australia * Based on data processed to 31 May 2013; 2012/13 is therefore incomplete. # Other includes the following peer groups, which each accounted for <1% of the provider count: IVF, Anaesthetics (specialist and non-specialist), Diagnostic Imagist (specialist and non-specialist), Dermatologist, Therapeutic Radiologist/Therapeutic Nuclear Medicine-

Specialist, Pathologist, Specialist physician - internal medicine, Acupuncture, Dentist/Orthodontist, Unclassified miscellaneous (specialist and

non-specialist), Other Medical Specialist, Other Allied Health, Abortion/fertility control € List of other providers not available

3.5 Frequency of requests for testing by provider

An analysis of vitamin D test requests by frequency from any one provider was conducted. For

item 66608, there was an increase over the period 2008/09 to 2012/13 in the overall number of

providers requesting vitamin D testing. As shown in Figure 3.5, the proportion of providers

requesting ten or fewer tests per year decreased from 53.6% in 2008/09 to 38.7% in 2012/13,

whereas the proportion of providers requesting 11-50 tests per year remained relatively stable

(from 25.4% to 24.5% over the five-year period). In contrast, the proportion of providers

requesting more than 50 tests per year has increased from 21.0% in 2008/09 to 36.8% in

2012/13. Each year, there is a small number of providers who request over 400 vitamin D tests

per year. In 2008/09, there were 682 of these providers (representing 2.1% of providers); in

2012/13 there were 1,867 providers requesting more than 400 tests per year (4% of providers

for item 66608).

For item 66609, the proportion of providers requesting one test per year increased from 54.5%

in 2007/08 to 64.1% in 2012/13 (Figure 3.5). In contrast, the proportion of providers

requesting two or more tests decreased from 44.5% in 2008/09 to 35.9% in 2012/13.

February 2014





Figure 3.5: Frequency of MBS items 66608 and 66609 requested per year by any provider,

2008/09 to 2012/13*


* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

2008/09 2009/10 2010/11 2011/12 2012/13

Per

cen

tage

of

req

ues

ts

Item 66608

0-10 11-50 51-100 101-200 201-300 301-400 401 +

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

2008/09 2009/10 2010/11 2011/12 2012/13

Per

cen

tage

of

req

ues

ts

Item 66609

1 2 3 4 5 6 7 8 9 10 11 +

February 2014


4 REVIEW OF GUIDELINES RELEVANT TO VITAMIN D TESTING

This Chapter presents the results of the literature search for clinical practice guidelines

relating to vitamin D testing.

4.1 Australian guidelines

The literature search identified several recent Australian clinical practice guidelines and

position statements that provide guidance regarding vitamin D testing in general healthy

populations and specific clinical conditions (Table 4.1). Clinical practice guidelines that

recommend vitamin D supplementation, but do not mention vitamin D testing or screening,

have not been included.

Table 4.1: Australian clinical practice guidelines relevant to vitamin D testing

Publishing body Release

date

Title of

guideline

Guidance regarding vitamin D

testing

Frequency of

testing

Adults The Royal College of

Pathologists of

Australasia

(RCPA)(83)

May

2013

Use and

interpretation of

vitamin D

testing; a

Position

Statement

Routine screening for vitamin D

deficiency is not recommended

in adults

Retesting three

months after

commencement

of

supplementation

Royal Australian

College of General

Practitioners

(RACGP)(84)

2012 Guidelines for

preventative

activities in

general practice,

8th

edition.



in low-risk populations

Targeted testing of people who

are at risk of osteoporosis and

who are at high risk of vitamin

D deficiency should be

considered

High-risk groups for vitamin D

deficiency in pregnancy may

benefit from vitamin D

screening

Not reported

Working Group of the

Australian and New

Zealand Bone and

Mineral Society,

Endocrine Society of

Australia and

Osteoporosis

Australia(19)

June

2012

Vitamin D and

health in adults

in Australia and

New Zealand: a

Position

Statement

Screening for 25-(OH)D levels

is recommended in high-risk

groups#

Screening should be performed

by a reputable laboratory

participating in a the Vitamin D

External Quality Assessment

Scheme proficiency program

Retesting three

months after

commencement

of

supplementation

Disease- or risk-factor specific The Royal College of

Pathologists of

Australasia

(RCPA)(83)

May

2013

Use and

interpretation of

vitamin D

testing; a

Position

Statement

Measurement of 25(OH)-D in

individuals at risk of vitamin D

deficiency is an appropriate

case-finding strategy

Retesting three

months after

commencement

of

supplementation

February 2014


The Royal College of

Pathologists of

Australasia

(RCPA)(83)

May

2013

Use and

interpretation of

vitamin D

testing; a

Position

Statement

Measurement of 25(OH)-D in


deficiency is an appropriate

case-finding strategy

Retesting three

months after

commencement

of

supplementation

Royal Australian

College of General

Practitioners

(RACGP)(85)

Feb 2010 Clinical

guideline for the

prevention and

treatment of

osteoporosis in

postmenopausal

women and

older men.

Serum 25-(OH)D is one of the

recommended laboratory tests

used for the diagnostic

assessment for osteoporotic

fractures, but only under

particular conditions*

Not reported

Kidney Health

Australia CARI

guidelines (Caring for

Australasians with

Renal Impairment)(86)

July 2012 Vitamin D

therapy

(supplementatio

n) in early

kidney disease.

Early chronic kidney disease

patients on vitamin D therapy

have their 25-(OH)D levels

monitored regularly

“Regular”

monitoring not

defined

Pregnant women and children The Royal College of

Pathologists of

Australasia

(RCPA)(83)

May

2013

Use and

interpretation of

vitamin D

testing; a

Position

Statement



in pregnant women, healthy

infants and children

Retesting three

months after

commencement

of

supplementation

Working Group of the

Australian and New

Zealand Bone and

Mineral Society and

Osteoporosis

Australia(45)

Feb 2013 Vitamin D and

health in

pregnancy,

infants, children

and adolescents

in Australia and

New Zealand: a

Position

Statement

Population-wide screening for

vitamin D status in infants,

children and adolescents is not

supported by the evidence

25-(OH)D levels should be

tested in those with one or more

risk factors for low vitamin D€

Infants, children and adolescents

with ongoing risk factors require

ongoing monitoring of vitamin

D status with annual testing

Recently arrived migrant

children at risk of low vitamin D

should have testing repeated at

the end of their first winter in

Australia.

Vitamin D testing could be

considered in exclusively

breastfed infants or mixed fed

infants with at least one other

risk factor

Universal screening of pregnant

women is not supported by the

evidence

Pregnant women with one or

more risk factors should be

tested at their first antenatal visit

and again at 28 weeks’ gestation

Annual testing

of people with

risk factors for

low vitamin D.

Follow-up

testing should be

performed in

patients on

vitamin D

supplementation

For neonates

with moderate or

severe

deficiency,

follow-up at one

month is

recommended;

in other groups,

follow-up at

three months is

usually more

practical; and in

the long term,

annual testing is

recommended.

Very frequent

testing should be

avoided.

February 2014


The Royal College of

Pathologists of

Australasia

(RCPA)(83)

May

2013

Use and

interpretation of

vitamin D

testing; a

Position

Statement



in pregnant women, healthy

infants and children

Retesting three

months after

commencement

of

supplementation

Munns et al, Medical

Journal of Australia.

[Working group

included members of

the Australasian

Paediatric Endocrine

Group and Paediatric

Bone Australasia](87)

2006 Prevention and

treatment of

infant and

childhood

vitamin D

deficiency in

Australia and

New Zealand: a

consensus

statement

All pregnant women, especially

those who are veiled or dark-

skinned, should have their serum

25-(OH)D concentration

evaluated during the first

trimester of pregnancy

Not mentioned,

but implied that

testing should

continue until

supplements

have restored

vitamin D levels

to normal.

* if fractures after minimal trauma were the reason for the diagnostic assessment; the medical history and/or clinical examination reveals or is compatible with secondary osteoporosis; the Z-score is less than -2.0 measured by Dual-energy X-ray Absorptiometry. # defined as: older or disabled people in low-level and high-level residential care, particularly housebound community-dwelling geriatric

patients admitted to hospital; dark-skinned people of either sex, particularly migrants and/or if modest dress is worn; people with a disability of chronic disease (e.g. multiple sclerosis); fair-skinned people and those at risk of skin cancer who avoid sun exposure; obese people; and

people working in an enclosed environment, such as office workers, factory or warehouse workers, taxi drivers, night-shift workers. € defined as lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors, chronic illness or hospitalisation, complex

disability, covering clothing for religious or cultural reasons or southerly latitude); dark skin; medical conditions or medications affecting

vitamin D metabolism and storage (obesity, end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease and inflammatory bowel disease]); in infants,

maternal vitamin D deficiency and exclusive breastfeeding combined with at least one other risk factor.

In 2013 the Royal College of Pathologists of Australasia (RCPA) published a Position

Statement for the use and interpretation of vitamin D testing. The purpose of the Statement is

to clarify the role of vitamin D testing in the context of diagnosing and monitoring vitamin D

deficiency states and their treatment. The recommendations in the Position Statement are

consistent with recent guidelines on the diagnosis and management of vitamin D deficiency in

adults, pregnant women, infants, children and adolescents in Australia and New Zealand.(19, 45)

The Position Statement does not recommend routine screening for vitamin D deficiency in

adults, including pregnant women, healthy infants and children. Measurement of 25-(OH)D

is considered to be an appropriate, case-finding strategy in individuals at risk of vitamin D

deficiency.

Initial testing for vitamin D status is recommended for adult patients (as well as paediatric

patients when relevant) with the following indications:










The Position Statement does not explicitly recommend routine testing for vitamin D status in

the general population. However, it recommends that serum vitamin D levels should be

retested after three months following the commencement of vitamin D supplementation. No

further testing is required once desirable 25-(OH)D target levels are achieved. The position

Statement recommends against high dose annual replacement of cholecalciferol as this has

February 2014


been associated with increased falls and fractures in elderly men and women. The Statement

recommends that the target level of serum 25-(OH)D should be >50 nmol/L at the end of

winter.

The Position Statement also includes sections on measurement of vitamin D and interpretation

of results. Serum 25-(OH)D, reported in nmol/L units, is considered to be the best marker for

clinical assessment of an individual’s vitamin D status. The Statement acknowledges the

imprecision of the current immunoassay method used for 25-(OH)D testing, and warns

clinicians to be aware of the variation in the current vitamin D assay methods. The Statement

advises monitoring of serum 25-(OH)D levels following treatment in the same laboratory. The

Statement recommends that a vitamin D assay that measures only one of the two vitamin D

isoforms (the 25-(OH)-D3 isoform) is adequate for use in Australia.

In 2012 the Royal Australian College of General Practitioners (RACGP) published

guidelines for preventative activities in general practice. The ‘red book’ has been published

since 1989 and is accepted as the main guide to preventative care in Australian general

practice. The intention is to provide a comprehensive and concise set of recommendations for

patients in general practice. The recommendations in the guidelines are based on current,

evidence-based guidelines for preventative activities relevant to Australian general practice.

Where Australian guidelines are not available or recent, other sources have been used, such as

Canadian or United States preventative guidelines or the results of systematic reviews.

In the section on prevention of chronic disease, a sub-section on nutrition states that vitamin

supplementation is not of established value in asymptomatic individuals (with the exception

of folate and iodine in pregnancy). Routine screening for vitamin D deficiency is not

recommended in low-risk populations. Patients with vitamin D deficiency (defined as <60

nmol) are identified as having increased risk of osteoporosis. However, the guidelines state

that screening for vitamin D is not indicated just for risk assessment. In terms of preventative

actions for osteoporosis, the guidelines state that population screening for vitamin D

deficiency is not recommended, but targeted testing of people who are at risk of osteoporosis

and who are at high risk of vitamin D deficiency should be considered. Vitamin D

supplements could be considered in deficient individuals if increasing sun exposure is

contraindicated or not feasible, or if deficiency is more than mild (i.e. <25 nmol/L) and so is

less likely to be corrected by safe sun exposure (Practice Point).

In terms of preventative interventions for falls, the guidelines state to consider prescribing

vitamin D for people with vitamin D levels <50 nmol/L for older people living in the

community (III,C) and consider routinely prescribing vitamin D (unless contraindicated) for

all older people living in residential aged care (I,B), as routine sun exposure in residential

aged care may not be feasible. Testing for vitamin D levels in these populations is not

specifically mentioned.

The guidelines include a section on screening tests of unproven benefit in low-risk general

practice populations. Due to the high prevalence of vitamin D deficiency, variability in

assessment and lack of rigorous evidence of benefit of screening, screening for vitamin D

deficiency is not recommended for chronic disease prevention. Vitamin D screening is

considered to be of indeterminate value in pregnancy. The reason cited is the moderate

prevalence and associated morbidity, but no RCT evidence of benefit. However, the

guidelines state that high-risk groups for vitamin D deficiency in pregnancy may benefit from

vitamin D screening and supplementation.

February 2014


In 2010 the Royal Australian College of General Practitioners (RACGP) published a

clinical guideline for the prevention and treatment of osteoporosis in postmenopausal women

and older men, which presents a comprehensive review of pharmacological management of

osteoporosis within the Australian health care context, based on the best available evidence to

2009.(85)

The guideline contains the following recommendations of relevance to vitamin D:

Recommendation 7 – Lifestyle (Grade D consensus) General practitioners should recommend adequate but safe exposure to sunlight as a source of vitamin D for all postmenopausal women and older men.

Recommendation 11 – Calcium and vitamin D supplementation (Grade C)

There is mixed evidence on the effectiveness of calcium and vitamin D supplementation

for prevention of bone loss and osteoporotic fractures in postmenopausal women and

older men. There may be some benefit for those who have inadequate levels, particularly

institutionalised patients.

Recommendation 18 – Calcium and vitamin D supplementation (Grade C)

There is good evidence for high prevalence of vitamin D insufficiency in institutionalised

and home bound individuals and vitamin D supplementation is considered to be standard

care in these populations. There may be some benefit for dietary change or calcium

supplementation in postmenopausal women and older men with osteoporosis who have

low dietary calcium intake.

The 2010 RACGP guideline described three systematic reviews with a focus on vitamin D in

conjunction with calcium supplementation and their effectiveness in the reduction of fractures

and bone loss.(85)

A systematic review by Tang et al. (2007)(88)

found that calcium

supplementation alone was associated with a 13% reduction in risk of fractures, and with 10%

reduction in risk of fractures in trials using calcium supplements in combination with vitamin

D. The guideline also described the Cochrane review of 38 RCTs by Avenell et al. (2009)(89)

which showed a significant reduction in incidence of new hip fracture and non-vertebral

fractures for vitamin D combined with calcium. However, the guideline cautioned that the

results for institutionalised older adults included in the systematic review may have

influenced the overall analysis as no significant effect was found for community dwelling

individuals. There was also no evidence for effectiveness of vitamin D alone for prevention

of fractures. The guideline also describes the systematic review by Boonen et al. (2007)(90)

which showed that vitamin D alone was not associated with a reduction in risk of hip fracture

or a reduction in risk of non-vertebral fractures when compared to placebo. Similar to the

Avenell review, significant reduction in the risk of hip fracture and non-vertebral fracture was

observed in patients receiving vitamin D in conjunction with calcium supplements when

compared to placebo or no treatment.(85)

Furthermore, the guideline listed serum 25-(OH)D as one of the recommended laboratory

tests used for the diagnostic assessment for osteoporotic fractures, with cut-off value less than

50 nmol/L defined as “vitamin D deficiency or insufficiency”. According to the evidence

statement, for some patients at risk, laboratory findings can reveal unsuspected secondary

osteoporosis or may influence some aspects of diagnostics and therapy. Laboratory tests are

used to exclude the most important forms of secondary osteoporosis and other potential bone

diseases. The evidence statement directs that laboratory tests (including serum 25-(OH)D)

should follow medical history, clinical examination and bone densitometry if(85)

:

fractures after minimal trauma were the reason for the diagnostic assessment;

the medical history and/or clinical examination reveals or is compatible with secondary

osteoporosis;

February 2014


the Z-score is less than -2.0 measured by Dual-energy X-ray Absorptiometry (DXA).

The guideline does not explicitly recommend routine screening for vitamin D status in the

elderly population or in individuals who are at general high risk of bone disease.(85)

The

guideline recommends the intake of vitamin D (and calcium) supplementation and

maintaining “high vitamin D status” as a preventive therapy against osteoporosis, but it is not

clearly stated whether serum vitamin D levels should be monitored via testing in this

population group.

The 2010 guideline identifies Asians, people with darker skin and veiled women to be at

greater risk of vitamin D insufficiency and relatively low calcium intakes, and both should be

corrected before initiating anti-osteoporotic therapy (vitamin D and calcium

supplementation). Correction of vitamin D insufficiency can be achieved by greater daily

sunlight exposure. The guideline refers to the current recommended amount of sunlight

required to produce optimum levels of vitamin D, defined as exposure of approximately 15%

of the body (i.e. hands, face and arms) for 6–8 minutes, 4–6 times per week, and before 10

am or after 2 pm (standard time) for moderately fair skinned people.(85)

In June 2012 the Working Group of the Australian and New Zealand Bone and Mineral

Society (ANZBMS), Endocrine Society of Australia, and Osteoporosis Australia published a Position Statement on vitamin D and health in adults in Australia and New

Zealand. The authors claim that the statement is evidence-based, but it is not clear whether it

was underpinned by a systematic literature review. On the basis of the evidence, the position

statement recommends that a serum 25-(OH)D level of ≥50 nmol/L at the end of winter (10-

20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal

musculoskeletal health. Vitamin D deficiency is defined as: mild 30-49 nmol./L, moderate

12.5-29 nmol/L, severe <12.5 nmol/L.

The statement acknowledges that higher serum 25-(OH)D levels are likely to play a role in the

prevention of some disease states, but there is insufficient evidence from RCTs to recommend

higher targets. It identifies the groups at greatest risk of vitamin D deficiency as:

older or disabled people in low-level and high-level residential care, particularly

housebound community-dwelling geriatric patients admitted to hospital;




obese people; and

people working in an enclosed environment, such as office workers, factory or warehouse

workers, taxi drivers, night-shift workers.

The statement notes the imprecision of current 25-(OH)D testing, and warns to exercise

caution when interpreting results in clinical practice. Although the performance of

radioimmunoassay and enzyme-linked assays is acceptable, the bias and imprecision of many

automated methods may be problematic at the lower, clinically and analytically important

range (< 50 nmol/L) of the assay. Adoption and alignment of assays to the National Institute

of Standards and Technology reference material should reduce bias (see Section 1.1.5);

however, imprecision will remain problematic. Consequently, some laboratories are using

more exacting methods of analysis, such as liquid chromatography–tandem mass

spectrometry. All Australian laboratories offering 25-(OH)D testing are required to be

February 2014


enrolled in external proficiency programs (see Section 1.1.4), which allow each laboratory to

monitor its performance compared with its peers.

The position statement includes recommendations for assessment and management of vitamin

D deficiency states. In high-risk groups, screening blood test for 25-(OH)D level is

recommended, followed by appropriate vitamin supplementation. The statement advises that

25-(OH)D levels should be checked after three months, as there is such an individual variation

of response to vitamin D supplementation. Retesting should not take place before three

months, as it may take up to 2-5 months for serum levels of 25-(OH)D to plateau. The

position statement recommends that supplementation without initial screening may be

appropriate for adults in disadvantaged communities at high risk of vitamin D deficiency (e.g.

dark-skinned migrants from low socioeconomic backgrounds, people in residential care

establishments).

In February 2013 the Working Group of the Australian and New Zealand Bone and

Mineral Society (ANZBMS) and Osteoporosis Australia published a position statement on

vitamin D and health in pregnancy, infants, children and adolescents in Australia and New

Zealand. The position statement is based on articles on vitamin D dosing in paediatric age

groups and during pregnancy and lactation, which were identified by a systematic search of

the Medline database (1946 to July 2011). According to the statement, there is inadequate

evidence to recommend population-wide screening for vitamin D status in infants, children

and adolescents in Australia. Those with one or more risk factors for low vitamin D should

have their serum 25-(OH)D, calcium, phosphate and alkaline phosphatase levels measured;

parathyroid hormone levels should also be measured in those with symptoms or signs of

deficiency, multiple risk factors or inadequate calcium intake. Infants, children or adolescents

with low serum calcium or phosphate and those who have clinical signs of rickets require

urgent specialist assessment and further investigations.

The position statement identified the following risk factors for low vitamin D:

lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors,

chronic illness or hospitalisation, complex disability, covering clothing for religious or

cultural reasons or southerly latitude);

dark skin;

medical conditions or medications affecting vitamin D metabolism and storage (obesity,

end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as

rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease

and inflammatory bowel disease]);



The position statement advises that infants, children and adolescents with low 25-(OH)D

levels should be treated to restore their 25-(OH)D levels to the normal range. Infants,

children and adolescents with ongoing risk factors for low vitamin D require ongoing

monitoring of vitamin D status with annual testing, as well as a long-term plan to maintain

normal 25-(OH)D levels and calcium status through behavioural change, where possible,

and/or supplementation if behavioural change is inadequate. It is acknowledged that it may

not be possible for people with risk factors (especially multiple risk factors) to maintain their

25-(OH)D levels during winter in the southern parts of Australia. Recently arrived migrant

children at risk of low vitamin D may have normal 25-(OH)D levels on initial health

screening, so testing should be repeated at the end of their first winter in Australia. Some

children with significant ongoing risk factors (e.g. dark skin and covering clothing) may

February 2014


require high-dose vitamin D supplementation more than once a year. The position statement

suggests that levels at the start and end of winter can be useful to guide dosing frequency.

The position statement advises that exclusively breastfed infants with at least one other risk

factor for low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the

first year of life and adherence should be monitored, particularly after the first months of

supplementation. Checking 25-(OH)D levels or adding daily vitamin D supplements should

be considered in infants with other risk factors for low vitamin D who are fed a mixture of

breast milk and formula, or who have appropriately reduced their formula intake after the

introduction of solids.

For pregnant women with one or more risk factors for low vitamin D, the position statement

advises that serum 25-(OH)D levels should be measured at their first antenatal visit. The

position statement acknowledges that a recommendation for universal screening of pregnant

women is not supported, due to the geographic variation in the prevalence of vitamin D

deficiency and insufficient evidence on the impact on maternal and child health of vitamin D

supplementation during pregnancy. The authors argue that while the cost of measuring 25-

(OH)D levels is significant, pregnant women undergo screening for conditions of much lower

prevalence, and there are no data or cost-effectiveness studies on alternative management

strategies (such as supplementation without testing during winter).

Pregnant women with 25-(OH)D levels < 50 nmol/L should be started on daily vitamin D3

supplementation. The position statement advises that testing should be repeated at 28 weeks’

gestation. In women whose 25-(OH)D levels have corrected to > 50 nmol/L, supplementation

(at a lower dose) should be given throughout the remainder of pregnancy.

Based on a review of 98 clinical trials of vitamin D supplementation, the position statement

provides recommended oral doses of vitamin D3 for the management of mild and moderate or

severe vitamin D deficiency in infants, children and adolescents. In terms of monitoring, the

position statement advises that adherence with daily dosing should be monitored and follow-

up blood tests should be performed. For neonates with moderate or severe deficiency, follow-

up at one month is recommended; in other groups, follow-up at three months is usually more

practical; and in the long term, annual testing is recommended. Very frequent testing should

be avoided. Follow-up blood tests should include tests for serum 25-(OH)D, calcium,

phosphate and alkaline phosphatase. Repeat high-dose therapy may be required if 25-(OH)D

levels are low at follow-up.

A 2006 consensus statement on the prevention and treatment of infant and childhood vitamin

D deficiency in Australia and New Zealand was also identified. The consensus statement was

developed by a working group which included members of the Australasian Paediatric

Endocrine Group, Paediatric Bone Australasia, migrant health paediatricians,

obstetricians, public health specialists and a member of the working group responsible for the

adult guidelines on vitamin D and bone health. Treatment guidelines were arrived at through

a combination of published best practice and local experience. The statement advises that

serum 25-(OH)D concentration provides the best indicator of vitamin D status, and should be

used when testing for deficiency states (normal concentration is defined as > 50 nmol/L). The

concentration of 1,25-(OH)2D must not be used, as it may be elevated even in severe vitamin

D deficiency. Different 25-(OH)D assays give different results, with some not determining

D2 as well as they do D3. The statement warns that this may result in spuriously reduced 25-

OHD results in children supplemented with ergocalciferol. The position statement advises

that routine vitamin D supplementation of all pregnant women cannot be recommended.

February 2014


However, all pregnant women, especially those who are veiled or dark-skinned, should have

their serum 25-(OH)D concentration evaluated during the first trimester of pregnancy. If they

are moderately to severely vitamin D deficient, pregnant women should receive vitamin D

supplementation until the serum 25-(OH)D concentration is over 50 nmol/L.

The Caring for Australasians with Renal Impairment (CARI) guidelines are published by

Kidney Health Australia (KHA) in association with the Council of the Australian and New

Zealand Society of Nephrology (ANZSN). These guidelines include a section on vitamin D

therapy in early chronic kidney disease (CKD). The aim of the CARI guidelines is to improve

the health care and outcomes of paediatric and adult patients with kidney disease, by helping

clinicians and health care workers to adhere to evidence-based medical practice as often as

possible.

The CARI guidelines on vitamin D supplementation in early CKD indicate that there is

insufficient evidence to determine the effect of vitamin D compounds on mortality and

cardiovascular outcomes in the CKD stages 1-3 population.(86)

The guidelines described one

RCT with CKD stages 1-3 patients which indicated that supplementation of calcium (1200

mg) and vitamin D3 (800 IU (20 μg)) to suboptimal diets significantly increased 25-(OH)D

and decreased Intact Parathyroid Hormone (iPTH) levels in patients (level I evidence).(91)

The guidelines noted that, currently, the optimal levels of serum vitamin D and dosage of

supplementation required are not clearly defined. There is also evidence that vitamin D

therapy in early CKD may be associated with potential harm, including hypercalcaemia,

elevated troponin T levels and accelerated progression of CKD.(92)

. In addition, the

guidelines indicate that currently there are no studies evaluating the cost-effectiveness of

prophylactic therapy in patients with CKD and its effects on patient-level outcomes.(86)

The CARI guidelines define vitamin D insufficiency and deficiency as serum 25-(OH)D

levels of 37.5-75 nmol/L and <37.5 nmol/L, respectively. The guidelines recommend that

early chronic kidney disease patients on vitamin D therapy have their calcium, phosphate,

PTH, alkaline phosphatase and 25-(OH)D levels monitored regularly (grade 1C

recommendation, according to GRADE approach). No further details are provided regarding

the frequency of regular monitoring.

4.2 International guidelines

Eleven guidelines related to vitamin D testing were identified and are summarised in Table

4.2. The summary does not include guidelines that referred to supplementation without

mentioning testing for vitamin D status.

Table 4.2: International clinical practice guidelines relevant to vitamin D testing


date Title of guideline Guidance regarding vitamin D testing Quality*

Adults American Medical

Directors

Association

(AMDA)(93)

2009

Osteoporosis and

fracture

prevention in the

long-term care

setting.

Routine administration of vitamin D3 in

long-term care residents

May be advisable to measure 25-(OH)D

levels in patients who are at risk of

osteoporosis and for those with a

diagnosis of osteoporosis to help

determine aetiology

Fair

quality

The Endocrine

Society(94)

2011 Clinical practice

guideline for

evaluation,

Screening only in individuals who are at

risk of vitamin D deficiency; population

screening of individuals not at risk is not

Good

quality

February 2014



date Title of guideline Guidance regarding vitamin D testing Quality*

treatment, and

prevention of

vitamin deficiency

recommended

Measurement of serum circulating 25-

(OH)D by a reliable assay is the

recommended method to screen


deficiency

Osteoporosis

Canada(95)

2010 Vitamin D in adult

health and disease In healthy adults at low risk for vitamin D

deficiency, serum 25-(OH)D should not

be measured

For individuals receiving pharmacologic

therapy for osteoporosis, measurement of

serum 25-(OH)D should follow 3-4

months of adequate supplementation and

should not be repeated if the optimal level

is achieved

Measurement of serum 25-(OH)D is

recommended for individuals with

recurrent fractures, bone loss despite

osteoporosis treatment or comorbid

conditions that affect vitamin D

absorption or action

Doses ≤ 50 µg (2000 IU) are safe and do

not require monitoring. Patients taking

daily doses above Health Canada’s

‘tolerable upper intake level’ should

undergo monitoring of serum 25-(OH)D

Good

quality

Pregnant and lactating women American Congress

of Obstetricians and

Gynecologists

(ACOG)(96)

2011 Vitamin D –

screening and

supplementation

during pregnancy

Routine screening of pregnant women is

not recommended.

Screening may be considered in pregnant

women considered to be at an increased

risk of deficiency.

Very

poor

quality

Children American Academy

of Paediatrics

(AAP)(97)

2008 Prevention of

rickets and

vitamin D

deficiency in

infants, children

and adolescents

In children who receive supplementation

due to increased risk of vitamin D

deficiency, such as those with

malabsorption disorders or use of certain

medications, serum 25-(OH)D levels

should be checked at 3 month intervals

until normal levels (defined as ≥50

nmol/L) have been achieved.

Good

quality

American Academy

of Paediatrics

(AAP)(98)

2011 Bone

densitometry in

children and

adolescents

Serum 25-(OH)D concentrations should

be measured in children with skeletal

fragility to ensure that adequate stores are

present

Good

quality

February 2014


Disease- and risk-factor specific National

Osteoporosis

Society(99)

April

2013

Vitamin D and

bone health: A

practical clinical

guideline for

patient

management

Measurement of serum 25-(OH)D is

the best way of estimating vitamin D

status

Universal screening of asymptomatic

healthy populations, including those

with risk factors for low vitamin D, is

not recommended

Serum 25-(OH)D measurement is

recommended for patients with: bone

diseases that may be improved with

vitamin D treatment; bone diseases,

prior to specific treatment where

correcting vitamin D deficiency is

appropriate; musculoskeletal

symptoms that could be attributed to

vitamin D deficiency

Routine vitamin D testing may be

unnecessary in patients with

osteoporosis or fragility fracture, who

may be co-prescribed vitamin D

supplementation with an oral

antiresorptive treatment

Routine monitoring of serum 25-

(OH)D is generally unnecessary but

may be appropriate in patients with

symptomatic vitamin D deficiency or

malabsorption and where poor

compliance with medication is

suspected

Assessment of 25-(OH)D status on

replacement therapy should be

undertaken after 3 or 6 months

Fair

quality

National Institute for

Health and Care

Excellence

(NICE)(100)

2012 The diagnosis and

management of

the epilepsies in

adults and

children in

primary and

secondary care

Monitoring vitamin D levels is

recommended every 2 to 5 years for

individuals who are receiving enzyme-

inducing drugs as part of their epilepsy

treatment regimen

Good

quality

Institute for Clinical

Systems

Improvement

(ICSI)(101)

2011 Diagnosis and

treatment of

osteoporosis

Serum 25-(OH)D testing in all patients

with osteoporosis (optimum level 75

nmol/L)

Good

quality

Kidney Disease:

Improving Global

Outcomes

(KDIGO)(102)

2009 Clinical practice

guideline for the

diagnosis,

evaluation,

prevention, and

treatment of

chronic kidney

disease–mineral

and bone disorder

In patients with chronic kidney disease

Stages 3-5D, 25-(OH)D levels might be

measured, and repeated testing

determined by baseline values and

therapeutic intervention

Good

quality

National Institute for

Health and Care

Excellence

(NICE)(103)

2008 Early

identification and

management of

chronic kidney

disease in adults

in primary and

secondary care

Routine measurement of vitamin D levels

in individuals with Stage 1, 2, 3A or 3B

chronic kidney disease is not

recommended

Good

quality

February 2014


* Assessed according to the Appraisal of Guidelines Research and Evaluation (AGREE) Instrument.

International guidelines are consistent with Australian guidance in terms of recommending

against routine screening for vitamin D status in adults, pregnant women and children.

However, there are several guidelines that support screening in high-risk individuals

(although definitions of at-risk were lacking in these guidelines), and testing vitamin D status

in populations with known poor bone health (such as children with skeletal fragility and

adults with osteoporosis). Follow-up testing is also recommended in people being treated

pharmaceutically for osteoporosis (at 3-4 months after commencement of therapy).

Guidelines relating to adults

The American Medical Directors Association (AMDA) released guidelines in 2009 on

osteoporosis and fracture prevention in the long-term care setting. The AMDA is a national

organisation in the United States comprised of medical directors, attending physicians, and

other practitioners who care for patients in the long-term care setting. Its clinical practice

guidelines are produced by interdisciplinary workgroups using both medical evidence and

medical consensus. In terms of vitamin D testing, AMDA considers serum 25-(OH)D testing

to be an appropriate companion test with serum calcium, creatinine, and alkaline phosphatase

testing in patients who have a history of fracture. AMDA stated that it may be advisable to

measure 25-(OH)D levels in patients who are at risk for osteoporosis and for those with a

diagnosis of osteoporosis to help to determine the etiology of the condition.

In 2011, The Endocrine Society in the United States released a clinical practice guideline on

the evaluation, treatment and prevention of vitamin D deficiency. The guideline was created

via a consensus process involving a Task Force, which commissioned two systematic reviews

of the literature to obtain information regarding vitamin D deficiency, as well as committees,

sponsors, and members of The Endocrine Society. On the basis of high quality evidence, the

guideline recommends that individuals who are at risk of vitamin D deficiency should be

screened, but population screening of individuals who are not at risk of deficiency is not

recommended. Risk is not defined in the recommendation; however, inadequate sun

exposure, skin pigmentation, high body mass index, renal disease, and vitamin D-depleting

medication are discussed in the background section. The guideline also recommends that

measurement of serum circulating 25-(OH)D by a reliable assay is the recommended method

to screen individuals at risk of vitamin D deficiency. The serum 1,24-dihydroxyvitamin D

assay is not recommended for this purpose. Both of these recommendations were based on

high-quality evidence and were designated as strong recommendations.

Osteoporosis Canada released a review and guideline statement on vitamin D in adult health

and disease in 2010. The guidelines were underpinned by a systematic review of the literature

(through June 2008) and a consensus process. Recommendations are graded according to the

type of supporting evidence that is available (Grade A=highest, D=lowest). The guidelines

recommend that laboratories performing 25-(OH)D testing should take part in external

proficiency surveys and should demonstrate that values reported for shared samples

approximate the consensus of values reported by others (level 4 evidence, grade D

recommendation). In healthy adults at low risk for vitamin D deficiency (defined as below

age 50 years, without osteoporosis or conditions affecting vitamin D absorption or action),

routine vitamin D supplementation is recommended. However, serum 25-(OH)D should not

be measured (grade D recommendation). The guideline advises that serum 25-(OH)D should

be measured only if deficiency is suspected or would affect the person’s response to therapy

(e.g. in cases of impaired intestinal absorption, such as celiac disease, or osteoporosis

requiring pharmacologic therapy. For individuals receiving pharmacologic therapy for

February 2014


osteoporosis, measurement of serum 25-(OH)D should follow 3 to 4 months of adequate

supplementation and should not be repeated if the optimal level is achieved (grade D

recommendation). Measurement of serum 25-(OH)D is recommended for individuals with

recurrent fractures, bone loss despite osteoporosis treatment, or comorbid conditions that

affect vitamin D absorption or action (grade D recommendation). In these cases, serum 25-

(OH)D should be measured as part of the initial assessment, and supplementation with

vitamin D should be based on the measured value. Dose requirements above Health Canada’s

current tolerable upper intake level (50 μg [2000 IU]) may be needed, in which case

monitoring of serum 25-(OH)D levels is required (grade D recommendation).

Guidelines relating to pregnant and lactating women

The American Congress of Obstetricians and Gynecologists (ACOG) released an opinion

statement by the Committee on Obstetric Practice regarding vitamin D screening and

supplementation during pregnancy. There is no indication that the statement is evidence-

based or was underpinned by a systematic review. The opinion statement advises that current

evidence is insufficient to support a recommendation to screen all pregnant women for

vitamin D deficiency. However, the statement advises that serum 25-(OH)D levels might be

tested in pregnant women considered to be at an increased risk of deficiency. Increased risk is

undefined in the recommendation statement, but vegetarian diet, inadequate sun exposure, and

dark skin are listed as risk factors in the background section.

Guidelines relating to children

The American Academy of Pediatrics (AAP) released a policy in 2008 on the prevention of

rickets and vitamin D deficiency in infants, children, and adolescents. The AAP recommends

that healthy infants, children, and adolescents receive vitamin D at 400 international units per

day (IU/day). No recommendations regarding screening were made. Specific

recommendations regarding supplementation were made for breastfed and partially breastfed

infants, non-breastfed infants, children and adolescents. The policy advised that children who

are at an increased risk of vitamin D deficiency, such as those with malabsorption disorders or

use of certain medications, may need higher doses of vitamin D supplementation. It was

recommended that serum 25-(OH)D levels should be checked at 3-month intervals until

normal levels (defined as ≥ 50 nmol/L in infants and children)have been achieved.

The American Academy of Pediatrics (AAP) also published a clinical report in 2011 on

bone densitometry in children and adolescents, which was derived from consensus statements

generated at a Paediatric Position Development Conference of the International Society of

Clinical Densitometry in 2007. The AAP recommends that serum 25-(OH)D concentrations

be measured in children with skeletal fragility to ensure that adequate stores are present.

Disease- or risk-factor specific guidelines

In 2013, the National Osteoporosis Society in the United Kingdom released a practical

clinical guideline for patient management relating to vitamin D and bone health. The

guideline focuses on the management of vitamin D deficiency in adults with, or at risk of

developing, bone disease. The developers used evidence from the Institute of Medicine

(IOM) report in 2010(20)

, supplemented by literature reviews, to identify subsequent published

papers. Where clear-cut evidence was unavailable to inform the guideline, the authoring

group offered pragmatic advice based on a consensus of their own views and experience. The

guideline recommends that measurement of serum 25-(OH)D is the best way of estimating

vitamin D status. The commentary around this recommendation states that the assay should

have the ability to recognise all forms of 25-(OH)D (D2 or D3) equally. In practice, this

February 2014


means that it should use either high performance liquid chromatography or, more likely,

tandem mass spectrometry. None of the immunoassays offer the ability to recognise all forms

of 25-(OH)D. The guideline recommends 25-(OH)D measurement for patients with bone

diseases that may be improved with vitamin D treatment, patients with bone diseases prior to

specific treatment where correcting vitamin D deficiency is appropriate, and patients with

musculoskeletal symptoms that could be attributed to vitamin D deficiency. Routine vitamin

D testing may be unnecessary in patients with osteoporosis or fragility fracture, who may be

co-prescribed vitamin D supplementation with an oral antiresorptive treatment. The guideline

states that routine monitoring of serum 25-(OH)D is generally unnecessary but may be

appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where

poor compliance with medication is suspected. The limited evidence for when to monitor

response to therapy is acknowledged. The guideline states that it is a waste of resources to

measure vitamin D levels too soon after therapy has started. A minimum of three months’

treatment must be given and it may be more prudent to wait until six months have passed.

The Institute for Clinical Systems Improvement (ICSI) released a guideline in 2011 on the

diagnosis and treatment of osteoporosis. The ICSI recommends that serum 25-(OH)D levels

be determined for all patients with osteoporosis, with the optimum defined as ≥ 75 nmol/L to

maximally suppress parathyroid hormone secretion.

The Australian CARI guidelines refer to 2009 clinical practice guidelines from the Chronic

Kidney Disease – Mineral and Bone Disorder (CKD–MDB) Work Group of Kidney Disease:

Improving Global Outcomes (KDIGO). These guidelines for the diagnosis, evaluation,

prevention and treatment of CKD–MDB4, suggest that in patients with CKD Stages 3-5D, 25-

(OH)D levels might be measured, and repeated testing determined by baseline values and

therapeutic intervention [grade 2C recommendation]. The guidelines suggest that vitamin D

deficiency and insufficiency is corrected using treatment strategies recommended for the

general population [grade 2C recommendation].

The National Institute for Health and Care Excellence (NICE) and the National

Collaborating Centre for Chronic Diseases developed guidance in 2008 on the early

identification and management of chronic kidney disease in adults in primary and secondary

care. NICE developed evidence-based guidance using its public health program process.

Although individuals with chronic kidney disease may develop osteoporosis and bone

metabolism complications, NICE does not recommend routine measurement of vitamin D

levels in individuals with stage I, 2, 3A, or 3B chronic kidney disease.

In 2012, NICE also prepared guidelines for the diagnosis and management of the epilepsies in

adults and children in primary and secondary care. NICE recommends monitoring vitamin D

levels, among other tests of bone metabolism, every 2 to 5 years for individuals who are

receiving enzyme-inducing drugs as part of their epilepsy treatment regimen.

4 Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice

guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone

disorder (CKD–MBD). Kidney International. 2009; 76 (Suppl 113): S1-S130.

February 2014


5 REVIEW OF THE CLINICAL EVIDENCE FOR VITAMIN D TESTING

This Chapter presents the results of the systematic literature review on vitamin D testing in

relation to the clinical research questions.

5.1 Evidence base

5.1.1 Search results

The search strategy retrieved a total of 4,873 citations. Appendix 6 provides a Quality of

Reporting Meta-analyses (QUOROM) flowchart describing the sequence of steps undertaken

to select relevant studies for the review of vitamin D testing. In total, 61 studies met the

inclusion criteria described in Table 2.3 (Chapter 2).

Data were extracted from 61 studies and reviews, and meta-analysis was performed on

eligible studies.

5.1.2 Existing health technology assessments and systematic reviews

The search for existing systematic reviews and HTAs on vitamin D testing identified 12

systematic reviews and two HTAs. Table 5.1 presents the characteristics and quality

assessment of these reviews. Data were extracted from all studies presented in Table 5.1 and

are summarised in Chapter 8.

Table 5.1: Characteristics and quality assessment of existing systematic reviews

Author and

Year Objectives Patient population

Included

studies Search period

Vitamin D supplementation for promotion of musculoskeletal health Chung

(2011)(104)

update to

Chung et al.

(2009)(9)

(AHRQ report)

To systematically review, with a

meta-analysis, to assess the

benefits and harms of vitamin D

supplementation with or without

calcium on outcomes of cancer

and fractures in adults.

All included RCTs

recruited adults >50

years old.

16 Up to July 2011

Murad et al.

(2011)(105)

To assess systematically, with a

meta-analysis, the effectiveness

vitamin D supplementation in

preventing falls.

All RCTs included

adult.

26 Up to August

2010

Michael et al.

(2010)(106)

(AHRQ report)

To evaluate systematically the

benefits and harms of

interventions (including vitamin

D or vitamin D +calcium) to

prevent falls among community

dwelling older adults.

All included RCTs


years old.

9 Up to Feb 2010

Avenell et al.

(2009)(107)

To systematically review, with

meta-analysis, the effects of

vitamin D or related compounds,

with or without calcium, for

preventing fractures in older

people.

All included RCTs

recruited men >65

years old and post-

menopausal women.

45 RCTs Up to Oct 2007

February 2014


Chung

(2011)(104)

update to

Chung et al.

(2009)(9)

(AHRQ report)

To systematically review, with a

meta-analysis, to assess the

benefits and harms of vitamin D

supplementation with or without

calcium on outcomes of cancer

and fractures in adults.

All included RCTs


years old.

16 Up to July 2011

Chung et al.

(2009)(9, 104)

(AHRQ report)

To systematically summarise the

evidence on the relationship

between vitamin D, calcium, and

a combination of both with a

wide range of health outcomes

identified by IOM, including

BMC/BMD, physical

performance and falls.

All included RCTs


years old.

9 RCTs

1 SR

Up to Dec 2008

Cranney et al.

(2007)(108)

(AHRQ report)

To assess systematically for

evidence-based EAR and RDA

values to be determined by the

IOM, with an emphasis on

musculoskeletal outcomes such

as BMC/BMD, physical

performance, and falls.

Studies included

children and adults.

17 RCTs Up to June 2006

Vitamin D supplementation in individuals with cancer Touvier et al.

(2011)(109)

To evaluate systematically, with

meta-analysis, the evidence of an

inverse relationship between

vitamin D intake and 25-(OH)D

levels and risk of colorectal

cancer.

All included

prospective studies


years old.

42

prospective

studies

(cohort or

nested case

control)

Up to June 2010

Vitamin D supplementation in individuals with cardiovascular disease Witham et al.

(2009)(110)


ability of vitamin D

supplementation or ultraviolet

radiation to reduce BP.

All included RCTs


years old.

7 RCTs From 1996 to

June 2006

Vitamin D supplementation in individuals with diabetes George et al.

(2012)(111)

To systematically review, with

meta-analysis, the evidence for

the effect of vitamin D

supplementation on glycaemia,

insulin resistance, progression to

diabetes and complications of

diabetes.

All included RCTs


years old.

15 RCTs Up to March

2011

Pittas et al.

(2010)(112)

(AHRQ report)


evidence on the association of

vitamin D levels and the effects

of vitamin D supplementation on

type 2 diabetes, hypertension or

cardiovascular disease.

All included RCTs

and observational

cohort studies


years old.

32 studies

(17 RCTs,

15

observational

cohort

studies)

Up to Nov 2009

Vitamin D supplementation during pregnancy De-Regil et al.

(2012)(113)

To systematically assess the

effects and safety of vitamin D

supplementation on maternal and

newborn outcomes.

All included RCTs

recruited pregnant

women.

6 RCTs Up to Oct 2011

Vitamin D supplementation in patients with MS Jagannath et al.

(2010)(114)

To systematically evaluate the

safety and effectiveness of

vitamin D in the management of

multiple sclerosis.

The included RCT

recruited patients

with MS.

1 RCT Up to May 2010

Vitamin D health technology assessments

February 2014


Hayes, Inc

(2012)(27)

Health technology assessment of

the evidence for vitamin D

supplementation in patients with

osteoporosis.

SRs and RCTs of

healthy populations

or patients with

chronic disease.

18 RCTs From 2002 to

July 2012

Ontario Health

Technology

Assessment

(2010)(115)

Health technology assessment

which evaluated the clinical

utility of vitamin D testing in

average risk Canadians and in

those with kidney disease. This

report also includes a systematic

literature review of the

prevalence of vitamin D

deficiency in these two

subgroups.

Studies included

children and adults.

14 Between

January 1998

and July 2009

5.2 Previous health technology assessments of vitamin D testing

As shown in Table 5.1, two HTAs were identified in the literature. One HTA from 2010 was

performed by the Ontario Health Technology Advisory Committee (OHTAC) for the Medical

Advisory Secretariat (MAS) of the Ministry of Health and Long-Term Care, Ontario.(115)

This

fair quality HTA reviewed the clinical utility of vitamin D testing. The assessment was

initiated due to the increased volume of Canadian laboratory vitamin D tests from 2004 to

2009. The purpose of the assessment was to evaluate vitamin D testing, with specific

reference to the prevalence rates of vitamin D deficiency in both the general population and in

patients with kidney disease. The assessment focused primarily on bone health and relied

heavily on two reports by the Agency for Healthcare Research and Quality (AHRQ).(9, 108) It

was noted that the use of vitamin D, with or without calcium, has been reported to reduce the

risk of fractures and falls in elderly men and postmenopausal women.

The OHTAC concluded that vitamin D testing was not warranted for the average-risk

population. Average risk was not defined, but the rationale for this conclusion included the

lack of precise target serum levels and the lack of clear supplementation guidelines from

Health Canada. The report also concluded that individuals with renal or liver disease,

osteoporosis, malabsorption syndromes, or conditions requiring medications that can affect

vitamin D absorption or metabolism should follow physician guidance regarding testing as

well as supplementation. With respect to non-bone related health, the report concluded that as

of August 2009, there were insufficient data to support a link between vitamin D and different

non-bone health outcomes such as cancer, all-cause mortality and some cardiovascular

outcomes.

The most recent HTA, undertaken by Hayes, Inc. for the Washington State Health Care

Authority in November 2012, assessed serum vitamin D testing in:

healthy populations – defined as generally healthy adults, including pregnant women, and

children without symptoms or findings of the outcome of interest; and


insufficiency, defined as adults and children with chronic diseases such as poor bone

health, obesity, cardiovascular disease, cancer, diabetes, multiple sclerosis, or

depression.(27)

The HTA was of good quality and included the following five key clinical questions, several

of which are relevant to the current MBS review:

February 2014


Q1: Has a relationship between serum vitamin D and health outcomes been demonstrated

and have clinically valid cutoff points for serum measurement been defined (clinical

validity)?

o in healthy populations

o in populations with chronic disease

Q2: Is there evidence that testing for serum vitamin D levels improves health outcomes

(clinical utility)?

o as a routine screening test in healthy patients

o in patients who already have chronic disease thought to be associated with low

serum vitamin D

Q3: Are there harms associated with vitamin D testing or with subsequent

supplementation?

Q4: What is the evidence of the differential clinical utility of vitamin D testing,

considering the risk of low serum concentrations and clinical impact of

supplementation doses in (i) healthy populations, and

(ii) patients who already have chronic disease, according to factors such as patient

characteristics and testing parameters?

Q5: What are the cost implications of vitamin D testing, including the cost-effectiveness

of testing compared with not testing?

The findings of the HTA in relation to each of these clinical questions are presented in the

following sections.

5.3 Relationship between vitamin D and health outcomes

Healthy populations

Four reports from the AHRQ provided evidence for the relationship between serum vitamin D

and health outcomes in healthy populations: Cranney et al. 2007 (bone health)(108), Chung et

al. 2009 (bone and other health outcomes)(9), Pittas et al. 2010 (cardiometabolic outcomes)(112)

and Chung et al. 2011 (cancer and fractures)(104). The data reported by the AHRQ reports

came from prospective cohort studies and nested case-control studies, which represent study

designs least subject to bias in assessing epidemiological associations. Individual studies

generally controlled for confounders but the studies varied as to which confounders were

considered.

On the basis of recent systematic reviews, narrative reviews, and clinical trials, the authors of

the HTA provided a summary of the link between serum levels of vitamin D and the risk of

disease (shown in Table 5.2).

February 2014


Table 5.2: Link between serum levels of vitamin D and the risk of disease

Disease/condition Association with serum 25-(OH)D

Cancer mortality in men Harmful

Bone health

Cardiovascular health

Type 2 diabetes

Colorectal cancer

Ovarian cancer

All-cause mortality

Protective

Cancer other than colorectal or ovarian cancer Unclear (inconsistent)

Obesity

Gestational diabetes

Multiple sclerosis

Depression and mood disorders

Insufficient*

Source: HTA undertaken by Hayes, Inc. for the Washington State Health Care Authority in November 2012(27)

* Evidence was missing, sparse, or based on lower quality study designs that are subject to bias (non-nested case-control studies or cross-

sectional studies).

The HTA cited fair quality (according to the key AHRQ systematic reviews) evidence

showing a link between serum 25-(OH)D and bone mineral density in some populations, but

noted that the evidence did not show a link with outcomes such as fracture or falls, and no

studies have investigated a link with any measure of bone health in younger adults. Analyses

by vitamin D assay type were missing in the reviewed literature.

In terms of cut-off values, the HTA concluded that for disease outcomes where a link has

been demonstrated, the evidence does not support definitive cut-off points at which 25-(OH)D

serum levels can be expected to predict optimal overall health. Although some studies have

conducted analyses according to different strata of serum levels, there was variation across

studies as to how those strata were defined. Other studies did not specify a cut-off point but

analysed associations treating serum level as a continuous variable. The HTA acknowledged

that optimal thresholds may vary by the outcome of interest, but stated that the evidence to

date is consistent with approximately 30 nmol/L as the level below which there is a risk of

deficiency and a threshold ≥ 50 nmol/L, and possibly as high as 70 nmol/L, for optimal

health. The authors concluded that “the lack of definitive cut-off points diminishes the validity

of serum measurements and thereby sheds doubt on the utility of vitamin D screening, and

findings of a possible harmful association between serum 25-(OH)D and cancer mortality in

men complicates interpretation of serum measurements”.

Populations with chronic disease

The authors noted very sparse evidence concerning an association between serum levels of

25-(OH)D and disease-related outcomes in individuals with chronic disease. They identified

a small number of studies in adults suggesting that higher levels of serum 25-(OH)D may be

associated with better prognosis for some types of cancer (colon, prostate and melanoma),

fewer cardiovascular events in individuals with hypertension, fewer complications in

individuals with diabetes, fewer relapses in individuals with MS, and less severe symptoms in

individuals with depression.

The authors concluded that vitamin D screening may have promise for establishing a

prognosis, or for assessing the risks of disease-related events and complications in some

patients; however, the evidence is too sparse to support clinical rules or cut-off points.

February 2014


5.4 Relationship between testing for vitamin D levels and health outcomes


patient behaviour, or clinical decisions were identified. The authors of the 2012 HTA also

noted that this type of evidence was not discussed in recent systematic reviews, narrative

review articles, or practice guidelines. Thus, trials of vitamin D supplementation were

reviewed as an indication of the potential utility of vitamin D screening/testing. The rationale

for this approach was that screening or testing would not improve health outcomes if there

were no effective treatment that could be recommended for individuals with low serum

vitamin D. The evidence for the effectiveness of supplementation was then used by the

authors to identify populations in which screening or testing might be effective. Due to the

large volume of literature available on vitamin D supplementation, only systematic reviews

and RCTs were included.

In total, the HTA identified six systematic reviews and 14 RCTs (23 publications) that

evaluated the effect of vitamin D supplementation on the health outcomes of interest in

healthy populations. In patients with chronic disease, three systematic reviews and 16 RCTs

(18 publications) were identified that evaluated the effect of vitamin D supplementation on

disease-related outcomes. However, in all studies, participants were not selected on the basis

of vitamin D test results. An assessment of the effectiveness of vitamin D supplementation on

healthy populations is presented in Section 5.7. An assessment of the effectiveness of vitamin

D supplementation on patients with chronic disease is presented in Section 5.8.

5.5 Evidence of the differential clinical utility of vitamin D testing

In terms of testing parameters, no studies directly evaluated the effectiveness of testing.

Therefore, differential effectiveness and safety by type of assay, frequency of monitoring, and

time of year that tests are conducted could not be directly evaluated. The trials that assessed

the relationship between baseline serum 25-(OH)D and a treatment effect from vitamin D

supplementation used assays that are often considered reference standards (such as

competitive protein binding assays, chromatographic assays, radioimmunoassay). Most

supplementation trials spanned all seasons of the year, but none analysed effects by season.

5.6 Harms associated with vitamin D testing or supplementation

In terms of harms, vitamin D testing relies on a blood draw, which is a safe procedure. The

authors of the 2012 HTA consider that the consequences of inaccurate or inappropriately

interpreted test results are relatively small. The rationale is that the review of the

effectiveness of vitamin D supplementation showed relatively modest effects at best;

therefore, safety issues associated with false-negative test results would be minimal (see

Sections 5.7 and 5.8 for the assessment of the effectiveness of vitamin D supplementation in

healthy populations, and patients with chronic disease, respectively). Furthermore, since

vitamin D supplementation was found to be a relatively safe therapy (albeit through low or

moderate quality evidence), the authors concluded that the consequences of false-positive test

results would not be serious.

The individual trials reviewed in the 2012 HTA did not discuss adverse events, indicated that

none were reported, or found no important difference between supplementation and placebo

groups. The most comprehensive data relating to adverse effects was from the WHI trial,

which randomised 36,282 women to 400 IU/day of vitamin D plus calcium or placebo and

February 2014


followed them for 7 years. The trial showed a statistically significant increased risk of kidney

stones (HR: 1.17, 95% CI: 1.02 to 1.4; P=0.02).(116)

However, there was no difference

between groups in self-reported symptoms such as moderate to severe abdominal symptoms.

A Cochrane review of vitamin D supplementation showed an increased risk of

hypercalcaemia with vitamin D supplementation.(117)

For inactive forms of vitamin D (12

trials; 11,091 participants), HR: 1.26 (95% CI: 0.78 to 2.05), and for active forms of vitamin

D (3 trials; 410 participants), HR: 3.18 (95% CI: 1.17 to 8.68).

5.7 Effectiveness of vitamin D supplementation in healthy populations

The literature does not provide direct evidence of the effectiveness of vitamin D testing on

health outcomes. However, as mentioned in Section 5.4, trials of vitamin D supplementation

provide an indication of the potential utility of vitamin D screening/testing. Six systematic

reviews and 14 RCTs (23 publications) evaluated the effect of vitamin D supplementation on

the following health outcomes:

musculoskeletal health, including bone mineral density (BMD), falls and fractures;

obesity;

cancer;

cardiovascular disease;

type 2 diabetes;

multiple sclerosis (MS);

mood disorders;

all-cause mortality;

outcomes related to pregnancy; and

children and adolescents.

A review of the evidence relating to the effectiveness of supplementation on the health

outcomes listed above is presented in Appendix 9.

Table 5.3 summarises the findings relating to vitamin D supplementation from the 2012

Hayes, Inc. HTA for the Washington State Health Care Authority.(27)

The evidence for the

benefits of supplementation was generally considered to be of low quality, except for

moderate quality evidence regarding prevention of mood disorders. Common weaknesses

included variable vitamin D doses across studies (with studies using low doses more likely to

report negative or non-significant results) and varied protocols with respect to the use of non-

study vitamin D. Where the evidence suggested a benefit, the effects were small.

February 2014


Table 5.3: Summary of the effectiveness of vitamin D supplementation in healthy populations

Source: HTA undertaken by Hayes Inc. for the Washington State Health Care Authority in November 2012(27)

* Predominantly postmenopausal women # Vitamin D plus calcium

Given the evidence suggesting positive effects of supplementation on musculoskeletal health

and general mortality in older adults, screening for low vitamin D status might be effective for

these two particular outcomes.(27)

Evidence regarding the effectiveness of increased vitamin

D intake through supplementation does not, in general, support vitamin D screening to

improve non-skeletal health outcomes other than mortality.

5.8 Effectiveness of vitamin D supplementation in patients with chronic disease

Three systematic reviews and 16 RCTs (18 publications) evaluated the effect of vitamin D

supplementation on disease-related outcomes in patients with chronic disease:

obesity

poor musculoskeletal health;

cancer;


type 2 diabetes;

multiple sclerosis;

depression and other mood disorders; and

all-cause mortality.

A review of the evidence relating to the effectiveness of supplementation on the health

outcomes listed above is presented in Appendix 10.

Table 5.4 summarises the findings from the 2012 Hayes Inc. HTA for the Washington State

Health Care Authority(27)

relating to vitamin D supplementation in patients with chronic

disease. The HTA considered the evidence regarding supplementation in patients with

chronic disease to be of low to moderate quality, depending on the disease population.

However, even in the disease populations where the evidence showed a benefit, the effects

were generally small and the clinical relevance was questionable. An exception was the

effects of active vitamin D supplementation on bone health in older adults with osteoporosis

or a history of fracture.

February 2014


Table 5.4: Summary of the effectiveness of vitamin D supplementation in patients with chronic

disease

Source: HTA undertaken by Hayes Inc. for the Washington State Health Care Authority in November 2012(27)

On the basis of the evidence of the effectiveness of supplementation with active forms of

vitamin D, vitamin D testing in patients who have evidence of osteoporosis has the potential

to improve bone-related outcomes.(27)

Furthermore, given the evidence showing

supplementation to modestly improve disease-related outcomes in individuals with

cardiovascular disease or abnormal blood glucose, vitamin D screening to assess the risk of

adverse disease outcomes might be effective in these populations. The available evidence

regarding the effectiveness of increased vitamin D intake through supplementation does not,

in general, support screening in other disease populations.

5.9 Overall summary from the clinical evidence

Vitamin D supplementation and vitamin D screening/testing are reasonably safe

interventions.(27)

No trials have directly assessed the impact of screening or testing on health

outcomes, patient behaviour, or clinical decision making therefore no definitive conclusions

can be drawn about the effectiveness of vitamin D screening or testing. However, there is

evidence for an association between serum levels and/or a positive effect of supplementation

on some health outcomes in some populations. Vitamin D screening/testing therefore has

potential utility for identifying individuals who could benefit from the preventative or disease-

modifying effects of supplementation.


25-(OH)D and health outcomes, the 2012 Hayes Inc. HTA for the Washington State Health

Care Authority(27)

concluded that knowledge of vitamin D serum levels might have value:





An additional indication for vitamin D screening may be to assess the need for

supplementation to promote musculoskeletal health in adult populations selected only because

February 2014


of older age. However, evidence that routine supplementation of postmenopausal or

institutionalised women without screening is cost-effective as a preventative treatment for

fracture suggests that screening is unnecessary in this population.

For other populations and outcomes, the available evidence suggests no benefit from vitamin

D screening or was insufficient to draw conclusions.

February 2014


6 REVIEW OF THE ECONOMIC EVIDENCE RELATING TO VITAMIN D TESTING

This Chapter presents a preliminary economic evaluation of vitamin D testing, which is

limited to a summary of the findings from the available studies identified through the

systematic literature review. A formal modelled economic evaluation of vitamin D testing

was not within the scope of this review.

6.1 Evidence base

The 2012 HTA prepared for the Washington State Health Care Authority aimed to assess the

cost implications of vitamin D testing and the cost-effectiveness of testing compared with not

testing.(27)

The relevant clinical question posed in the 2012 HTA was: What are the cost

implications of vitamin D testing, including the cost-effectiveness of testing compared with not

testing?

The HTA did not identify any systematic reviews undertaken to evaluate the cost-

effectiveness of vitamin D testing. The HTA identified one poor-quality cost analysis of

vitamin D testing.(118)

However, no cost-effectiveness studies of vitamin D screening or

testing were identified. In the absence of evidence for the cost-effectiveness of testing, the

authors sought evidence for the cost-effectiveness of vitamin D supplementation and

identified seven potentially relevant studies, of which four were excluded because of serious

limitations in the assumption about prevalence or the basis of the effectiveness estimate. The

three included studies evaluated vitamin D supplementation for the prevention of fractures

and/or falls in older adult populations.(119-121)

Importantly, none of studies considered vitamin

D testing to be one of the costs associated with supplementation. Thus, these studies are only

briefly discussed below.

6.2 Cost implications of vitamin D testing

The poor-quality cost analysis identified by the 2012 HTA was based on a retrospective chart

review of Veterans Medical Centers in the southeastern United States.(118)

The cost analysis

suggested that, assuming at least one routine vitamin D test, subsequent monitoring of serum

vitamin D levels could reduce medical costs from the perspective of Veterans Administration

(VA) Medical Centres.(118)

Data for 15,340 patients seen at six VA centres were collected.

Total outpatient and total inpatient costs were analysed according to the number of follow-up

tests after an initial vitamin D test, vitamin D sufficiency at the time of initial test, the latitude

and season of initial blood draw, and site.

Both inpatient and outpatient costs over a one-year time frame following blood draw were

lower in individuals who had sufficient serum vitamin D levels at initial testing (and thus no

need for monitoring) compared with individuals who tested as vitamin D deficient. However,

inpatient and outpatient costs were lower in patients who had ≥ 2 follow-up tests, compared

with no follow-up or one follow-up test. All factors were statistically significant explanations

of cost variation. However, the lack of data on initial test results, the distribution of vitamin

D-replete and vitamin D-deficient individuals who had no follow-up test, disease prevalence

and severity, and prescribed supplementation regimens makes these findings difficult to

interpret. Furthermore, there was no comparison of costs between individuals who had no

vitamin D testing at all and those who had ≥ 1 test.(27)

February 2014


6.3 Cost-effectiveness of vitamin D supplementation

The three included cost-effectiveness studies identified by the 2012 Hayes Inc HTA evaluated

vitamin D supplementation in different older adult populations, generally from a payer

perspective(119-121)

. All three studies assumed that individuals would receive 800 IU/day of

vitamin D3 combined with calcium. The summary of findings for each study is found in

Appendix 8 (Table A8.3).

The economic analysis by Gajic-Veljanoski et al. (2012)(119)

demonstrated that vitamin D plus

calcium supplementation in a population of 50-year-old postmenopausal women in Canada

could reduce the direct medical costs associated with fracture. Lifetime cost savings were

estimated to be $US4,196 to $US4,283 per woman in 2009, taking into account long-term

care. As noted in Appendix 8 (Table A8.3), there are some concerns that suggest the

effectiveness estimate may be somewhat biased in favour of the cost-savings finding.

The economic analysis by Lilliu et al. (2003)(120)

found supplementation to be cost-saving for

prevention of hip fracture in institutionalised women. The analysis used data from seven

European countries to estimate costs associated with treating a hip fracture. Effectiveness

estimates were derived from a placebo-controlled RCT of vitamin D supplementation to

prevent hip fractures in elderly women.(122)

The results suggested total savings of $US87,137

to $US784,233 per 1,000 women, depending on how costs were reported and the follow-up

interval (≤ 1 year postfracture). The cost savings reported by Lilliu and colleagues are

imprecise because of the variable manner in which costs were reported by different

countries.(27)

The study by Singh et al. (2004)(121)

considered vitamin D and calcium supplementation to be

standard care and conducted a study of the cost utility of hip protectors for elderly nursing

home residents in Canada. The perspective of the analysis was described as societal, but only

direct medical costs were considered. The cost of hip protectors and supplements were

obtained from local retail suppliers. The cost of fracture treatment included only immediate

hospitalisation in the base case and was estimated by the finance department of a local

hospital associated with the nursing home. Effectiveness estimates were obtained from a

Cochrane Review of hip protectors and a 1992 placebo-controlled RCT of vitamin D

supplementation in elderly women(122)

. The economic analysis concluded that hip protectors

were cost-saving in comparison with supplementation for women and men.

February 2014


7 FINDINGS AND CONCLUSIONS

This Chapter sets out the findings and conclusions of the review of vitamin D testing – as

represented by MBS item numbers 66608 and 66609 – based on the analysis of the available

MBS data; evidence obtained through systematic literature review; and the information

derived from the stakeholder consultations.

7.1 Current usage of vitamin D testing services in Australia

The number of MBS claims for vitamin D testing (item 66608 and 66609) has increased each

year over the past ten years, from 117,474 claims in 2003/04 to 4,331,030 claims in 2012/13.

This represents a 3,587% increase in vitamin D testing services. Over the same time period, a

similar increase (3,450%) was seen in benefits paid, which rose from $4,256,772 in 2003/04

to $151,129,505 in 2012/13.

Over 98% of vitamin D testing services are for MBS item 66608. The proportion of services

bulk billed for this item from 2008/09 to 2012/13 was high (more than 95% of services),

which is consistent with the high proportion of out-of-hospital services for this item (over

98%). MBS item 66609 was listed on the MBS in May 2007. After a peak in services in

2010/11 (15,414 claims), use of this item has since declined (6,944 claims in 2012/13). For

item 66609, over 85% of services were bulk billed from 2008/09 to 2012/13.

Between 2008/09 and 2012/13, the majority of all claims for item 66608 were from NSW and

Victoria; the other states and territories together accounted for less than 30% of total claims in

each year. Victoria had the highest rate of claiming per capita (25,267 claims per 100,000

population), followed by the ACT and NSW. The lowest per capita rates of vitamin D testing

services were in the northernmost states and territories (NT and Queensland). Item 66609

showed much more variability over time, and relatively high usage in Queensland as a

proportion of total claims. The highest number of claims per capita in 2012/13 was for

Tasmania and the ACT, while Victoria had the lowest.

Item numbers 66608 and 66609 are claimed by both genders; however, from 2008/09 to

2012/13, 70.2% of claims for MBS item 66608 and 68.9% of claims for item 66609 were for

females. The number of claims is particularly significant for females aged between 24 and 84

years. Australian guidelines for general practice recommend that targeted vitamin D testing

should be considered for people who are at risk of osteoporosis and who are at high risk of

vitamin D deficiency. Prevalence estimates from Australia indicate that 31%-36% of adults

are deficient in vitamin D (defined as serum 25-(OH)D levels < 50 nmol/L), increasing to

50%-62% in women during winter-spring or in people residing in southern states. The gender

imbalance and peak in testing for vitamin D levels within the 55-64 year age category is

consistent with epidemiological trends for vitamin D deficiency and osteoporosis. However,

the reason for the high rate of testing in the 45-54 year age category is less clear. An

examination of total services for MBS item 66608 in 2012/13 showed no difference in the

proportion of tests claimed in winter-spring (when the prevalence of vitamin D deficiency is

reported to be at its highest) compared with summer-autumn.

An analysis of vitamin D testing frequency per patient was conducted. The proportion of

patients who received only one test per year increased slightly over time for item 66608

(81.8% in 2008/09 and 83.4% in 2012/13), whereas the proportion of patients who received

two tests per year decreased from 14.8% to 13.9%, and the proportion of patients who

February 2014


received three or more tests per year decreased from 3.4% to 2.8%. For item 66609, the

proportion of patients who received one or two tests per year was relatively stable over time

whereas the proportion of patients who received three or more tests decreased from 3.1% in

2008/09 to 2.1% in 2012/13. Taken together with the age profile of patients being tested,

these data suggest that the majority of vitamin D testing services are being undertaken for the

purposes of screening/testing rather than monitoring.

From 2008/09 to 2012/13, there were no material changes in the pattern of requesting

providers. GPs and OMPs accounted for nearly two-thirds of all providers requesting vitamin

D testing services for item 66608. Internal medicine consultant physicians accounted for

another 15% of all provider counts, followed by specialist general surgeons, non-specialist

surgeons, interns, psychiatrists, obstetricians/gynaecologists, and other temporary resident

doctors. There were a large variety of other provider types requesting services, but they each

accounted for less than 1% of provider counts. For item 66609, GPs and OMPs accounted for

over 60% of all providers requesting vitamin D testing services, followed by internal

medicine consultant physicians (approximately 28%).

An analysis of vitamin D test requests by frequency from any one provider was conducted.

For item 66608, there was an increase over the period 2008/09 to 2012/13 in the overall

number of providers requesting vitamin D testing. The proportion of providers requesting ten

or fewer tests per year decreased from 53.6% in 2008/09 to 38.7% in 2012/13, whereas the

proportion of providers requesting 11-50 tests per year remained relatively stable (from 25.4%

to 24.5%). In contrast, the proportion of providers requesting more than 50 tests per year has

increased from 21.0% in 2008/09 to 36.8% in 2012/13. Each year, there is a small number of

providers who request over 400 vitamin D tests per year (682 in 2008/09 rising to 1,867 in

2012/13). For item 66609, the proportion of providers requesting one test per year increased

from 54.5% in 2007/08 to 64.1% in 2012/13. In contrast, the proportion of providers

requesting two or more tests decreased from 44.5% in 2008/09 to 35.9% in 2012/13.




7.2 Clinical guidance on vitamin D testing

The MBS data indicate that the majority of requests for vitamin D testing are initiated by GPs

and OMPs. The relevant College proving practice advice is the Royal Australian College of

General Practitioners (RACGP). The 2012 RACGP guidelines for preventative activities in

general practice advise that routine screening for vitamin D deficiency is not recommended in

low risk populations. However, targeted testing of people who are at risk of osteoporosis and

who are at high risk of vitamin D deficiency should be considered. High-risk groups for

vitamin D deficiency in pregnancy may also benefit from vitamin D screening. The

guidelines do not advise on the frequency of testing.

The RACGP has also produced a 2010 clinical guideline for the prevention and treatment of

osteoporosis in postmenopausal women and older men. Serum 25-(OH)D is one of the

recommended laboratory tests for the diagnostic assessment for osteoporotic fractures, but

only under particular conditions (e.g. if secondary osteoporosis is suspected). The guideline

does not mention vitamin D testing for the management of osteoporosis.

The Royal College of Pathologists of Australasia (RCPA) released a Position Statement in

May 2013 for the use and interpretation of vitamin D testing. The Position Statement

February 2014


recommended testing for vitamin D status in individuals at risk of vitamin D deficiency and

showing the following indications:










The Position Statement did not explicitly recommend routine testing for vitamin D status in

the general population (including healthy adults, pregnant women, and children). However, it

recommended that serum vitamin D levels be retested after three months following the

commencement of vitamin D supplementation. No further testing is required once desirable

25-(OH)D target levels are achieved. The position Statement recommended against high dose

annual replacement of cholecalciferol as this was associated with increased falls and fractures

in elderly men and women. The Statement recommended that the target level of serum 25-

(OH)D should be >50 nmol/L at the end of winter.

The Working Group of the Australian and New Zealand Bone and Mineral Society

(ANZBMS), Endocrine Society of Australia and Osteoporosis Australia released a position

statement in 2012 for vitamin D and health in adults in Australia and New Zealand. The

position statement recommended screening for 25-(OH)D levels in high-risk groups. The

following high-risk groups were identified:

older or disabled people in low-level and high-level residential care, particularly

housebound community-dwelling geriatric patients admitted to hospital;




obese people; and

people working in an enclosed environment, such as office workers, factory or warehouse

workers, taxi drivers, nigh-shift workers.

The position statement advised for retesting of vitamin D levels three months after

commencement of supplementation.

In 2013, the Working Group of the ANZBMS and Osteoporosis Australia also released a

position statement on vitamin D and health in pregnancy, infants, children and adolescents.

The position statement advised that universal screening for vitamin D status in pregnant

women, infants, children and adolescents is not supported by the evidence. However, 25-

(OH)D levels should be tested in those with one or more risk factors for low vitamin D. Risk

factors for low vitamin D in pregnancy, infants, children and adolescents include:

lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors,

chronic illness or hospitalisation, complex disability, covering clothing for religious or

cultural reasons or southerly latitude);

dark skin;

February 2014


medical conditions or medications affecting vitamin D metabolism and storage (obesity,

end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as

rifampicin and anticonvulsants, or fat malabsorption [e.g. in cystic fibrosis, coeliac disease

and inflammatory bowel disease]); and



Infants, children and adolescents with ongoing risk factors require ongoing monitoring of

vitamin D status with annual testing. Recently arrived migrant children at risk of low vitamin

D should have testing repeated at the end of their first winter in Australia. Pregnant women

should be tested at their first antenatal visit and again at 28 weeks’ gestation. Vitamin D

testing should also be considered in exclusively breastfed infants or mixed fed infants with at

least one other risk factor. The position statement advises that follow-up testing should be

performed in patients on vitamin D supplementation. For neonates with moderate or severe

deficiency, follow-up at one month is recommended; in other groups, follow-up at three

months is usually more practical; and in the long term, annual testing is recommended. Very

frequent testing should be avoided.

In 2012, Kidney Health Australia published CARI (Caring for Australasians with Renal

Impairment) guidelines on vitamin D therapy (supplementation) in early kidney disease. The

guidelines recommend that patients with early chronic kidney disease on vitamin D therapy

have their 25-(OH)D levels monitored regularly. Further details on the frequency of testing

are not provided.

The Australian guidelines are consistent with international guidelines that recommend against


there are guidelines that support screening in high-risk individuals (although definitions of at-

risk were lacking in these guidelines), and testing vitamin D status in populations with known

poor bone health (such as children with skeletal fragility and adults with osteoporosis).

Follow-up testing is also recommended in people being treated pharmaceutically for

osteoporosis (at 3-4 months after commencement of therapy).

Recommendations against routine screening are consistent with the lack of direct evidence

that vitamin D testing improves outcomes, as well as the lack of moderate or high quality

evidence that supplementation improves outcomes in healthy populations. Recommendations

for testing in populations with known poor bone health are weakly supported by evidence of

the effectiveness of supplementation in these populations, but there is no direct evidence

concerning the clinical utility of testing (see below).

Several guidelines mention that measurement of serum 25-(OH)D is the best way of

estimating vitamin D status. 25-(OH)D has a relatively long half-life and is therefore a better

indicator of vitamin D stores, whether obtained from sunlight or dietary sources. The main

methods available to estimate 25-(OH)D levels are immunoassay or LC-MS (see Section

1.1.4). Immunoassays are often automated and are therefore cheaper and faster to run a large

number of samples. Apart from issues of calibration and standardisation, a weakness is the

inability to quantify vitamin D2 and vitamin D3 separately, which means they give an

estimation of total 25-(OH)D. LC-MS is considered to be the ‘gold’ standard’ and is able to

simultaneously estimate 25-(OH)D in its two analyte forms, D2 and D3. The technique is

more sensitive than immunoassay but is more labour intensive and requires expensive

equipment and skilled staff.

February 2014


The performance of radioimmunoassay is generally considered to be acceptable; however, the


and analytically important range (< 50 nmol/L) of the assay. Prior to the recent introduction

of the standard reference material for 25-(OH)D from the National Institute of Standards and

Technology (NIST), there were numerous publications reporting that different immunoassays

may be yielding different results. However, the introduction of the reference standard has

helped to assess the accuracy of the different immunoassays for the measurement of serum

25-(OH)D and can serve as an adjunct to quality assurance programs for vitamin D

measurements. As discussed in Section 1.1.5, all Australian and New Zealand laboratories

offering 25-(OH)D testing are required to be enrolled in external proficiency programs, which

allow each laboratory to monitor its performance compared with its peers. These

standardisation efforts are essential to the reliable diagnosis, evaluation, and treatment of

vitamin D deficiency and help clinicians to more accurately interpret the results from vitamin

D testing.

7.3 Relationship between vitamin D and health outcomes

On the basis of a review of recent systematic reviews, narrative reviews and clinical trials in

healthy populations, the evidence suggests a harmful association of serum 25-(OH)D with

cancer mortality in men, but a protective association of serum 25-(OH)D with bone health,

cardiovascular health, type 2 diabetes, colorectal cancer, ovarian cancer and all-cause

mortality. There was an ‘unclear’ link between serum 25-(OH)D and cancer (other than

colorectal or ovarian) and insufficient evidence regarding an association of serum 25-(OH)D

with obesity, gestational diabetes, multiple sclerosis, depression and mood disorders.

For disease outcomes where a link has been demonstrated, the evidence does not support

definitive cut-off points at which 25-(OH)D serum levels can be expected to predict optimal

overall health. However, the evidence is consistent with approximately 30 nmol/L as the

level below which there is a risk of deficiency and a threshold ≥ 50 nmol/L, and possibly as

high as 70 nmol/L, for optimal health. Optimal thresholds may vary by the outcome of

interest.

There was very sparse evidence concerning an association between serum levels of 25-(OH)D

and disease-related outcomes in individuals with chronic disease. Vitamin D screening may

have promise for establishing a prognosis in patients with colon cancer, prostate cancer or

melanoma and for assessing the risk of disease-related events and complications in patients

with hypertension and diabetes; however, the evidence is too sparse to support clinical rules

or cut-off points.

7.4 Relationship between testing for vitamin D levels and health outcomes


patient behaviour or clinical decisions were identified. Therefore trials of vitamin D

supplementation were reviewed as an indication of the potential utility of vitamin D

screening/testing. The rationale was that screening or testing would not improve health

outcomes if there were no effective treatment that could be recommended for individuals with

low serum vitamin D.

Due to a lack of studies directly evaluating the effectiveness of testing, differential

effectiveness and safety by type of assay, frequency of monitoring and time of year that tests

February 2014


are conducted could not be directly evaluated. Most supplementation trials spanned all

seasons of the year, but none analysed effects by season.

7.5 Effectiveness of vitamin D supplementation

A 2010 HTA from the Ontario Health Technology Advisory Committee (OHTAC) reviewed

the clinical utility of vitamin D testing. The HTA noted that the use of vitamin D, with or

without calcium, has been shown to reduce the risk of fractures and falls in elderly men and

postmenopausal women. There were insufficient data to support a link between vitamin D

and non-bone health outcomes such as cancer, all-cause mortality and some cardiovascular

outcomes. The OHTAC recommended that routine testing of vitamin D levels should not be

endorsed for the general population, but only conducted for patients with certain bone-related

conditions, renal disease or malabsorption syndromes.

A good quality HTA published in November 2012 for the Washington State Health Care

Authority evaluated the effect of vitamin D supplementation in:

healthy populations – defined as generally healthy adults, including pregnant women, and

children without symptoms or findings of the outcome of interest; and


insufficiency, defined as adults and children with chronic diseases such as poor bone

health, obesity, cardiovascular disease, cancer, diabetes, multiple sclerosis, or depression.

The effect of vitamin D supplementation on outcomes in healthy populations was evaluated in

six systematic reviews and 14 RCTs (23 publications). Participants were not selected on the

basis of vitamin D test results. The evidence base was generally considered to be of low

quality, except for moderate-quality evidence regarding prevention of mood disorders.

Common weaknesses included variable vitamin D doses across studies and varied protocols

with respect to the use of non-study vitamin D. Where the evidence suggested a benefit, the

effects were small.

In summary, the evidence suggests positive effects of supplementation on musculoskeletal

health and general mortality in older adults. Evidence regarding the effectiveness of

increased vitamin D intake through supplementation does not, in general, support vitamin D

screening to improve non-skeletal health outcomes other than mortality.

The effect of vitamin D supplementation on disease-related outcomes in patients with chronic

disease was evaluated in three systematic reviews and 16 RCTs (18 publications).

Participants were not selected on the basis of vitamin D test results. The evidence was

considered to be of low to moderate quality, depending on the disease population. However,

even in the disease populations where the evidence showed a benefit, the effects were

generally small and the clinical relevance was questionable.

An exception was the effect of active vitamin D supplementation on bone health in older

adults with osteoporosis or a history of fracture. On the basis of a moderate body of evidence

showing benefit of supplementation in this population, the HTA concluded that vitamin D

testing in patients who have evidence of osteoporosis has the potential to improve bone-

related outcomes. Given the evidence showing supplementation to modestly improve disease-

related outcomes in individuals with cardiovascular disease or abnormal blood glucose,

vitamin D screening to assess the risk of adverse disease outcomes might also be effective in

these populations. The available evidence regarding the effectiveness of increased vitamin D

February 2014


intake through supplementation does not, in general, support screening in other disease

populations.


25-(OH)D and health outcomes, the 2012 HTA concluded that knowledge of vitamin D serum

levels might have value:





7.6 Harms associated with vitamin D testing or supplementation

Testing for vitamin D status is a relatively safe procedure that relies on a blood draw. The

consequences of inaccurate or inappropriately interpreted test results (false negative and false

positive tests) are relatively small considering that vitamin D supplementation provides

relatively modest effects and is a relatively safe therapy.

Supplementation with inactive vitamin D is associated with a moderate increase in the risk of

both hypercalcaemia and kidney stones (which are related conditions). The evidence base is

of moderate quality. Based on low quality (and quantity) evidence, treatment with active

(pharmaceutical) vitamin D is associated with an approximately threefold increase in the risk

of hypercalcaemia. Vitamin D therapy may be associated with musculoskeletal and

gastrointestinal symptoms, but a causal relationship has not been proven. No serious adverse

events have been reported in trials of vitamin D supplementation.

7.7 Cost implications of vitamin D testing

As no trials have assessed the effectiveness of vitamin D testing itself, a cost-effectiveness

analysis of vitamin D testing is not possible. The 2012 HTA for the Washington State Health

Care Authority identified one poor-quality cost analysis of vitamin D testing, which was

based on a retrospective chart review of Veterans Medical Centers in the United States. There

was no comparison of costs between individuals who had no vitamin D testing at all and those

who had one or more tests.

Three cost-effectiveness studies of vitamin D supplementation were identified, all relating to

the prevention of fractures and/or falls in older adult populations. The studies were generally

well designed and the evidence was considered to be of moderate quality. However, the

selected studies did not consider vitamin D testing to be one of the costs associated with

supplementation.

The authors of the 2012 HTA concluded that there is consistent evidence that suggests that

routine supplementation in older populations reduces costs associated with hip fracture.

Therefore, there is no need for vitamin D screening to identify subpopulations in whom there

is a potential for such cost savings. For other populations and outcomes, there is no evidence

relating to the cost implications of vitamin D testing or screening.

7.8 Conclusions

There has been a substantial increase in the number of claims for vitamin D testing over the

past ten years. Analysis of MBS data indicates that the majority of vitamin D testing services

February 2014


are requested by GPs and OMPs for the purposes of screening or testing, rather than follow-

up monitoring. Australian and international clinical practice guidelines recommend against


screening is supported in individuals at high risk of vitamin D deficiency (particularly

pregnant women and paediatric populations) and testing is supported in populations with

known poor bone health (such as children with skeletal fragility and adults with osteoporosis).

Follow-up testing at 3-4 months is also recommended in people with osteoporosis or chronic

kidney disease being treated pharmaceutically. Recommendations for testing in populations

with known poor bone health are weakly supported by evidence of the effectiveness of

supplementation in these populations, but there is no direct evidence concerning the clinical

utility of testing in any population.

February 2014


APPENDIX 1 – References

1. Pedersen JI. Vitamin D requirement and setting recommendation levels - current Nordic view.

Nutr Rev 2008 Oct;66(10 Suppl 2):S165-9.

2. Mosekilde L. Vitamin D requirement and setting recommendation levels: long-term

perspectives. Nutr Rev 2008 Oct;66(10 Suppl 2):S170-7.

3. Holick MF. Vitamin D deficiency. N Engl J Med 2007 Jul 19;357(3):266-81.

4. Johnson MA, Kimlin MG. Vitamin D, aging, and the 2005 Dietary Guidelines for Americans.

Nutr Rev 2006 Sep;64(9):410-21.

5. Office of Dietary Supplements. Dietary supplement fact sheet. Vitamin D. 2009; Available

from: http://ods.od.nih.gov/factsheets/VitaminD_pf.asp.

6. AGD Nutrition LLC. Vitamin D3 Story. 2012; Available from:

http://www.agdnutrition.com/d3-story.html.

7. Rhodes LE, Webb AR, Fraser HI, Kift R, Durkin MT, Allan D, et al. Recommended summer

sunlight exposure levels can produce sufficient (> or =20 ng ml(-1)) but not the proposed

optimal (> or =32 ng ml(-1)) 25(OH)D levels at UK latitudes. J Invest Dermatol 2010

May;130(5):1411-8.

8. Johal M, Levin A. Vitamin D and parathyroid hormone in general populations: understandings

in 2009 and applications to chronic kidney disease. Clin J Am Soc Nephrol 2009

Sep;4(9):1508-14.

9. Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and calcium: a systematic

review of health outcomes. Evid Rep Technol Assess (Full Rep) 2009 Aug(183):1-420.

10. Health Council of the Netherlands. Towards an adequate intake of vitamin D. 2008. p. 162.

11. Heaney RP. The Vitamin D requirement in health and disease. J Steroid Biochem Mol Biol

2005 Oct;97(1-2):13-9.

12. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin

Proc 2006 Mar;81(3):353-73.

13. Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada:

current status and data needs. Am J Clin Nutr 2004 Dec;80(6 Suppl):1710S-6S.

14. Norman AW, Bouillon R, Whiting SJ, Vieth R, Lips P. 13th Workshop consensus for vitamin

D nutritional guidelines. J Steroid Biochem Mol Biol 2007 Mar;103(3-5):204-5.

15. Food Standards ANZ. Adding vitamins and minerals to food. 2012; Available from:

http://www.foodstandards.gov.au/consumerinformation/fortification.cfm.

16. Calvo MS, Whiting SJ. Prevalence of vitamin D insufficiency in Canada and the United

States: importance to health status and efficacy of current food fortification and dietary

supplement use. Nutr Rev 2003 Mar;61(3):107-13.

17. Vatanparast H, Calvo MS, Green TJ, Whiting SJ. Despite mandatory fortification of staple

foods, vitamin D intakes of Canadian children and adults are inadequate. J Steroid Biochem

Mol Biol 2010 Jul;121(1-2):301-3.

http://ods.od.nih.gov/factsheets/VitaminD_pf.asp

http://www.agdnutrition.com/d3-story.html

http://www.foodstandards.gov.au/consumerinformation/fortification.cfm

February 2014


18. National Health and Medical Research Council; New Zealand Ministry of Health. Nutrient

reference values for Australia and New Zealand including recommended dietary intakes. .

2006; Available from:

http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/n35.pdf?q=publications/syn

opses/_files/n35.pdf.

19. Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM, et al. Vitamin D

and health in adults in Australia and New Zealand: a position statement. Med J Aust 2012 Jun

18;196(11):686-7.

20. Institute of Medicine (US). Dietary reference intakes for calcium and vitamin D. 2010;

Available from: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-

and-Vitamin-D.aspx

21. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of

vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3

synthesis in human skin. J Clin Endocrinol Metab 1988 Aug;67(2):373-8.

22. van der Mei IA, Ponsonby AL, Engelsen O, Pasco JA, McGrath JJ, Eyles DW, et al. The high

prevalence of vitamin D insufficiency across Australian populations is only partly explained

by season and latitude. Environ Health Perspect 2007 Aug;115(8):1132-9.

23. Huotari A, Herzig KH. Vitamin D and living in northern latitudes--an endemic risk area for

vitamin D deficiency. Int J Circumpolar Health 2008 Jun;67(2-3):164-78.

24. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J

Clin Nutr 1999 May;69(5):842-56.

25. Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res 2007 Dec;22 Suppl

2:V64-8.

26. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008 Aug;88(2):582S-6S.

27. Hayes I. Vitamin D Screening and Testing: WA Health Care Authority2012.

28. Lips P. Relative value of 25(OH)D and 1,25(OH)2D measurements. J Bone Miner Res 2007

Nov;22(11):1668-71.

29. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann

Epidemiol 2009 Feb;19(2):73-8.

30. Briot K, Audran M, Cortet B, Fardellone P, Marcelli C, Orcel P, et al. [Vitamin D: skeletal

and extra skeletal effects; recommendations for good practice]. Presse Med 2009

Jan;38(1):43-54.

31. Mason RS, Lissner D, Grunstein HS, Posen S. A simplified assay for dihydroxylated vitamin

D metabolites in human serum: application to hyper- and hypovitaminosis D. Clin Chem 1980

Mar;26(3):444-50.

32. Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008 Apr;87(4):1087S-

91S.

33. Farrell CJ, Martin S, McWhinney B, Straub I, Williams P, Herrmann M. State-of-the-art

vitamin D assays: a comparison of automated immunoassays with liquid chromatography-

tandem mass spectrometry methods. Clin Chem 2012 Mar;58(3):531-42.

http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/n35.pdf?q=publications/synopses/_files/n35.pdf

http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/n35.pdf?q=publications/synopses/_files/n35.pdf

http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx

http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx

February 2014


34. Wallace AM, Gibson S, de la Hunty A, Lamberg-Allardt C, Ashwell M. Measurement of 25-

hydroxyvitamin D in the clinical laboratory: current procedures, performance characteristics

and limitations. Steroids 2010 Jul;75(7):477-88.

35. Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant

proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate

measurement and interpretation of vitamin D status. J Clin Endocrinol Metab 2006

Aug;91(8):3055-61.

36. Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, et al. Comparison of vitamin

D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a

systematic review and meta-analysis. Am J Clin Nutr 2012 Jun;95(6):1357-64.

37. Hollis BW. Editorial: The determination of circulating 25-hydroxyvitamin D: no easy task. J

Clin Endocrinol Metab 2004 Jul;89(7):3149-51.

38. Binkley N, Krueger DC, Morgan S, Wiebe D. Current status of clinical 25-hydroxyvitamin D

measurement: an assessment of between-laboratory agreement. Clin Chim Acta 2010 Dec

14;411(23-24):1976-82.

39. National Institute of Standards and Technology (NIST). Standard Reference Material 972.

Vitamin D in Human Serum. 2009.

40. The National Institute of Standards and Technology (NIST). Development of a Standard

Reference Material for Vitamin D in Human Serum. . 2012; Available from:

http://www.nist.gov/mml/csd/organic/vitamindinserum.cfm#.

41. The National Institute of Standards and Technology (NIST). NIST Releases Vitamin D

Standard Reference Material. . 2009.

42. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998

Mar 14;351(9105):805-6.

43. Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Deeg DJ, Smit J, et al. Vitamin D status

predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007

Jun;92(6):2058-65.

44. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, et al. Higher 25-

hydroxyvitamin D concentrations are associated with better lower-extremity function in both

active and inactive persons aged > or =60 y. Am J Clin Nutr 2004 Sep;80(3):752-8.

45. Paxton GA, Teale GR, Nowson CA, Mason RS, McGrath JJ, Thompson MJ, et al. Vitamin D

and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a

position statement. Med J Aust 2013 Feb 18;198(3):142-3.

46. Stechschulte SA, Kirsner RS, Federman DG. Vitamin D: bone and beyond, rationale and

recommendations for supplementation. Am J Med 2009 Sep;122(9):793-802.

47. Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, et al. Bone

mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest

bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 2010

Feb;25(2):305-12.

48. Hanley DA, Davison KS. Vitamin D insufficiency in North America. J Nutr 2005

Feb;135(2):332-7.

http://www.nist.gov/mml/csd/organic/vitamindinserum.cfm

February 2014


49. Terrence H Diamond JAE, Rebecca S Mason, Caryl A Nowson, Julie A Pasco, Philip N

Sambrook and John D Wark. Vitamin D and adult bone health in Australia and New Zealand:

a position statement. Med J Aust 2005 Mar 21;182(6):281-5.

50. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences

for bone loss and fractures and therapeutic implications. Endocr Rev 2001 Aug;22(4):477-501.

51. Daly RM, Gagnon C, Lu ZX, Magliano DJ, Dunstan DW, Sikaris KA, et al. Prevalence of

vitamin D deficiency and its determinants in Australian adults aged 25 years and older: a

national, population-based study. Clin Endocrinol (Oxf) 2012 Jul;77(1):26-35.

52. Boyages S, Bilinski K. Seasonal reduction in vitamin D level persists into spring in NSW

Australia: implications for monitoring and replacement therapy. Clin Endocrinol (Oxf) 2012

Oct;77(4):515-23.

53. Durvasula S, Kok C, Sambrook PN, Cumming RG, Lord SR, March LM, et al. Sunlight and

health: attitudes of older people living in intermediate care facilities in southern Australia.

Arch Gerontol Geriatr 2010 Nov-Dec;51(3):e94-9.

54. Springbett P, Buglass S, Young AR. Photoprotection and vitamin D status. J Photochem

Photobiol B 2010 Nov 3;101(2):160-8.

55. Thieden E, Philipsen PA, Heydenreich J, Wulf HC. Vitamin D level in summer and winter

related to measured UVR exposure and behavior. Photochem Photobiol 2009 Nov-

Dec;85(6):1480-4.

56. Linos E, Keiser E, Kanzler M, Sainani KL, Lee W, Vittinghoff E, et al. Sun protective

behaviors and vitamin D levels in the US population: NHANES 2003-2006. Cancer Causes

Control 2012 Jan;23(1):133-40.

57. Thandrayen K, Pettifor JM. Maternal vitamin D status: implications for the development of

infantile nutritional rickets. Rheum Dis Clin North Am 2012 Feb;38(1):61-79.

58. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin

D in obesity. Am J Clin Nutr 2000 Sep;72(3):690-3.

59. Oudshoorn C, van der Cammen TJ, McMurdo ME, van Leeuwen JP, Colin EM. Ageing and

vitamin D deficiency: effects on calcium homeostasis and considerations for vitamin D

supplementation. Br J Nutr 2009 Jun;101(11):1597-606.

60. Patel S, Barron JL, Mirzazedeh M, Gallagher H, Hyer S, Cantor T, et al. Changes in bone

mineral parameters, vitamin D metabolites, and PTH measurements with varying chronic

kidney disease stages. J Bone Miner Metab 2011 Jan;29(1):71-9.

61. Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis 2009

Autumn;19(4 Suppl 5):S5-8-11.

62. Lo CW, Paris PW, Clemens TL, Nolan J, Holick MF. Vitamin D absorption in healthy

subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr 1985

Oct;42(4):644-9.

63. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to

treat. Mayo Clin Proc 2010 Aug;85(8):752-7; quiz 7-8.

64. Wang S. Epidemiology of vitamin D in health and disease. Nutr Res Rev 2009 Dec;22(2):188-

203.

February 2014


65. Sohl E, van Schoor NM, de Jongh RT, de Vries OJ, Lips P. The impact of medication on

vitamin D status in older individuals. Eur J Endocrinol 2012 Mar;166(3):477-85.

66. Serhan E, Holland MR. Calcium and vitamin D supplementation failed to improve bone

mineral density in Indo-Asians suffering from hypovitaminosis D and secondary

hyperparathyroidism. Rheumatol Int 2005 May;25(4):276-9.

67. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common

genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet

2010 Jul 17;376(9736):180-8.

68. Osteoporosis Australia. What is osteoporosis. 2012; Available from:

http://www.osteoporosis.org.au/about/about-osteoporosis/what-is-osteoporosis/.

69. Australian Institute of Health and Welfare (AIHW). A snapshot of Osteoperosis in Australia

2011 Canberra, ACT Australian Institute of Health and Welfare. 2011.

70. PubMed Health. Osteomalacia. 2012; Available from:

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001414/.

71. N. DPaB. Rickets. Paediatric and Child Health 2007;17(7).

72. Munns CF, Simm PJ, Rodda CP, Garnett SP, Zacharin MR, Ward LM, et al. Incidence of

vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance

Unit study. Med J Aust 2012 Apr 16;196(7):466-8.

73. Australian Institute of Health and Welfare (AIHW). An overview of Chronic Kidney Disease

in Australia 2009 Canberra, ACT 2009.

74. PubMed Health. Crohn's disease. 2012; Available from:


75. Wilson J, Hair C, Knight R, Catto-Smith A, Bell S, Kamm M, et al. High incidence of

inflammatory bowel disease in Australia: a prospective population-based Australian incidence

study. Inflamm Bowel Dis 2010 Sep;16(9):1550-6.

76. Anderson RP. Coeliac disease is on the rise. Med J Aust 2011 Mar 21;194(6):278-9.

77. Health. P. Cystic Fibrosis. 2012; Available from:


78. Scott C Bell PTPB, Peter J Cooper, A James Martin, Karen O McKay, Phillip J Robinson,

Gerard F Ryan and Geoff C Sims. Cystic fibrosis in Australia, 2009: results from a data

registry. MJA 2011;195(7):396-400.

79. Bell DS. Protean manifestations of vitamin D deficiency, part 2: deficiency and its association

with autoimmune disease, cancer, infection, asthma, dermopathies, insulin resistance, and type

2 diabetes. South Med J 2011 May;104(5):335-9.

80. Bliuc D, Nguyen ND, Nguyen TV, Eisman JA, Center JR. Compound risk of high mortality

following osteoporotic fracture and re-fracture in elderly women and men. J Bone Miner Res

2013 Apr 24.

81. AGREE Next Steps Consortium. The AGREE II Instrument 2009; Available from:

http://www.agreetrust.org

http://www.osteoporosis.org.au/about/about-osteoporosis/what-is-osteoporosis/

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001414/



http://www.agreetrust.org/

February 2014


82. Richardson WS, Scott MD WM, et al. The well built clinical question: a key to evidence based

decisions. ACP Journal Club 1995;123:ppA-12. .

83. The Royal College of Pathologists of Australasia (RCPA). Use and interpretation of vitamin D

testing. 2013.

84. Royal Australian College of General Practitioners (RACGP). Guidelines for preventative

activities in general practice, 8th edition East Melbourne Royal Australian College of General

Practitioners. 2012

85. RACGP. Clinical guideline for the prevention and treatment of osteoporosis in

postmenopausal women and older men2010.

86. Kidney Health Australia. CARI-Guidelines-Vitamin D Therapy for Chronic Kidney Disease.

2012.

87. Munns C, Zacharin MR, Rodda CP, Batch JA, Morley R, Cranswick NE, et al. Prevention and

treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a

consensus statement. Med J Aust 2006 Sep 4;185(5):268-72.

88. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in

combination with vitamin D supplementation to prevent fractures and bone loss in people aged

50 years and older: a meta-analysis. Lancet 2007 Aug 25;370(9588):657-66.

89. Avenell A, Gillespie WJ, Gillespie LD, O'Connell D. Vitamin D and vitamin D analogues for

preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane

Database Syst Rev 2009(2):CD000227.

90. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for

additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence

from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab

2007 Apr;92(4):1415-23.

91. Kooienga L, Fried L, Scragg R, Kendrick J, Smits G, Chonchol M. The effect of combined

calcium and vitamin D3 supplementation on serum intact parathyroid hormone in moderate

CKD. Am J Kidney Dis 2009 Mar;53(3):408-16.

92. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, et al. Vitamin D

therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO

randomized controlled trial. Jama 2012 Feb 15;307(7):674-84.

93. (AMDA) AMDA. Osteoporosis and fracture prevention in the long-term care setting:

American Medical Directors Association. 2009.

94. Society E. Evaluation, Treatment, and Prevention of Vitamin D Deficiency. 2011.

95. Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD, Cole DE, et al. Vitamin D in adult

health and disease: a review and guideline statement from Osteoporosis Canada. Cmaj 2010

Sep 7;182(12):E610-8.

96. American Congress of Obstetricians and Gynecologists (ACOG). Vitamin D: Screening and

Supplementation During Pregnancy American Congress of Obstetricians and Gynecologists.

2011 Contract No.: 495.

97. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and

adolescents. Pediatrics 2008 Nov;122(5):1142-52.

February 2014


98. Bachrach LK, Sills IN. Clinical report-bone densitometry in children and adolescents.

Pediatrics 2011 Jan;127(1):189-94.

99. Francis R, Aspray T, Fraser W, Gittoes N, Javaid K, Macdonald H, et al. Vitamin D and bone

health: A practical clinical guideline for patient management 2013

100. National Institute for Health and Clinical Excellence (NICE). The epilepsies: the diagnosis

and management of the epilepsies in adults and children in primary and secondary care. .

London, UK National Institute for Health and Clinical Excellence (NICE)2012 Contract No.:

137.

101. Institute of Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosis.

2011.

102. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO

clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic

kidney disease–mineral and bone disorder (CKD–MBD). Kidney International. 2009

103. National Institute for Health and Clinical Excellence (NICE). Chronic kidney disease: Early

identification and management of chronic kidney disease in adults in primary and secondary

care. . London, UK. : National Collaborating Centre for Chronic Conditions. National

Institute for Health and Clinical Excellence. 2008 Contract No.: 73.

104. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium

supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S.

Preventive Services Task Force. Ann Intern Med 2011 Dec 20;155(12):827-38.

105. Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM, et al.

Clinical review: The effect of vitamin D on falls: a systematic review and meta-analysis. J

Clin Endocrinol Metab 2011 Oct;96(10):2997-3006.

106. Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R. Primary care-relevant

interventions to prevent falling in older adults: a systematic evidence review for the U.S.

Preventive Services Task Force. Ann Intern Med 2010 Dec 21;153(12):815-25.

107. Avenell A, Handoll HH. Nutritional supplementation for hip fracture aftercare in the elderly.

Cochrane Database Syst Rev 2004(1):CD001880.

108. Cranney A HT, O'Donnel S, Weiler H, Puil L, Ooi D et al. Effectiveness and safety of vitamin

D in relation to bone health2007: Available from:

http://www.ncbi.nlm.nih.gov/books/NBK38410/.

109. Touvier M, Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, et al. Meta-analyses of

vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and

colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2011 May;20(5):1003-16.

110. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic

review and meta-analysis. J Hypertens 2009 Oct;27(10):1948-54.

111. George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic

control and insulin resistance: a systematic review and meta-analysis. Diabet Med 2012

Aug;29(8):e142-50.

112. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review:

Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010 Mar 2;152(5):307-14.

http://www.ncbi.nlm.nih.gov/books/NBK38410/

February 2014


113. De-Regil LM, Palacios C, Ansary A, Kulier R, Pena-Rosas JP. Vitamin D supplementation for

women during pregnancy. Cochrane Database Syst Rev 2012;2:CD008873.

114. Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the

management of multiple sclerosis. Cochrane Database Syst Rev 2010(12):CD008422.

115. Ontario health technology. Clinical utility of vitamin D testing: an evidence-based

analysis2010. Report No.: 1915-7398 (Electronic)

1915-7398 (Linking) Contract No.: 2.

116. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, et

al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med

2006 Feb 16;354(7):684-96.

117. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin

D supplementation for prevention of mortality in adults. The Cochrane database of systematic

reviews 2011(7):CD007470.

118. Bailey BA, Manning T, Peiris AN. Vitamin D testing patterns among six Veterans Medical

Centers in the southeastern United States: links with medical costs. Mil Med 2012

Jan;177(1):70-6.

119. Gajic-Veljanoski O, Bayoumi AM, Tomlinson G, Khan K, Cheung AM. Vitamin K

supplementation for the primary prevention of osteoporotic fractures: is it cost-effective and is

future research warranted? Osteoporos Int 2012 Nov;23(11):2681-92.

120. Lilliu H, Pamphile R, Chapuy MC, Schulten J, Arlot M, Meunier PJ. Calcium-vitamin D3

supplementation is cost-effective in hip fractures prevention. Maturitas 2003 Apr

25;44(4):299-305.

121. Singh S, Sun H, Anis AH. Cost-effectiveness of hip protectors in the prevention of

osteoporosis related hip fractures in elderly nursing home residents. J Rheumatol 2004

Aug;31(8):1607-13.

122. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and

calcium to prevent hip fractures in the elderly women. N Engl J Med 1992 Dec

3;327(23):1637-42.

123. NHMRC. NHMRC levels of evidence and grades for recommendations for developers of

guidelines. [Internet]. Canberra, ACT: National Health and Medical Research Council; 2009.

Available from:

http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf.

124. Dhesi JK, Jackson SH, Bearne LM, Moniz C, Hurley MV, Swift CG, et al. Vitamin D

supplementation improves neuromuscular function in older people who fall. Age Ageing 2004

Nov;33(6):589-95.

125. Hayes I. Vitamin D supplementation for patients with osteoporosis Lansdale, PA Hayes, Inc.

2012

126. Buttigliero C, Monagheddu C, Petroni P, Saini A, Dogliotti L, Ciccone G, et al. Prognostic

role of vitamin d status and efficacy of vitamin D supplementation in cancer patients: a

systematic review. Oncologist 2011;16(9):1215-27.

127. Mozaffari-Khosravi H, Hosseinzadeh-Shamsi-Anar M, Salami MA, Hadinedoushan H,

Mozayan MR. Effects of a single post-partum injection of a high dose of vitamin D on glucose

http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf

February 2014


tolerance and insulin resistance in mothers with first-time gestational diabetes mellitus. Diabet

Med 2012 Jan;29(1):36-42.

128. Eftekhari MH, Akbarzadeh M, Dabbaghmanesh MH, Hasanzadeh J. Impact of treatment with

oral calcitriol on glucose indices in type 2 diabetes mellitus patients. Asia Pac J Clin Nutr

2011;20(4):521-6.

129. Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium

supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at

high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized

controlled trial. Am J Clin Nutr 2011 Aug;94(2):486-94.

130. Nikooyeh B, Neyestani TR, Farvid M, Alavi-Majd H, Houshiarrad A, Kalayi A, et al. Daily

consumption of vitamin D- or vitamin D + calcium-fortified yogurt drink improved glycemic

control in patients with type 2 diabetes: a randomized clinical trial. Am J Clin Nutr 2011

Apr;93(4):764-71.

131. Soilu-Hanninen M, Aivo J, Lindstrom BM, Elovaara I, Sumelahti ML, Farkkila M, et al. A

randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to

interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012

May;83(5):565-71.

132. Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in

multiple sclerosis patients. Immunol Invest 2011;40(6):627-39.

133. Kimball SM, Burton JM, O'Connor PG, Vieth R. Urinary calcium response to high dose

vitamin D3 with calcium supplementation in patients with multiple sclerosis. Clin Biochem

2011 Jul;44(10-11):930-2.

134. Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, et al. A phase I/II dose-

escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010 Jun

8;74(23):1852-9.

135. Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT. Cytokine profile in patients with

multiple sclerosis following vitamin D supplementation. J Neuroimmunol 2003 Jan;134(1-

2):128-32.

136. Witham MD, Crighton LJ, Gillespie ND, Struthers AD, McMurdo ME. The effects of vitamin

D supplementation on physical function and quality of life in older patients with heart failure:

a randomized controlled trial. Circ Heart Fail 2010 Mar;3(2):195-201.

137. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D

supplementation improves cytokine profiles in patients with congestive heart failure: a double-

blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006 Apr;83(4):754-9.

138. Brunner RL, Wactawski-Wende J, Caan BJ, Cochrane BB, Chlebowski RT, Gass ML, et al.

The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's

Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr Cancer

2011;63(6):827-41.

139. Grimnes G, Figenschau Y, Almas B, Jorde R. Vitamin D, insulin secretion, sensitivity, and

lipids: results from a case-control study and a randomized controlled trial using hyperglycemic

clamp technique. Diabetes 2011 Nov;60(11):2748-57.

February 2014


140. Sanders KM, Stuart AL, Williamson EJ, Jacka FN, Dodd S, Nicholson G, et al. Annual high-

dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry 2011

May;198(5):357-64.

141. Daly RM, Nowson CA. Long-term effect of calcium-vitamin D(3) fortified milk on blood

pressure and serum lipid concentrations in healthy older men. Eur J Clin Nutr 2009

Aug;63(8):993-1000.

142. LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA, Cummings SR, et al. Calcium

plus vitamin D supplementation and mortality in postmenopausal women: the Women's

Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med

Sci 2009 May;64(5):559-67.

143. Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, et

al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst

2008 Nov 19;100(22):1581-91.

144. de Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, et al. Calcium plus

vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative.

Diabetes Care 2008 Apr;31(4):701-7.

145. Margolis KL, Ray RM, Van Horn L, Manson JE, Allison MA, Black HR, et al. Effect of

calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative

Randomized Trial. Hypertension 2008 Nov;52(5):847-55.

146. Caan B, Neuhouser M, Aragaki A, Lewis CB, Jackson R, LeBoff MS, et al. Calcium plus

vitamin D supplementation and the risk of postmenopausal weight gain. Arch Intern Med

2007 May 14;167(9):893-902.

147. Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P, et al. Calcium/vitamin D

supplementation and cardiovascular events. Circulation 2007 Feb 20;115(7):846-54.

148. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium

supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007

Jun;85(6):1586-91.

149. Dumville JC, Miles JN, Porthouse J, Cockayne S, Saxon L, King C. Can vitamin D

supplementation prevent winter-time blues? A randomised trial among older women. J Nutr

Health Aging 2006 Mar-Apr;10(2):151-3.

150. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol)

supplementation on fractures and mortality in men and women living in the community:

randomised double blind controlled trial. Bmj 2003 Mar 1;326(7387):469.

151. Winzenberg T, Powell S, Shaw KA, Jones G. Effects of vitamin D supplementation on bone

density in healthy children: systematic review and meta-analysis. Bmj 2011;342:c7254.

152. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D

status: United States, 2001-2006. NCHS Data Brief 2011 Mar(59):1-8.

153. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of

fractures and falls: results of a randomised trial in elderly people in residential

accommodation. Age Ageing 2006 Sep;35(5):482-6.

February 2014


154. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D

supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J

Bone Miner Res 2002 Apr;17(4):709-15.

155. Inkovaara J, Gothoni G, Halttula R, Heikinheimo R, Tokola O. Calcium, vitamin D and

anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term

clinical trial. Age Ageing 1983 May;12(2):124-30.

156. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al.

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly

people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-

controlled trial. Lancet 2005 May 7-13;365(9471):1621-8.

157. Harwood RH, Sahota O, Gaynor K, Masud T, Hosking DJ. A randomised, controlled

comparison of different calcium and vitamin D supplementation regimens in elderly women

after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Age Ageing 2004

Jan;33(1):45-51.

158. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and

fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann

Intern Med 1996 Feb 15;124(4):400-6.

159. Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, et al. Preventing

fractures among older people living in institutional care: a pragmatic randomised double blind

placebo controlled trial of vitamin D supplementation. Osteoporos Int 2007 Jun;18(6):811-8.

160. Peacock M, Liu G, Carey M, McClintock R, Ambrosius W, Hui S, et al. Effect of calcium or

25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the

age of 60. J Clin Endocrinol Metab 2000 Sep;85(9):3011-9.

161. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual

intramuscular vitamin D on fracture risk in elderly men and women--a population-based,

randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 2007

Dec;46(12):1852-7.

162. Avenell A, Grant AM, McGee M, McPherson G, Campbell MK, McGee MA. The effects of

an open design on trial participant recruitment, compliance and retention--a randomized

controlled trial comparison with a blinded, placebo-controlled design. Clin Trials

2004;1(6):490-8.

163. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined

calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of

secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int

2002 Mar;13(3):257-64.

164. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D

supplementation on bone density in men and women 65 years of age or older. N Engl J Med

1997 Sep 4;337(10):670-6.

165. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled

trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of

fractures in primary care. Bmj 2005 Apr 30;330(7498):1003.

February 2014


166. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus

vitamin D supplementation and the risk of fractures. N Engl J Med 2006 Feb 16;354(7):669-

83.

167. Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, et al. Two-

year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium

on the bone health of older women. J Bone Miner Res 2007 Apr;22(4):509-19.

168. Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D

and cancer mortality in the United States. J Natl Cancer Inst 2007 Nov 7;99(21):1594-602.

169. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of

mortality in the general population. Arch Intern Med 2008 Aug 11;168(15):1629-37.

170. Forman MR, Levin B. Calcium plus vitamin D3 supplementation and colorectal cancer in

women. N Engl J Med 2006 Feb 16;354(7):752-4.

171. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, et al. Serum vitamin D

concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 2008

Jun 4;100(11):796-804.

172. Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and

prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000

Oct;11(9):847-52.

173. Baron JA, Beach M, Wallace K, Grau MV, Sandler RS, Mandel JS, et al. Risk of prostate

cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol

Biomarkers Prev 2005 Mar;14(3):586-9.

174. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic

levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control 1995

May;6(3):235-9.

175. Jacobs ET, Giuliano AR, Martinez ME, Hollis BW, Reid ME, Marshall JR. Plasma levels of

25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid

Biochem Mol Biol 2004 May;89-90(1-5):533-7.

176. Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of

plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS

Med 2007 Mar;4(3):e103.

177. Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Vitamin D

receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-

hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Prostate 2007 Jun

15;67(9):911-23.

178. Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, et al. Serum

vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii,

United States). Cancer Causes Control 1998 Aug;9(4):425-32.

179. Park SY, Cooney RV, Wilkens LR, Murphy SP, Henderson BE, Kolonel LN. Plasma 25-

hydroxyvitamin D and prostate cancer risk: the multiethnic cohort. Eur J Cancer 2010

Mar;46(5):932-6.

180. Travis RC, Crowe FL, Allen NE, Appleby PN, Roddam AW, Tjonneland A, et al. Serum

vitamin D and risk of prostate cancer in a case-control analysis nested within the European

February 2014


Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol 2009 May

15;169(10):1223-32.

181. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, et al. Both high and

low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal,

nested case-control study in the Nordic countries. Int J Cancer 2004 Jan 1;108(1):104-8.

182. Nilas L, Christiansen C. Treatment with vitamin D or its analogues does not change body

weight or blood glucose level in postmenopausal women. Int J Obes 1984;8(5):407-11.

183. Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other

metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr

Soc 2013 Feb;72(1):89-97.

184. Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, et al. Circulating 25-

hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European

Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of

prospective studies. Diabetologia 2012 Aug;55(8):2173-82.

185. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy

vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research

Council Ely Prospective Study 1990-2000. Diabetes 2008 Oct;57(10):2619-25.

186. Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J

Clin Nutr 2011 Sep;65(9):1005-15.

187. Ortega RM, Lopez-Sobaler AM, Aparicio A, Bermejo LM, Rodriguez-Rodriguez E, Perea JM,

et al. Vitamin D status modification by two slightly hypocaloric diets in young

overweight/obese women. Int J Vitam Nutr Res 2009 Mar;79(2):71-8.

188. Harris S, Dawson-Hughes B. Seasonal mood changes in 250 normal women. Psychiatry Res

1993 Oct;49(1):77-87.

189. Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, et al. Vitamin D

supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J

1980 Mar 15;280(6216):751-4.

190. Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during

pregnancy: effect on neonatal calcium homeostasis. J Pediatr 1986 Aug;109(2):328-34.

191. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation

in pregnancy: a controlled trial of two methods. Obstet Gynecol 1986 Sep;68(3):300-4.

192. Marya RK, Rathee S, Dua V, Sangwan K. Effect of vitamin D supplementation during

pregnancy on foetal growth. Indian J Med Res 1988 Dec;88:488-92.

193. Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D supplementation on

toxaemia of pregnancy. Gynecol Obstet Invest 1987;24(1):38-42.

194. Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation

during pregnancy. Clin Endocrinol (Oxf) 2009 May;70(5):685-90.

195. Roth DE, Al Mahmud A, Raqib R, Akhtar E, Black RE, Baqui AH. Pharmacokinetics of high-

dose weekly oral vitamin D3 supplementation during the third trimester of pregnancy in

Dhaka, Bangladesh. Nutrients 2013 Mar;5(3):788-810.

February 2014


196. Roth DE, Al Mahmud A, Raqib R, Akhtar E, Perumal N, Pezzack B, et al. Randomized

placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in

Bangladesh: the AViDD trial. Nutr J 2013 Apr 12;12(1):47.

197. Soheilykhah S, Mojibian M, Moghadam MJ, Shojaoddiny-Ardekani A. The effect of different

doses of vitamin D supplementation on insulin resistance during pregnancy. Gynecol

Endocrinol 2013 Apr;29(4):396-9.

198. Poel YH, Hummel P, Lips P, Stam F, van der Ploeg T, Simsek S. Vitamin D and gestational

diabetes: a systematic review and meta-analysis. Eur J Intern Med 2012 Jul;23(5):465-9.

199. Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, et al. Effect of weekly

vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in

India up to age 6 months: randomised controlled trial. Bmj 2011;342:d2975.

200. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D

supplementation on symptoms of depression in overweight and obese subjects: randomized

double blind trial. J Intern Med 2008 Dec;264(6):599-609.

201. Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors

in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern

Med 2010 May;267(5):462-72.

202. Major GC, Alarie F, Dore J, Phouttama S, Tremblay A. Supplementation with calcium +

vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein

concentrations. Am J Clin Nutr 2007 Jan;85(1):54-9.

203. Rosenblum JL, Castro VM, Moore CE, Kaplan LM. Calcium and vitamin D supplementation

is associated with decreased abdominal visceral adipose tissue in overweight and obese adults.

Am J Clin Nutr 2012 Jan;95(1):101-8.

204. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in

weight reduction in overweight and obese subjects. Eur J Endocrinol 2008 Dec;159(6):675-84.

205. Zittermann A, Frisch S, Berthold HK, Gotting C, Kuhn J, Kleesiek K, et al. Vitamin D

supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk

markers. Am J Clin Nutr 2009 May;89(5):1321-7.

206. Major GC, Alarie FP, Dore J, Tremblay A. Calcium plus vitamin D supplementation and fat

mass loss in female very low-calcium consumers: potential link with a calcium-specific

appetite control. Br J Nutr 2009 Mar;101(5):659-63.

207. Steffensen LH, Jorgensen L, Straume B, Mellgren SI, Kampman MT. Can vitamin D

supplementation prevent bone loss in persons with MS? A placebo-controlled trial. J Neurol

2011 Sep;258(9):1624-31.

208. Kampman MT, Steffensen LH, Mellgren SI, Jorgensen L. Effect of vitamin D3

supplementation on relapses, disease progression, and measures of function in persons with

multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial.

Mult Scler 2012 Aug;18(8):1144-51.

209. Gloth FM, 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the

treatment of seasonal affective disorder. J Nutr Health Aging 1999;3(1):5-7.

February 2014


210. Khajehei M, Abdali K, Parsanezhad ME, Tabatabaee HR. Effect of treatment with

dydrogesterone or calcium plus vitamin D on the severity of premenstrual syndrome. Int J

Gynaecol Obstet 2009 May;105(2):158-61.

February 2014


APPENDIX 2 – Review Consultation Committee members

As part of the MBS Review process, the Department established a Review Consultation

Committee (RCC). The RCC is a time-limited committee of nominated representatives to

provide advice to the Department to inform the review process, such as the development of

review reports, i.e. scope and protocol documents, clinical practice and policy issues.

Name Representing

A/Prof Ken Sikaris Royal College of Pathologists of Australasia

A/Prof Hans Schneider Royal College of Pathologists of Australasia

Dr Zhong Lu Royal College of Pathologists of Australasia

Dr Paul Glendenning Royal College of Pathologists of Australasia

Dr Richard Whiting Australian Medical Association

Dr Andrew Boyden NPS Medicinewise

Prof Rebecca Mason Osteoporosis Australia

Dr Shelley Evans Osteoporosis Australia (to September 2013)

Dr Gail Morgan Osteoporosis Australia (from September 2013)

Prof Markus Seibel Australian and New Zealand Bone and Mineral Society

Dr Ie-Wen Sim Endocrine Society of Australia

Dr Peter Harman IVD Australia

Dr Dan McLaughlin Australian and New Zealand Association of Neurologists

Dr Walid Jammal General Practitioner MSAC Evaluation Sub-Committee (ESC) member

Chair and Secretariat Department of Health

February 2014


APPENDIX 3 – MBS information

The MBS item numbers for vitamin D testing in scope of this review include 66608 and

66609 (see Table A3.1)

Table A3.1: Vitamin D testing services listed on the MBS

Item number MBS item number descriptor

66608 Vitamin D or D fractions - 1 or more tests

Fee: $39.05 Benefit: 75% = $29.30 85% = $33.20

66609 A test described in item 66608 if rendered by a receiving APP - 1 or more tests

(Item is subject to rule 18)

Fee: $39.05 Benefit: 75% = $29.30 85% = $33.20

Description of Rule 18: The term “Episode Cone” describes an arrangement under which Medicare

benefits payable in a patient episode for a set of pathology services, containing more than three items,

ordered by a general practitioner for a non-hospitalised patient, will be equivalent to the sum of the

benefits for the three items with the highest Schedule fees.

Item 66609 is not included in the count of the items performed when applying the episode cone. Source: Department of Human Services – Medicare Australia, accessed September 2013

Note: APP is an approved pathology practitioner

Table A3.2 shows when the MBS item numbers for vitamin D testing were included on the

MBS.

Table A3.2: Item number, descriptor and schedule fee start dates for MBS item numbers

Source: Department of Human Services – Medicare Australia, accessed September 2013

February 2014


APPENDIX 4 – Search term strategy

The literature search strategies focused on the clinical evidence for vitamin D testing (Table

A4.1) and the cost implications associated with vitamin D testing (Table A4.2).

Table A4.1: Search strategy for clinical evidence

Population Search Terms

Healthy

population Embase and Medline Population – (‘preeclampsia ’/exp OR ‘preeclampsia’ OR ‘pregnancy’/exp OR ‘pregnancy’ OR

‘infant’/exp OR ‘infant’ OR ‘human milk’/exp OR ‘human milk’ OR ‘lactation’/exp OR

‘lactation’ OR ‘dark skin’/exp OR ‘dark skin’ OR ‘obesity’/exp OR ‘obesity’ OR ‘elderly’/exp

OR ‘elderly’ OR ‘aged’/exp OR ‘aged’ OR ‘indoor workers’)

AND

Intervention – (Vit*D OR ‘vitamin D’/exp OR’ vitamin D’ OR 25-OHD OR 25OHD3 OR 25-

(OH)D3 OR 25-OHD3 OR 25-(OH)D3 OR ‘25-hydroxyvitamin D’/exp OR ‘25-hydroxyvitamin

D’ OR ‘25-hydroxycholecalciferol’/exp OR ‘25-hydroxycholecalciferol’ OR ‘25-

hydroxyergocalciferol’/exp OR ‘25-hydroxyergocalciferol’ OR ‘calcidiol’/exp OR ‘calcidiol’

OR ‘cholecalciferol’/exp OR ‘cholecalciferol’ OR ‘ergocalciferol’/exp OR ‘ergocalciferol’)

AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR ‘haematologic test*’)

AND

Limits – [humans]/lim AND [english]/lim

Cochrane Population – ((MeSH descriptor Preeclampsia explode all trees) OR (MeSH descriptor

Pregnancy explode all trees) OR (MeSH descriptor Infant explode all trees) OR (MeSH

descriptor Human Milk explode all trees) OR (MeSH descriptor Lactation explode all trees) OR

(MeSH descriptor Obesity explode all trees) OR (MeSH descriptor Aged explore all trees) OR

((preeclampsia) OR (preeclampsia):ti,ab,kw) OR ((pregnancy) OR (pregnancy):ti,ab,kw) OR

((infant) OR (infant):ti,ab,kw) OR ((human milk) OR (human milk):ti,ab,kw) OR ((lactation)

OR (lactation):ti,ab,kw) OR ((dark skin) OR (dark skin):ti,ab,kw) OR ((obesity) OR

(obesity):ti,ab,kw) OR ((indoor worker) OR (indoor worker):ti,ab,kw))

AND

Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR

(MeSH descriptor 25-OHD explode all trees) OR (25-OHD):ti,ab,kw OR (MeSH descriptor

25OHD3 explode all trees) OR (25OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode

all trees) OR (25-(OH)D3):ti,ab,kw OR (MeSH descriptor 25-OHD3 explode all trees) OR (25-

OHD3):ti,ab,kw OR (MeSH descriptor 25-(OH)D3 explode all trees) OR (25-(OH)D3):ti,ab,kw

OR (MeSH descriptor 25-Hydroxyvitamin D explode all trees) OR (25-Hydroxyvitamin

D):ti,ab,kw OR (MeSH descriptor 25-Hydroxycholecalciferol explode all trees) OR (25-

Hydroxycholecalciferol):ti,ab,kw OR (MeSH descriptor 25-Hydroxyergocalciferol explode all

trees) OR (25-Hydroxyergocalciferol):ti,ab,kw OR (MeSH descriptor Calcidiol explode all trees)

OR (Calcidiol):ti,ab,kw OR (MeSH descriptor Cholecalciferol explode all trees) OR

(Cholecalciferol):ti,ab,kw OR (MeSH descriptor Ergocalciferol explode all trees) OR

(Ergocalciferol):ti,ab,kw) AND ((MeSH descriptor Testing explode all trees) OR

(Testing):ti,ab,kw OR (MeSH descriptor Haematologic test* explode al trees) OR

(Haematologic test*):ti,ab,kw)

AND

Limits [humans]/lim AND [english]/lim

Patients

diagnosed

with

osteoporosis

and

osteomalacia

Embase and Medline Population – (‘osteoporosis’/exp OR ‘osteoporosis’ OR ‘osteomalacia’/exp OR ‘osteomalacia’

OR ‘bone density’/exp OR ‘bone density’ OR ‘bone’/exp OR ‘bone’ OR ‘fractures’/exp OR

‘fractures’ OR ‘falls’/exp OR ‘falls’ OR osteoporo* OR osteomalac*)

AND





February 2014





AND


Cochrane Population – ((MeSH descriptor Osteoporosis explode all trees) OR (MeSH descriptor

Osteomalacia explode all trees) OR (MeSH descriptor Bone density explode all trees) OR

(MeSH descriptor Bone explode all trees) OR (MeSH descriptor Fractures explode all trees) OR

(MeSH descriptor Falls explode all trees) OR ((osteoporosis) OR (osteoporosis):ti,ab,kw) OR

((osteomalacia) OR (osteomalacia):ti,ab,kw) OR ((bone density) OR (bone density):ti,ab,kw)

OR ((bone) OR (bone):ti,ab,kw) OR ((fractures) OR (fractures):ti,ab,kw) OR ((falls) OR

(falls):ti,ab,kw) OR osteoporo* OR osteomalac*)

AND















AND


Children

diagnosed

with rickets

Embase and Medline Population – ((‘rickets’/exp OR ‘rickets’) OR (‘rachitis’/exp OR ‘rachitis’) OR (‘bone

development’/exp OR ‘bone development’))

AND







AND


Cochrane Population – ((MeSH descriptor Rickets explode all trees) OR (MeSH descriptor rachitis

explode all trees) OR (MeSH descriptor Bone Development explode all trees) OR((rickets) OR

(rickets):ti,ab,kw) OR ((rachitis) OR (rachitis):ti,ab,kw) OR ((bone development) OR (bone

development):ti,ab,kw))

AND











February 2014







AND


Patients with

chronic

disease

Embase and Medline Population – ((‘cardiovascular disease’/exp OR ‘cardiovascular disease’) OR (‘heart

disease’/exp OR ‘heart disease’) OR (‘ coronary disease’/exp OR ‘coronary disease’) OR

‘myocardial infarct*’ OR (‘stroke’/exp OR ‘stroke’) OR (‘ischemia’/exp OR ‘ischemia’) OR

‘pulmonary embol*’ OR ‘embol*’ OR (‘heart failure’/exp OR ‘heart failure’) OR (‘peripheral

vascular disease’/exp OR ‘peripheral vascular disease’) OR (‘kidney disease’/exp OR ‘kidney

disease’) OR (‘diabetes mellitus’/exp OR ‘diabetes mellitus’) OR (‘rheumatoid arthritis’/exp OR

‘rheumatoid arthritis’) OR (‘multiple sclerosis’/exp OR ‘multiple sclerosis’) OR (‘breast

cancer’/exp OR ‘breast cancer’) OR (‘prostate cancer’/exp OR ‘prostate cancer’) OR

(‘inflammatory bowel disease’/exp OR ‘inflammatory bowel disease’) OR (‘Crohn’s

disease’/exp OR ‘Crohn’s disease’) OR (‘ulcerative colitis’/exp OR ‘ulcerative colitis’))

AND







AND


Cochrane Population – ((MeSH descriptor Cardiovascular Disease explode all trees) OR (MeSH descriptor

Heart Disease explode all trees) OR (MeSH descriptor Coronary Disease explode all trees) OR

(MeSH descriptor Myocardial Infarction explode all trees) OR (MeSH descriptor Stoke explode

all trees) OR (MeSH descriptor Ischemia explode all trees) OR (MeSH descriptor Pulmonary

Embolism explode all trees) OR (MeSH descriptor Heart Failure explode all trees) OR (MeSH

descriptor Peripheral Vascular Disease explode all trees) OR (MeSH descriptor Kidney Disease

explode all trees) OR (MeSH descriptor Diabetes Mellitus explode all trees) OR (MeSH

descriptor Rheumatoid Arthritis explode all trees) OR (MeSH descriptor Multiple Sclerosis

explode all trees) OR (MeSH descriptor Breast Cancer explode all trees) OR (MeSH descriptor

Prostate Cancer explode all trees) OR (MeSH descriptor Inflammatory Bowel Disease explode

all trees) OR (MeSH descriptor Crohn’s Disease explode all trees) OR (MeSH descriptor

ulcerative colitis explode all trees) OR (Cardiovascular disease) OR (cardiovascular

disease):ti,ab,kw OR (heart disease) OR (heart disease):ti,ab,kw OR (coronary disease) OR

(coronary disease):ti,ab,kw OR (myocardial infarction) OR (myocardial infarction):ti,ab,kw OR

(stroke) OR (stroke):ti,ab,kw OR (ischemia) OR (ischemia):ti,ab,kw OR (heart failure) OR

(heart failure):ti,ab,kw OR (peripheral vascular disease) OR (peripheral vascular

disease):ti,ab,kw OR (kidney disease) OR (kidney disease):ti,ab,kw OR (diabetes mellitus) OR

(diabetes mellitus):ti,ab,kw OR (rheumatoid arthritis) OR (rheumatoid arthritis):ti,ab,kw OR

(multiple sclerosis) OR (multiple sclerosis):ti,ab,kw OR (breast cancer) OR (breast

cancer):ti,ab,kw OR (prostate cancer) OR (prostate cancer):ti,ab,kw OR (inflammatory bowel

disease) OR (inflammatory bowel disease):ti,ab,kw OR (Crohn’s disease) OR (Crohn’s

disease):ti,ab,kw OR (ulcerative colitis) OR (ulcerative colitis):ti,ab,kw)

AND









February 2014









AND


Table A4.2: Search strategy for economic evidence


Patients

undertaking

vitamin D

testing

Embase and Medline Intervention – (Vit*D OR ‘vitamin D’/exp OR ’vitamin D’ OR 25-OHD OR 25OHD3 OR 25-






AND

Economic Terms – (‘economic aspect’/exp OR ‘cost benefit analysis’ OR cost* OR ‘cost

effectiveness’)

AND


Cochrane Intervention – ((MeSH descriptor Vitamin D explode all trees) OR (Vitamin D):ti,ab,kw OR














AND

Economic Terms – (((economic aspect) OR (economic aspect):kw) OR ((cost benefit) OR (cost

benefit):kw)) OR ((cost effectiveness) OR (cost effectiveness):kw) OR (MeSH descriptor Cost-

Benefit Analysis explode all trees) OR (MeSH descriptor Costs and Cost Analysis explode all

trees))

AND


February 2014


APPENDIX 5 – Tools for assessing the evidence in the systematic review

Table A5.1: NHMRC Dimensions of Evidence(123)

Type of evidence Definition

Strength of the evidence

Level

Quality

Statistical precision

The study design used, as an indicator of the degree to which bias has been

eliminated by design.

The methods used by investigators to minimise bias within a study design.

The p-value or, alternatively, the precision of the estimate of the effect (as

indicated by the confidence interval). It reflects the degree of certainty about the

existence of a true effect.

Size of effect The distance of the study estimate from the “null” value and the inclusion of only

clinically important effects in the confidence interval.

Relevance of evidence The usefulness of the evidence in clinical practice, particularly the appropriateness

of the outcome measures used.

Table A5.2: NHMRC designations of levels of evidence for an intervention

(123)

Level Intervention

I A systematic review of level II studies

II A randomised controlled trial

III-1 A pseudo randomised controlled trial (i.e. alternate allocation or some other

method)

III-2 A comparative study with concurrent controls:

Non-randomised, experimental trial

Cohort study

Case-control study

Interrupted time series with a control group

III-3 A comparative study without concurrent controls:

Historical control study

Two or more single arm study

Interrupted time series without a parallel control group

IV Case series with either post-test or pre-test/post-test outcomes

Source: Hierarchies adapted and modified from: NHMRC 1999; Bandolier 1999; Lijmer et al. 1999; Phillips et al. 2001

Table A5.3: NHMRC quality criteria for RCTs, cohort studies, case-control studies and systemic

reviews(123)

Study type Quality criteria

Randomised controlled

trialsa

Was the study double blinded?

Was allocation to treatment groups concealed from those responsible for recruiting

the subjects?

Were all randomised participants included in the analysis?

Cohort studiesb How were subjects selected for the ‘new intervention’?

How were subjects selected for the comparison or control group?

Does the study adequately control for demographic characteristics, clinical features

and other potential confounding variables in the design or analysis?

Was the measurement of outcomes unbiased (i.e. blinded to treatment group and

comparable across groups)?

Was follow-up long enough for outcomes to occur?

Was follow-up complete and were there exclusions from the analysis?

Case-control studiesb How were cases defined and selected?

February 2014


Study type Quality criteria

How were controls defined and selected?

Does the study adequately control for demographic characteristics and important

potential confounders in the design or analysis?

Was measurement of exposure to the factor of interest (e.g. the new intervention)

adequate and kept blinded to case/control status?

Were all selected subjects included in the analysis?

Systematic reviewsc Was an adequate search strategy used?

Were the inclusion criteria appropriate and applied in an unbiased way?

Was a quality assessment of included studies undertaken?

Were the characteristics and results of the individual studies appropriately

summarised?

Were the methods for pooling the data appropriate?

Were sources of heterogeneity explored? Source: National Health and Medical Research Council (NHMRC), 2000. How to review the evidence: systematic identification and review

of the scientific literature, NHMRC, Commonwealth of Australia, Canberra. aBased on work of Schulz et al (1995) and Jadad et al (1996) bBased on quality assessment instruments developed and being tested in Australia and Canada cBased on articles by Greenhalgh (1997) and Hunt and McKibbon (1997).

February 2014


APPENDIX 6 – QUOROM flowchart

The QUOROM flowchart below shows the process used to select studies that were eligible for

the clinical review of vitamin D testing.

Figure A6.1: QUOROM flowchart for the review of the clinical evidence

Potentially relevant studies

identified in the literature

searches and screened for

retrieval: (n= 4873)

Studies retrieved for more

detailed evaluation: (n= 355)

Studies excluded because they

did not meet the inclusion

criteria: (n=4518)

Eligible studies to be included

in the systematic review: (n=

61)

Studies excluded because they

did not meet the inclusion

criteria: (n= 294)

Wrong study type (n= 182)

Wrong intervention (n= 49)

Level IV studies (n= 63)

February 2014


APPENDIX 7 - Grading of Recommendations

Assessment, Development, and Evaluation (GRADE) quality criteria

Tools used in Washington State HTA include internally developed Quality Checklists for

evaluating the quality (internal validity) of different types of studies, a checklist for judging

the adequacy of systematic reviews used instead of de novo analysis, and Hayes Evidence-

Grading Guides for evaluating bodies of evidence for different types of technologies. Hayes

methodology is in alignment with the GRADE (Grading of Recommendations, Assessment,

Development, and Evaluation) system, which was developed by the GRADE Working Group,

an international collaborative body.

Table A7.1: Quality criteria according to GRADE

Step 1

Individual study appraisal

a. Initial rating according to study design

Good: Randomised Controlled Trials

Fair: Nonrandomised Trial (controlled, parallel group, quasi-randomised)

Poor: Observational Analytic Studies (prospective or retrospective trials involving historical

controls, pre-test posttest control trial [patients legitimately serve as their own controls],

casecontrol,

registry/chart/database analysis involving a comparison group)

Very Poor: Descriptive Uncontrolled Studies (case reports, case series, cross-sectional surveys

[individual-level data], correlation studies [group-level data])

b. Consider the methodological rigor of study execution according to items in a proprietary

Quality Checklist

c. Repeat for each study

Step 2

Evaluation of each body of evidence by outcome, key question, or application

a. Initial quality designation according to best study design in a body of evidence

b. Downgrade/upgrade

Downgrade factors: Study weaknesses (Quality Checklists), lack of applicability, inconsistency

of results, small quantity of data, publication bias (if adequate information is available)

Possible upgrade factors: Strong association, dose-response effect, bias favoring no effect

c. Assign final rating: High-Moderate-Low-Very Low

d. Repeat for each outcome/question/application

Step 3

Evaluation of overall evidence

a. Rank outcomes by clinical importance

b. Consider overall quality of the evidence for each critical outcome

c. Assign overall rating based on lowest-quality body: High-Moderate-Low-Very Low

Step 4 Evidence-based conclusion

Overall quality of the evidence + Balance of benefits and harms

February 2014


APPENDIX 8 – Summary of included studies and systematic reviews

Table A8.1: Summary of findings from systematic reviews assessing the effectiveness of vitamin D supplementation on musculoskeletal health and

chronic diseases

Author and

year Description No of SRs/ RCTs

Search

date Key findings and conclusions Quality of included studies

Vitamin D supplementation for promotion of musculoskeletal health Chung

(2011)(104)

(update to

Chung et al.

2009)

USPSTF Focused

update SR-MA

(funded by AHRQ)

to assess the

benefits and harms

of vitamin D

supplementation

with or without

calcium on

outcomes of cancer

and fractures in

adults

16 RCTs Up to

July 2011 RR of fracture, vitD with or without calcium vs placebo in elderly men and women:

Overall: RR=1.03 (CI, 0.84-1.26; moderate heterogeneity) (5 RCTs); RRs in

individual studies ranged from 0.80-1.33)

Institutionalised: RR=0.99 (CI, 0.72-1.34; low heterogeneity) (2 RCTs) Community

dwelling: RR=1.06 (CI, 0.77- 1.46; high heterogeneity) (3 RCTs)

RR of fracture, vitD+calcium vs placebo in mostly postmenopausal women:

Overall: RR=0.88 (CI, 0.79-0.99; low heterogeneity) (11 RCTs; RRs in individual

studies ranged from 0.0.46- 1.08)

Institutionalised: RR=0.71 (CI, 0.57-0.89; no heterogeneity) (3 RCTs)

Community dwelling: RR=0.89 (CI, 0.76- 1.04; low heterogeneity) (6 RCTs)

Community dwelling with history of fracture: RR=1.02 (CI, 0.89-1.16; no

heterogeneity) (2 RCTs)

Meta-regression analysis of RR:

Per 100-IU increase in vitD dose: RR=1.01 (CI, 0.97-1.07) (16 RCTs)

Per 100 IU increase in BL serum 25-(OH)D: RR=1.02 (CI, 0.86-1.2) (12 RCTs)

Authors’ conclusions: VitD+calcium supplementation can reduce fracture risk, but

the effects may be smaller among community-dwelling older adults than among

institutionalized elderly persons

According to Chung et al. 5

RCTs of vitD alone were of

good (1), fair (3), and poor

(1); 11 RCTs of

vitD+calcium were good (2),

fair (5), and poor (4),

May not be applicable to

adults <50 yrs.

Murad et al.

(2011)(105)

SR-MA to assess

the effectiveness of

vitamin D

supplementation in

preventing falls

26 RCTs (45,782

participants)

Up to

August

2010

Overall OR: OR=0.86 (CI, 0.77-0.96), range 0.10-1.31 in individual trials (I2=66%;

P=0.01)

Vitamin D deficient vs not deficient: OR=0.53 (CI, 0.39-0.72) vs OR=0.90 (CI, 0.81-

0.99) (P=0.00)

Co-administration of calcium: VitD+calcium had greater effect compared with calcium

alone (OR=0.63; CI, 0.50-0.81) than compared with placebo (OR=0.83; CI, 0.72-0.93)

and greater placebo-controlled effect (OR=0.83) than vitD alone (OR=0.97; CI, 0.84-

1.11) (global P=0.01). NOTE: vitamin D alone had NS effect. Other: No sig interaction

of treatment with community vs institution, intramuscular vs oral, documented increase

in serum 25-(OH)D, D2 vs D3, adherence, high dose (>800 IU/day), and study quality.

Authors’ conclusions: VitD combined with calcium reduces the risk of falls in a

population consisting primarily of elderly women.

According to Murad et al.:

Allocation concealed in 18

trials, double blinding in 18,

mean loss to follow-up 10%

(NR in 9 trials); commercial

funding in 34% of studies.

Moderate statistical

heterogeneity. Results may

not be generalisable to

populations with lower

baseline risk of falls or

adequate vitD status.

Michael et al.

(2010)(106)

SR and MA to

describe the

9 RCTs (5780

participants);

Up to Feb

2010 Overall RR, vitD with or without calcium: RR=0.83 (CI, 0.77-0.89); NS statistical

heterogeneity. RRs in individual studies ranged from 0.60-0.98 and were generally NS

According to Michael et al.:

All vitD studies, fair; most

February 2014


Chung

(2011)(104)

(update to

Chung et al.

2009)

USPSTF Focused

update SR-MA

(funded by AHRQ)

to assess the

benefits and harms

of vitamin D

supplementation

with or without

calcium on

outcomes of cancer

and fractures in

adults

16 RCTs Up to






















(1); 11 RCTs of




adults <50 yrs.

benefits and harms

of interventions

(including vitamin

D or vitamin D

+calcium) to

prevent falls among

community

dwelling older

adults

(CIs crossed null).

Reanalysis, including a trial (Sanders 2010) published after the search ended and

showing an increase in falls with a 1-time dose of 500,000 IU, yielded a new estimate of

RR=0.83 (CI, 0.71-0.979). The other included RCT using a megadose (Dhesi 2004 (124))

reported neither a positive or negative effect on risk of falling

Effect of patient characteristics on pooled estimate: None according to age, sex

distribution, history of falls, or risk status (history of falls or vitD deficiency).

Authors’ conclusion: VitD supplementation can reduce falls in community-dwelling

older adults

trials underpowered and

most assessed self-reported

falls retrospectively with

recall of 6 wks – 12 mos.

Chung et al.

(2009)(9, 104)

AHRQ report to

support IOM

possible revision of

DRI. SR and MA

to summarise the

evidence on the

relationship

between vitamin D,

calcium, and a

combination of

both with a wide

range of health

outcomes

identified by IOM,

including

1 SR (Cranney

2007)/ 9 new

RCTs selected for

assessment of the

effect of

vitD or

vitD+calcium

supplementation

on incidence of

BMD and falls

Up to Dec

2008 BMD/BMC: In the newly published RCTs, effects of vitD alone on BMC/BMD

(children/adolescents, 3 poor-fair RCTs) or BMD (adults, 4 generally fair-good RCTs)

were small (difference in % change, –0.3% to 7.0% and, in most studies, NS, but CIs

around differences in % change were large in some studies of postmenopausal women.

Physical performance: Very small between-group differences in change. Significant for

chair stands and walking time; NS for grip strength (1 poor RCT).

Falls: HR=0.95 (CI, 0.79-1.15; NS) (Lyons 2007); RR=0.82 (CI, 0.59-1.16; NS)

(Burleigh 2007); NS difference in fall-free survival curves (Bunout 2006)

Stress fracture: RR=0.8 (CI, 0.64-0.99; P=0.026); OR=0.79 (CI, 0.62-1.01; P=0.059)

(Lappe 2008)

Other fracture: See Chung et al. (2011)

Effect of patient characteristics: Not discussed

Assay kits: Large variation, according to authors, but specifics not discussed.

Authors’ conclusions: the conclusion of Cranney et al. (2007) regarding to

vitD3+calcium in postmenopausal women (vitD supplementation has, at best, small

According to Chung et al.:

Potential bias in most

studies, especially in older

adults; generally fair.

Other comments: VitD doses

were usually less than

current IOM

recommendations.

February 2014


Chung

(2011)(104)

(update to

Chung et al.

2009)

USPSTF Focused

update SR-MA

(funded by AHRQ)

to assess the

benefits and harms

of vitamin D

supplementation

with or without

calcium on

outcomes of cancer

and fractures in

adults

16 RCTs Up to






















(1); 11 RCTs of




adults <50 yrs.

BMC/BMD,

physical

performance, and

falls

positive effects on BMD and physical performance; suggests small effects on BMD in

adolescent girls and on stress fractures in healthy Navy recruits; and identifies new

populations in which vitD supplementation may reduce falls) was cited; no other

conclusions about musculoskeletal health were stated.

Cranney et al.

(2007)(108)

AHRQ report to

provide support

for evidence-based

EAR and RDA

values to be

determined by the

IOM, with an

emphasis on

musculoskeletal

outcomes such as

BMC/BMD,

physical

performance, and

falls.

17 RCTs Up to

June 2006 BMD, quantitative analysis, adults:

VitD3+calcium vs placebo: Small effect on lumbar spine, femoral neck, and total

body BMD (WMD range 0.60-1.40, all sig) (7 RCTs). NS for effect on forearm

(1RCT).

VitD3+calcium vs calcium: NS in 5 RCTs; small effect on BMD in femoral neck

(1 RCT).

VitD3 vs placebo: Small effect on BMD in femoral neck (1 RCT); NS but wide CI

(WMD=0.06; CI, –3.74 to 3.86), forearm (1 RCT).

BMD/BMC, qualitative findings by population:

Infants: Inconsistent findings (2 RCTs) (quality fair-high).

Older children and adolescents: Inconsistent across sites (2 RCTs) (higher

quality).

Postmenopausal women and older men: No effect in 5 RCTs; positive effect in 1

RCT (quality fair-high).

According to Cranney et al.:

13 trials were of higher

quality on Jadad scale but

did not adequately report

allocation concealment.

Vitamin D supplementation in individuals with osteoporosis

February 2014


Hayes, Inc

(2012)(125)

Health technology

assessment of

vitamin D

supplementation for

patients with

osteoporosis

18 RCTs, 3601

participants

From

2002 to

July 2012

VitD3+calcium: Conflicting results for effect on BMD at different sites; positive effects

were small (2 RCTs involving patients with history of fracture). 1 RCT found a

pronounced increase in lumbar spine BMD in patients ≤70 yrs of age (0.993±0.131) and

a decrease in patients >70 yrs (0.868±0.216; P<0.05).

Dose effects (vitD3): No clear effect (2 RCTs)

Active vitD:

Significant effect on BMD compared with no vitD (2 RCTs).

More effective than inactive vitD (BMD, fractures, and falls) (2 RCTs).

Less effective than bisphosphonate (BMD) (4 RCTs).

Combination with bisphosphonate more effective than either drug alone (BMD

and/or fractures and falls, 3 RCTs)

Less effective than HRT (1 RCT)

Combination with HRT more effective than HRT alone (BMD and/or fractures; 2

RCTs)

Authors’ conclusions: Active vitD combined with bisphosphonate is effective; active

vitD combined with HRT may be effective; insufficient evidence for inactive vitD; no

dose-response effect of inactive vitD has been proven.

Limitations of selected

evidence according to Hayes:

follow-up ≤1 yr in 11 RCTs

(limits assessment of effect

on fractures/falls); lack of

blinding in many studies;

small sample sizes;2 studies

were commercially funded;

individual study quality

ratings NR

Vitamin D supplementation in individuals with cancer Buttigliero et

al. (2011)(126)

SR (including MA

of overall survival

data) to determine

whether

hypovitaminosis D

is associated with

poor prognosis and

if vitD repletion

improves prognosis

of cancer patients

3 RCTs, 1273

participants

Up to

June 2010 Adjusted HR (<1 favours vitD): Beer 2007: 0.67 (CI, 0.45-0.97; P=0.07) Scher 2010:

1.33 (P=0.19)

Median overall survival OS (vitD arm, control) (mos): Scher 2010: 16.8, 19.9

(significance NR) Attia: 17.8, 16.4 (NS)

Median Relapse Free Survival (RFS): No difference in Attia 2008; NR for other 2

studies.

Pooled estimate of RR of death:

Fixed effects model: 1.07 (CI, 0.93-1.23)

Random-effects model: 1.00 (CI, 0.71-1.40)

Test for heterogeneity was significant (P=0.001)

Limitations of selected

evidence according to

Buttigliero et al.: Adequate

sequence generation and

allocation concealment

unclear; potential bias due to

early stopping in 2 trials

(Attia 2008 , Scher 2010),

different chemotherapy

schedules in the 2 arms (Beer

2007), primary endpoint was

biochemical response in 2

studies (Attia 2008, Scher

2010).

Statistical heterogeneity,

perhaps due to heterogeneity

in tx protocols; largest study

(Scher 2010) lacked a true

control grp; no analysis of

differential effectiveness

according to pt factors

February 2014


Vitamin D supplementation in individuals with cardiovascular disease Witham et al.

(2009)(110)

SR and MA to

assess the ability of

vitD

supplementation or

ultraviolet radiation

to reduce BP

7 RCTs, <545

participants

From

1996 to

June 2006

Pooled estimate of difference in change (vitD minus control) (7 RCTs):

SBP: –3.3 mm Hg (CI, –8.2 to 1.7; NS)

DBP: –2.3 mm Hg (CI, –4.6 to 0.0; P=0.05)

Significant heterogeneity >50% was present across the 8 studies in hypertension (HTN)

populations, which included 1 study of ultraviolet radiation.

Individual study estimates of difference in change (vitD minus control):

SBP: –13.9 to 5 mm Hg

DBP: –9.2 to 0.4 mm Hg

Activated vitD vs vitD2/vitD3:

Effect on SBP was significant only in the subgrp of studies using vitD2/vitD3, but CIs

for the 2 subgrp estimates overlapped. No difference in effect on DBP.

Data from studies reporting other outcomes are captured for this report in other evidence

tables. Witham et al. did not report a pooled estimate for outcomes other than BP.

Authors’ conclusions: There is weak evidence of a small reduction in BP using vitD

compounds in patients with HTN. Witham et al. cited a study suggestion that a 3 mm Hg

reduction in SBP translates to a 10% reduction in CV deaths at population level.

All studies were RCTs;

generally insufficient detail

to allow assessment of

allocation concealment or

ITT analysis; blinding in

most studies; no suggestion

of publication bias in funnel

plot; statistical heterogeneity;

insufficient reporting and/or

too few studies to allow

assessment of effect

modification by BL 25-

(OH)D or vitD dose; few

studies reported a rigorous

method for measuring BP.

Vitamin D supplementation in individuals with abnormal blood glucose George et al.

(2012)(111)

SR and MA 6 RCTs, 622

participants

Up to

March

2011

Pooled SMD (George 2012):

Insulin resistance IR: 0.03 (CI, –0.18 to 0.23) (no heterogeneity)

FPG: –0.25 (CI, –0.48 to –0.03) (no heterogeneity)

HbA1C: –0.32 (CI, –0.57 to –0.07) (no heterogeneity)

Authors’ conclusions: Current evidence is insufficient to recommend vitD

supplementation for improving glycaemia or insulin resistance in patients with diabetes.

Unclear or missing ITT

analysis in most studies;

otherwise, criteria were met;

too few studies to allow

meta-regression analysis of

effect modification by BL

25-(OH)D level or BL

glucose

Pittas et al.

(2010)(112)

SR and MA (but

MAs were not

applicable to this

evidence report) to

evaluate the

evidence on the

association of

vitamin D levels

and the effects of

vitamin D

supplementation on

type 2 diabetes,

hypertension or

cardiovascular

disease

4 RCTs, 243

participants

Up to

Nov 2009

check

papers

after this

date

Authors’ conclusion: No clinically significant effect of vitD supplementation at the

dosages given.

All studies judged to be fair

February 2014


Table A8.2: Summary of vitamin D studies included in the review

Author Protocol Sample size Results Quality

Diabetes or insulin resistance Mozaffari-

Khosravi et al.

(2012)(127)

Women with first time gestational diabetes randomised

to vitD (1 injection of 300,000IU immediately after

delivery)or control

45 Changes in fasting plasma glucose (FPG), (oral glucose tolerance test

(OGTT), and glycated hemoglobin (HbA1C) were similar and change

differences NS.

Insulin sensitivity substantially dropped in control grp but remained

stable in vitD grp (P=0.002).

Insulin resistance stayed high in control grp but declined in vitD gr

(homeostasis model assessment, P=0.004; C-peptide P=0.05

Fair

Eftekhari et al.

(2011)(128)

Women with gestational diabetes randomised to vitamin

D (calcitriol 0.5μg/day) or placebo

70 There were no significant differences in the mean FPG, fasting insulin,

or HbA1C between grps at any time point of study.

Repeated measurements analyses revealed significant increases in FPG

in placebo grp (P=0.038) but not vitD grp (P=0.712; difference

between grps P<0.05). Fasting insulin and HbA1C significantly

increased in both grps (all analyses P≤0.01).

Good

Mitri et al.

(2011)(129)

Patients at high risk of diabetes were randomised to one

of the following groups:

VitD and calcium grp: VitD3 2000 IU and calcium

800 mg daily

VitD grp: VitD3 2000 IU and calcium placebo

daily

Calcium grp: Calcium 800 mg and vitD placebo

daily

Placebo grp: Calcium placebo and vitD placebo

daily

92 Adjusted change (P for treatment):

VitD vs no vitD: HbA1C, 0.08% vs 0.03% (P=0.024) after elimination

of 2 outliers; no effect on FPG or 2-hr plasma glucose

VitD+calcium vs placebo: HbA1C, 0.05% vs 0.18% (P=0.036)

VitD vs placebo: FPG. 24 mmol/L vs 8.4 mmol/L (P-0.051)

Fair

Nikooyeh et al.

(2011)(130)

Diabetic patients were randomised to receiving either

plain yogurt drink (placebo grp), yogurt drink with

vitD3 500 IU and calcium 150 mg (vitD/low calcium

grp), or yogurt drink with vitD3 500 IU and calcium 250

mg (vitD/high calcium grp) twice daily for 12 wks; all

participants participated in weight maintenance diabetic

diet

90 Differences in change in FPG, fasting serum insulin, insulin resistance,

HbA1C, weightt, BMI, waist circumference, and waist-to-hip ratio

were small but statistically significant and favored vitD or

vitD+calcium.

Change in BP did not differ between grps

There was a significant inverse relationship between changes in 25-

(OH)D and changes in wt (r=– 0.331, P=0.001), FPG (r=–0.208,

P=0.049), serum insulin (r=–0.308, P=0.003), and HbA1C (r=–0.215,

P=0.042).

Poor

February 2014


Multiple sclerosis Soilu-Hanninen

et al. (2012)(131)

Patients with multiple Sclerosis (MS) randomized to

vitD3 (Weekly vitD3 (20,000 IU);or placebo

66 Increase in T2 burden of disease was greater in placebo grp (287 mm3)

than in vitD grp (83 mm3) (NS). Fewer gadolinium enhancing lesions

on T1 MRI at 12 mos in vitD grp (P=0.004). Most other differences in

MRI changes were NS

Improvement in Expanded Disability Status Scale (EDSS) score and

walking test times favored vitD grp but were NS. No difference in

relapse rates at 12 mos

Good

Mosayebi et al.

(2011)(132)

Participants were randomised to either receiving

intramuscular injection of vitD3 300,000 IU or placebo

every mo for 6 mos; all participants received interferon

B- 1a

62 NS changes in Expanded Disability Status Scale (EDSS) and # lesions

within or between grps (all analyses P>0.05).

Fair

Burton et al.

(2010) Kimball

etl. al. (2011)(133,

134)

Participants were either randomised to either receiving

vitD (vitD and calcium 1200 mg/day calcium was

initiated 2 wks before initiation of vitD; vitD dose

increased stepwise from 4000 IU/day to a maximum of

40,000 IU/day then decreased to 0 for final 4 wks of

study (average 14,000 IU/day); calcium supplementation

ceased in final 4 wks of study.) or control

49 Clinical responses: Annual relapse rate was lower in vitD grp (0.26; CI,

–0.06 to 0.53) than control grp (0.45; CI, 0.19-0.72), but the difference

between grps was NS (P=0.09).

Proportion of participants completing trial with increased EDSS was

0.08 for vitD grp and 0.375 for control grp (P=0.019)

Peripheral blood mononuclear cell proliferative responses: Reduction in

response to 7 of 17 antigens was significantly greater in vitD+calcium

grp than in control grp (P≤0.001). Differences with respect to the other

10 antigens were NS. Between-grp differences were significant overall

and for 3 of 5 subsets of antigens

Fair

Mahon et al.

(2003)(135)

Patients with MS were randomised to either vitD (1000

IU/day) + calcium (n=17) or calcium+placebo (n=22)

39 At 6 mos, TGFB1 levels were substantially higher in vitD+calcium grp

and unchanged in placebo grp.

IL-2 levels diminished to a greater extent in vitD+calcium grp than in

placebo grp, but significance of between-grp differences was NR.

Changes and between-grp differences in inflammatory cytokines were

contradictory and NS.

Mean 25-(OH)D level at 6 mos in the vitD grp was 70 nmol/L.

Fair

Cardiovascular disease Witham et al.

(2010)(136)

Participants randomized to vitD (vitD2 100,000 IU) or

placebo at baseline and at 10 wks

105 There were no significant changes in the Functional Limitations Profile

within or between grps (all analyses P≥0.13).

No difference in improvement in 6-min walk time.

VitD grp had a greater increase in the Minnesota Living With Heart

Failure questionnaire score at 20 wks compared with placebo

(difference between grps = 5.3; CI, 0.5-10.2; P=0.03); BL scores were

23.6 and 24.7.

Good

Schleithoff et al.

(2006)(137)

Patients were assigned to 2000 IU/day

vitD3+calcium or placebo+calcium

93 Differences in change at 9 mos from BL were NS and generally slight

for cardiovascular biochemical and hemodynamic variables.

15-mo survival was very similar.

Poor

February 2014


Witham et al.

(2010)(136)

Participants randomized to vitD (vitD2 100,000 IU) or

placebo at baseline and at 10 wks

105 There were no significant changes in the Functional Limitations Profile

within or between grps (all analyses P≥0.13).

No difference in improvement in 6-min walk time.

VitD grp had a greater increase in the Minnesota Living With Heart

Failure questionnaire score at 20 wks compared with placebo

(difference between grps = 5.3; CI, 0.5-10.2; P=0.03); BL scores were

23.6 and 24.7.

Good

25-(OH)D levels at 9 mos exceeded 50 nmol/L in vitD grp and almost

reached that level in placebo grp. Dietary intake of vitD and calcium

and medication use did not change significantly in either grp during

study period.

Healthy individuals Brunner et al.

(2011)(138)

Postmenopausal women randomised to vitD (400 IU and

calcium 1000 mg/day) or placebo

Follow up: 7 years

34,670 Invasive cancer in 1306 participants (7%) in vitD grp and 1333

participants (7.4%) in placebo grp (HR=0.98; CI, 0.9-1.05; P=0.54).

There were no differences between grps for the incidence of specific

invasive cancers. Similar HR after omission of nonadherent participants

from analysis.

Cancer mortality in 315 participants (1.7%) in vitD grp and 347

participants (1.9%) in placebo grp (HR=0.9; CI, 0.77-1.05).

Greater protective treatment effect in participants with first-degree

relative with cancer and in past smokers (significant interaction).

Harmful effect (HR=1.22; 95% CI, 1.02-1.45) when total vitD intake at

BL was ≥ 600 IU/day; NS protective or neutral effects at lower levels

of BL intake (P<0.04 for treatment-intake interaction).

There was a greater incidence of invasive cancers in vitD grp for

participants in highest quartile of total vitD intake (HR=1.22; CI, 1.02-

1.45; P<0.04).

Age, ethnicity, education, BMI, physical activity, caloric intake,

calcium intake, latitude, solar irradiation, alcohol intake, and current

smoking status were not associated with the rate of invasive cancer.

Good

Grimnes et al.

(2011)(139)

Participants were randomised to vitD (20,000IU vitD

twice/wk) or placebo

Follow up: 6 months

104 Serum HbA1C (vitD; placebo) (% patients):

BL: 5.5%; 5.44%

6 mos: 5.64%; 5.64%

(differences between grps NS)

Fair

Sanders et al.

(2011)(140)

Community-dwelling older women randomised to vitD

(single oral dose of vitD 500,000 IU/year in autumn or

winter) or placebo

Follow up: 3-5 years

2,258 10.2% of vitD grp and 9.8% of placebo grp withdrew from study.

Overall SF-12 scores (vitD; placebo):

Physical score: 41.4; 41.2

Mental score: 52.5; 52.6

(all analyses NS)

Overall GHQ score ≥3 (vitD; placebo) (% patients):

BL: 14%; 15%

Good

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

12 mos: 13.8%; 13.7%

15 mos: 17.7%; 16.9%

(all analyses NS)

Daly and

Nowson

(2009)(141)

Men were randomised to vitD (milk fortified with vitD

400 IU and calcium) or placebo

167 Weight change (kg) (vitD; control):

6 mos: 0; –0.3

12 mos: 0.5; 0.1

18 mos: 0; –0.7

24 mos: 0.6; 0.1

There was no significant effect of supplementation in subgrp who had

BL 25-OHD levels <75 nmol/L.

Fair

LaCroix et al.

(2009)(142)



Follow up: 7 years

36,282 There were 744 mortalities in vitD grp and 807 in placebo grp

(HR=0.91; CI, 0.83-1.01). HRs close to unity for specific causes of

mortality, including stroke, cancer, CAD, and other causes

HRs for total mortality, CVD death, CAD death, cerebrovascular death,

cancer death, and other/I death were similar in subgrps defined by age

(<70 vs ≥70 yrs).Interaction by ethnicity, calcium use, total calcium

intake, total vitD intake latitude, BL blood pressure, smoking status,

physical activity, CVD risk, BMI, history of CVD, number of chronic

conditions, and self-reported health status with treatment was NS for

effect on total mortality.

Nested case-control analysis (n=323) suggested a protective effect

(OR=0.79; NS) in the subgrp with BL 25-(OH)D <35.4 nmol/L and a

harmful effect (NS) in the higher tertiles of BL 25-(OH)D. NS

interaction.

Good

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

Subgrp analysis suggested greater reduction in total mortality for

adherent women within <70 yrs age grp

Chlebowski et

al. (2008)(143)



Follow up: 7 years

36,282 Breast cancer in 668 participants (0.52%) in vitD grp and 693

participants (0.54%) in placebo grp (HR=0.96; CI, 0.85-1.09). Tumor

size was 1.54 cm in vitD grp and 1.71 cm in placebo grp (P=0.05).

There were 23 cancer-related mortalities in each grp. Cancer stage and

histology were similar between grps.

Effect of BL vitD intake: Participants in highest quartile had more

breast cancer in vitD than placebo grp (HR=1.34; CI, 1.01- 1.78) and

those in lowest quartile had fewer breast cancers in vitD than placebo

grp (HR=0.79; CI, 0.65-0.97) (P=0.003 for interaction). However, there

were no significant interactions in the nested case-control analyses

between BL characteristics, including serum 25-(OH)D, and treatment

assignment, after adjustment for other factors.

Logistic regression analysis of nested case-control subgrp adjusted for

age, race, latitude, breast cancer family history, prior breast biopsies,

hormone treatment, and participation in hormone treatment or diabetes

mellitus trials revealed that higher BL 25-(OH)D levels were associated

with lower breast cancer risk (P=0.04). This association was lost when

analyses further adjusted for BMI and physical activity (P trend=0.2)

Good

de Boer et al.

(2008)(144)



Follow up: 7 years

33,951 Main effect

Unadjusted: HR=0.97 (CI, 0.86- 1.09)

Adjusted for non-study use of calcium or vitD: HR=1.01 (CI, 0.94

to 1.10) (overlapping CIs indicate NS difference in the 2 HR

Good

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

estimates)

Effect according to patient factors: NS interaction with age,

race/ethnicity, education, family history of diabetes, calcium intake at

BL (trend toward significance), vitD intake at BL, multivitamin use,

alcohol intake, smoking, sun exposure, physical activity, BMI, waist

circumference, hormone treatment at BL, FPG, metabolic syndrome,

25-(OH)D level (<32.2/32.2-43.6/43.7-60.1/≥60.2 nmol/L; no clear

pattern in variation of HRs)

Margolis et al.

(2008)(145)



Follow up: 7 years

36,282 By end of study, systolic BP declined by 1 mm Hg and diastolic by 4

mm Hg; however, differences between grps was NS. No subgrps,

including demographic characteristics, hypertension risk factors,

calcium and vitD intake, and 25-(OH)D levels, had a significant change

in BP associated with vitD treatment.

Hypertension developed in 3377 participants (19.6%) in vitD grp and

3315 participants (18.3) in placebo grp (HR=1.01; CI, 0.96- 1.06).

Treatment effect by BL 25-(OH)D:

<34.4 nmol/L, HR=1.52 (CI, 0.89-2.59);

34.4-47.6 nmol/L, HR=1.48 (CI, 0.89-2.46);

47.7-64.6 nmol/L, HR=1.15 (CI, 0.69-1.92);

≥64.7 nmol/L, HR=0.79 (CI, 0.51-1.22)

(P=0.01 for interaction)

Good

Caan et al.

(2007)(146)



36,282 Participants in vitD grp had smaller annual weight gains than those in

placebo grp (mean difference – 0.13 kg, range –0.21 to –0.05;

Good

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

Follow up: 7 years P=0.001).

Mean difference in weight change according to BL BMI (kg/m2) (kg)

(range):

<25: –0.08 (–0.23 to 0.06)

25 to <30: –0.09 (–0.22 to 0.04)

30 to <35: –0.23 (–0.4 to –0.06)

≥35: –0.17 (–0.38 to 0.04)

Participants who were heavier (i.e., higher BMI) had a greater

treatment effect (P=0.04 for interaction).

Treatment effects did not vary for other BL characteristics, including

ethnicity, age, education level, waist circumference, total calcium and

vitD intake, energy intake, smoking, physical activity, and fruit and

vegetable intake.

Odds of weight gain after 3 yrs in study (1-3 kg gain; >3 kg gain):

Effect of calcium+vitD: OR=0.95 (CI, 0.90-1.01); OR=0.94 (CI,

0.90- 0.99) (P=0.05 for interaction)

Calcium <1200 mg: OR=0.89 (CI, 0.83-0.96); OR=0.89 (CI, 0.84-

0.95)

Calcium >1200 mg: OR=1.05 (CI, 0.96-1.15); OR=1.01 (CI, 0.93-

1.10) (total calcium intake P=0.008 for interaction)

Hsia et al.

(2007)(147)

Postmenopausal women randomised to vitD (total dose

of 400IU vitD and 1000mg calcium/day) or placebo

Follow up: 7 years

36,282 Main effects

MI or CAD death: HR=1.04 (CI, 0.92-1.18)

Stroke: HR=0.95 (CI, 0.82-1.10)

Risk of coronary revascularization, hospitalized heart failure,

Good

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

confirmed angina, TIA, and composite outcomes were similar

between grps.

Effect on MI or CAD death by BMI subgrp:

<25 kg/m2: HR=1.16; ≈CI, 0.8-1.5

25-<30 kg/m2: HR=1.18; ≈CI, 0.9-1.5

≥30 kg/m2: HR=0.91; ≈CI, 0.7-1.2

(P=0.04 for interaction)

Effect on MI or CAD death by other subgrps: NS test for interaction for

age, waist circumference, medication use, CVD risk factors or CVD at

BL, and calcium/vitD intake at BL.

Effect on stroke by use of anticholesterol medication:

Yes, HR=0.69 (≈CI, 0.5-1.0);

no, HR=1.04 (≈CI, 0.8-1.5) (P=0.04 for interaction)

Effect on stroke by CAD risk factors:

None, HR=1.14 (≈CI, 0.7- 1.6);

1-2, HR=0.9 (≈CI, 0.7-1.1);

≥3, HR=0.76 (≈CI, 0.3-2.2) (P=0.02 for interaction)

Effect on stroke by use of statin at BL:

Yes, HR=0.54 (≈CI, 0.2-0.9);

no, HR=1.0 (≈CI, 0.8-1.2) (P=0.04 for interaction)

Effect on CAD or stroke by calcium or vitD intake at BL: No

interaction

Lappe et al.

(2007)(148)

Community-dwelling women randomised to calcium

(1400mg calcium citrate or 1500 mg calcium carbonate),

1179 Cancer incidence (vitD; calcium; placebo) (# patients):

Yrs 1-4: 13; 17; 20

Good

Lack of vitD only

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

vitD 1000 IU+calcium, or placebo

Follow up: 4 years

Yrs 2-4: 8; 15; 18

VitD and calcium grps had lower incidence of cancer compared with

placebo grp (P<0.03). Cancer risk in vitD and calcium grps, RR=0.402

(CI, 0.20-0.82; P=0.013) and RR=0.532 (CI, 0.27-1.03; P=0.006),

respectively. Cancer risk after yr 1, RR=0.232 (CI, 0.09-0.60; P<0.005)

in vitD grp and unchanged in calcium grp.

Logistic regression revealed that treatment assignment was an

independent predictor of cancer incidence after adjustment for 12-mo

25-(OH)D (P<0.03) independent determinant of cancer risk. Cancer

risk per unit concentration of serum 25-(OH)D at BL, RR=0.983 (CI,

0.968-0.997; P<0.01) after adjustment for tx; 35% reduced risk of

cancer for every 25 nmol/L increase in serum 25-(OH)D. No subgrp

analysis or test for interaction between treatment and BL 25-(OH)D

level.

group

Dumville et al.

(2006)(149)

Healthy participants randomised to vit D combined with

calcium (800 IU oral cholecalciferol for 6 months) or

placebo

2117 74.6% of vitD grp and 78.1% of control grp had valid score at both

assessment times.

Differences between grps mean MCS (100-point scale) at BL (–0.59;

CI, –1.51 to –0.33) and 6 mos (1.76; CI, –0.81 to –1.16) were NS.

Differences were NS after controlling for BL score and age (– 0.49; CI,

–1.34 to –0.81).

Fair

Wactawski-

Wende et al.

(2006)(116)

Postmenopausal women randomized to vitD (total dose

of 400IU vitD and 1000mg calcium/day) or placebo

followup: 7 years

36,282 Invasive colorectal cancer (CRC): HR=1.08 (CI, 0.86- 1.4; NS).

Similar HRs after exclusion for poor adherence or history of CRC. NS

differences in HRs across subgrps defined by age at screening,

race/ethnicity, education, 1st-degree relative with CRC, history of

Good (fair for CRC

outcome)

February 2014


Brunner et al.

(2011)(138)



Follow up: 7 years





from analysis.










1.45; P<0.04).




Good

polyp removal, BMI, physical activity, total energy intake, energy from

saturated fat, total calcium intake, total vitD intake, regional solar

exposure, multivitamin use, smoking status, NSAID use, and hormone-

treatment use.

Other outcomes:

Cancer: HR=0.98 (CI, 0.91-1.05; NS)

CRC-related mortality: HR=0.82 (CI, 0.52-1.29; NS)

Cancer-related mortalilty: HR=0.89 (CI, 0.77-1.03; NS)

All-cause mortality: HR=0.91 (CI, 0.8-1.01; NS)

Analysis of nested case-control subgrp (306 pairs) revealed a

significant interaction between treatment grp and BL 25-OHD (P=0.02

for trend). . ORs decreased from 1.15 at ≥58.4 nmol/L to 0.7 at <31.0

nmol/L, but all were NS.

February 2014


Trivedi et al.

(2003)(150)

Healthy participants randomised to vit D (100,00 IU oral

cholecalciferol every four months for 5 years) or

placebo

2686 Mortality (vitD; placebo) (age adjusted RR) (%):

All-cause: 16.7; 18.4 (RR=0.88; CI, 0.74-1.06)

CVD: 7.5; 8.7 (RR=0.84; CI, 0.65- 1.10)

Cancer: 4.7; 5.4 (RR=0.86; CI, 0.61- 1.2)

(All analyses NS)

Incidence (vitD; placebo) (age adjusted RR) (%):

CVD: 35.5; 37.5 (RR=0.90; CI, 0.77- 1.06)

Cancer: 14.0; 12.9 (RR=1.09; CI, 0.86-1.36)

Subgroup analysis according to sex:

All RRs remained NS within men and women subgrps. Compared

with RRs for men, RRs for women were higher for CVD, and

exceeded 1.00 for cerebrovascular disease; RRs for women were

dramatically lower for cancer. However, men women differences

were NS (overlapping CIs).

Good

Table A8.3: Cost-effectiveness studies and cost analyses as reported by in the 2012 Hayes Inc. HTA(27)

Author/year Population/Intervention/

Comparators/Outcomes Data sources/methods Findings and conclusions

Bailey et al. (2012)(118)

6 VA Medical Centres

Cross-sectional analysis of

costs vs vitamin D status and

monitoring (retrospective

chart review)

Perspective: VA

Medical Centres

15,340 patients(mean age

67

yrs; mean BMI 29; 93%

men; 88% white) seen at

6 VA Medical Centres

F/u vitamin D testing vs no

f/u

Total input and output

costs

<20 ng/mL was considered vitamin D

insufficient.

% patients with ≥ f/u test ranged from approx

48% to 69%.

Discounting: N/A

Base year/inflation rate: NR

Total output costs (no f/u test, 1 f/u test; ≥2 f/u tests, vitamin D

deficient, non-deficient): Approx $76,000; $83,000; $10,200;

$10,000, $8000

Total input costs (no f/u test, 1 f/u test; ≥2 f/u tests, vitamin D

deficient, non-deficient): Approx $11,500; $7500; $6250; $11,000,

$7000

Latitude, season of vitamin D draw, and vitamin D status, and

monitoring were statistically significant explanations of cost

variation, but considerable residual variation was attributed to site.

Authors’ conclusions: Testing serum vitamin D once or twice yearly

until stable and appropriate levels are documented is appropriate

Gajic-Veljanoski et al.

(2012)(119)

University of Toronto,

Toronto, Canada

Cost-effectiveness study of

vitD+calcium and

vitD+calcium+vitK

(probabilistic decision

analytic

postmenopausal

women without

osteoporosis

VitD3 (800 IU/day) +

calcium (1200

mg/day);

VitD3+calcium+vitK2

; VitD3+calcium+Vit

K1; VitK2alone

No supplementation

Hip, clinical vertebral,

Assumptions: Duration of QOL and cost

impact varied by fracture. Woman would take

alendronate for 5 years after first clinical

fracture.

Fracture risk: Swedish Malmö registry (age-

and site specific) and published MA (for

successive fractures).

Mortality risk: Canadian life tables; increased

for 1 year after hip fracture.

Effectiveness:

VitD: Authors’ MA of 3 RCTs† (hip,

VitD+calcium: Cost-saving (–$4196 to – $4283 per woman) over a

lifetime. Because of dominance over no supplementation,

vitD+calcium became relevant comparison for vitK treatments.

VitD+calcium+vitK: $9557-$12,896/QALY

VitK2 alone: More expensive and less effective than

vitD+calcium+vitK

ICERs were the result of computer simulation with repeated

sampling; thus, estimates varied slightly for different sets of

calculations for different vitK interventions.

Sensitivity analyses: Varied all input parameters and several base

case assumptions. Most sensitive to assumptions regarding

February 2014




model)

Perspective: Payer

Time horizon: Lifetime or

age 100 yrs

Funding source: No external

funding

morphometric

vertebral, or wrist

fracture

RR=0.68; vertebral, RR=0.87; wrist,

RR=0.69)

VitK2: Published MA and single study in

Japanese patients

VitK1: Single RCT in postmenopausal

Canadian women

Utility weights: Published literature

Costs: All direct medical costs for treated

fracture, including LTC. Cost of alendronate,

vitD3+calcium (CAD 89.90/yr [USD 85.69];

no dispensing costs), and vitK.

Discounting: 3% for costs and life-years

Base year, inflation adjustment: 2009 USD, NR

effectiveness and costs of vitK.

Authors’ conclusions: No overall conclusion concerning vitD

supplementation since vit K supplementation was the focus.

Lilliu et al. (2003)(120)

Cost data from 7

European countries

Cost-effectiveness and cost

analysis

Perspective: Mixed

Time horizon: ≤1 yr post-

fracture (costs)

Institutionalized women

Supplementation with

vitD3 (800 IU/day) +

calcium (1200 mg/day)

No supplementation

Hip fracture

Fracture risk: Prevalence in the study grp of the

effectiveness estimate source (Chapuy et al.,

1992)(122).

Effectiveness: RCT with placebo control and

ITT analysis (Chapuy et al., 1992 (122)); 25%

fewer cases (RR 0.75)*

Costs: Published data for each country. (1)

Supplements (€0.29/day-€0.54/day); (2)

treatment of hip fracture.

Cost components varied by country (medical

only vs societal, incremental vs total, 6 mos to

1 yr, initial costs only vs midterm rehab also,

derived from previously non-institutionalised

population in 1 country). Estimates

corresponded to 880 IU/day vitD and/or 1000

mg/day calcium in some countries. Cost of

delivering supplements considered negligible.

Long-term institutionalization not included as a

cost consequence.

Discounting: N/A

Base year, inflation adjustment: NR (2003

assumed), N/A

Cost-saving for all countries: €79,000- €711,000 (USD 87,137-USD

784,233)/1000 women.

Greatest cost savings for the country (UK) for which cost estimates

derived from non-institutionalised population.

Sensitivity analyses: For worst case scenario (20% increase in #

fractures), results suggested that supplementation either remained

cost-saving (€123,000- €174,000/1000 women [USD 135,669- USD

191,922/1000 women]) or was reasonably cost-effective (€64,000-

€134,000/1000 women [USD 70,592-USD 147,802/1000 women]) in

additional costs.

Highly cost-saving for all countries under best-case scenario (20%

fewer fractures). Daily supplementation price for equal costs in

supplementation and placebo grps, €0.64-€1.45 (USD 0.64-USD

1.60).

Currency conversions based on rates as of April 25, 2003.

Authors’ conclusions: Analysis probably underestimates cost-

effectiveness since supplementation has been shown to also prevent

non-vertebral fractures other than hip.

Singh et al. (2004)(121)

Canada

Cost-effectiveness and Cost-

utility analysis (decision

Elderly NH residents

Hip protectors vs

standard care

BL incidence: 43/1000 persons/yr, based on

chart review of a local NH facility.

Effectiveness estimate: Obtained from a

Cochrane Review of hip protectors (RR=0.37)

and from Chapuy et al. (1992)(122) for

Cost savings/hip fracture averted: Hip protector vs no treatment:

CAD 10,713 (USD 7820) Hip protector vs supplementation: CAD –

10,198 (USD –7445)

Cost savings/QALY gained (women; men): Hip protector vs no

treatment: CAD 16,204 (USD 11,829); CAD 18,272 (USD 13,339)

February 2014




analytic modeling using

hypothetical cohort)

Perspective: Described as

“societal” but only direct

medical costs were

considered; equivalent to

payer perspective

Time horizon: 1 yr

postfracture (costs), lifetime

(QALYs gained)

No treatment or

vitD3+calcium

supplementation (800

IU/day vitD, 1200 mg/day

calcium)

Hip fractures averted,

QALYs gained

supplementation (RR=0.73).

Utility values (for QALY estimates): Published

study of EuroQol scores for patients aged 75-

84 yrs with and without hip fracture for 1st and

2nd yrs postfracture; subsequent yrs assumed

to be equivalent to 2nd yr. Probability of death

for 1st yr, 10%; for subsequent yrs, based on

Canadian Life Table data for NH home

residents without fracture. 0.63, no fracture;

0.43, 1 yr postfracture; 0.53, 2nd or subsequent

yr postfracture

Costs (1 year): Cost of fracture treatment

included only immediate hospitalisation in the

base case and was estimated by finance

department of local hospital associated with

NH. Cost of hip protector (CAD 150, USD

110) and supplements (CAD 56, USD 41)

obtained from local retail suppliers; cost of side

effects excluded (evidence suggests they are

negligible).

Discounting: N/A for costs; 3% for QALYs.

Base year/inflation rate: 2001, N/A

Hip protector vs supplementation: CAD 15,426 (USD 11,261); CAD

17,394 (USD 12,698)

2-way and 1-way sensitivity analysis, hip protector vs

supplementation: Limits of 95% CI of effectiveness estimate for hip

protectors, 33% increase and decrease in costs, and addition of

nursing aide for putting on protector. Analyses yielded C/E ratios of

$299-$18,727/fracture averted and $403-$28,326/QALY, when cost

of nursing aid was considered and/or upper limit of effectiveness was

assumed; otherwise, cost savings were maintained.

Probabilistic sensitivity analysis (computer simulation), hip protector

vs supplementation: 95% probability that cost/fracture averted is

<CAD 20,000 (USD 14,600); 96% probability of cost savings if no

nursing aide time is required and cost of hip protector is <CAD 150

(USD 110). Similar findings for QALYs gained as the outcome.

Authors’ conclusion: Hip protectors appear to be a cost-effective

treatment option.

February 2014


APPENDIX 9 – Review of the effectiveness of supplementation in healthy patient populations

The 2012 Hayes Inc. HTA for the Washington State Health Care Authority(27)

identified six

systematic reviews and 14 RCTs (23 publications) that evaluated the effect of vitamin D

supplementation on the following health outcomes:

musculoskeletal health, including bone mineral density (BMD), falls and fractures;

cancer;


type 2 diabetes;

obesity;

multiple sclerosis;

mood disorders;

all-cause mortality;

outcomes related to pregnancy; and

children and adolescents.

A9.1 Effect of vitamin D supplementation on musculoskeletal health

Evidence relating to musculoskeletal health was obtained from six systematic reviews of

RCTs.(9, 104-106, 108, 151)

One of the selected RCTs was the Women’s Health Initiative (WHI), a

seven-year U.S. study following 36,282 postmenopausal women, all of whom were aged 50

years or older. Women were randomised to 400 IU/day of vitamin D plus calcium, or to

placebo, and were allowed continued use of personal supplements. Baseline serum 25-(OH)D

levels were not reported for the overall study group; however, in a nested case-control

analysis derived from this study, 72% of women had baseline serum levels < 52.4 nmol/L.(142)

When compared with the overall American population, the WHI trial population had a much

greater prevalence of vitamin D insufficiency (72% vs 28% the prevalence of vitamin D

insufficiency in American Women aged ≥ 50 years)(152)

. Nine different publications provided

data from this trial.

Based on an analysis of more than seven RCTs (including meta-analyses where possible), the

AHRQ report by Cranney et al. (2007)(108)

concluded that vitamin D3 (≤ 800 IU/day) plus

calcium resulted in small increases in BMD of the spine, total body, femoral neck and total

hip in populations consisting predominantly of women in late menopause. This conclusion is

consistent with the AHRQ review by Chung et al. (2009)(9)

, which included three additional

RCTs in older women. However, five RCTs included in the two AHRQ reports showed

inconsistent findings for an effect on physical performance measures.

Another systematic review with meta-analysis by Michael et al. (2010)(106)

, also from the

AHRQ, found that vitamin D at median doses of 800 IU/day, with or without calcium,

reduced the incidence of falls by 14% (risk ratio [RR]: 0.82; 95% confidence interval [CI]:

0.77 to 0.89) in community-dwelling older adults (nine RCTs; 5,780 participants).(106)

A more recent systematic review and meta-analysis by Murad et al. (2011)(105)

, commissioned

by the Endocrine Society, reported results very similar to those reported by Michael et al.

(2010), although no restriction on participant dwelling was made (results from community

and institutionalised participants were pooled): the odds ratio (OR) was 0.86 (95% CI: 0.77 to

February 2014


0.96) for vitamin D with or without calcium, based on 26 RCTs and a total of 45,782

participants with a mean age of 76 years.(105)

In the studies reviewed by Murad et al. (2010),

patients generally received vitamin D at doses of 400 to 1000 IU/day. The population

represented by the studies included in the review by Murad et al. (2010) was at a substantial

risk of falls (median risk 50%; range 15% to 69% across studies). Statistical tests for

interaction suggested that the treatment effect did not differ by community versus institutional

dwelling.

Combined data from 18 studies (N=13,628) was used to evaluate the effect of vitamin D

supplementation (with or without calcium) on the risk of falls (Figure A9.1). Meta-analysis

shows that supplementation with vitamin D significantly reduces the risk of falls in the elderly

population (OR: 0.73; 95% CI: 0.60 to 0.89).

Figure A9.1: Meta-analysis of the effects of vitamin D alone or with calcium, compared with

placebo, on the risk of falls

Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people

who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the

overall meta-analysis.

The data were analysed to determine the effect of vitamin D plus calcium on the risk of falls

in the elderly population. Nine studies (N=6,033) were included in the meta-analysis (Figure

A9.2). The results show that supplementation with vitamin D in combination with calcium

significantly reduces the risk of falls (OR: 0.73; 95% CI: 0.58 to 0.92).

February 2014


Figure A9.2: Meta-analysis of the effects of vitamin D plus calcium, compared with placebo, on

the risk of falls

Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people

who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.

A meta-analysis was also conducted to examine the effect of vitamin D alone on the risk of

falls. Data from nine studies (N=7,594) were included in the meta-analysis (Figure A9.3).

The results show that supplementation with vitamin D alone significantly reduces the risk of

falls in the elderly population (OR: 0.73; 95% CI: 0.54 to 0.98).

Figure A9.3: Meta-analysis of the effects of vitamin D alone, compared with placebo, on the risk

of falls

Source: Meta-analysis conducted for the purposes of this review, using Review Manager from the Cochrane Collaboration Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate number of people

who have had at least one fall and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the

overall meta-analysis.

A9.2 Effect of vitamin D supplementation on fractures

There was a single Cochrane systematic review of RCTs performed by Avenell and

colleagues (2009)(89)

which assessed the efficacy of supplementation with vitamin D or a

vitamin D-related compound in the reduction of hip, non-vertebral, vertebral or any new

fracture. It included 42 RCTs, one cluster randomised trial(153)

, and two quasi-randomised

trials(154, 155)

. The included RCTs compared vitamin D2, vitamin D3, or 25-(OH)D, with or

without co-administration of calcium, against placebo, no treatment or calcium alone.(89)

February 2014


Ten of the 42 RCTs evaluated the effects of vitamin D supplementation alone versus placebo

or no treatment on fracture reduction.(107, 150, 153, 154, 156-161)

Nine trials (24,749 participants)

compared vitamin D alone with placebo on the risk of hip fracture. Meta-analysis of these

trials showed no statistically significant reduction in hip fracture due to vitamin D

supplementation (RR: 1.15, 95% CI: 0.99 to 1.33, Figure A9.4).(89)

Figure A9.4: Meta-analysis of the effects of vitamin D supplementation alone compared with

placebo on new hip fracture

Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis (Review)(89)

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip

fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.

One trial of 3,440 participants showed no statistically significant effect of vitamin D alone

compared with placebo on non-vertebral fracture (RR: 0.96, 95% CI: 0.80 to 1.15). Figure

A9.5 presents a meta-analysis comparing the effects of vitamin D alone on the risk of

vertebral fractures. Based on five trials with 9,138 participants, there was no statistically

significant effect of vitamin D alone versus placebo on vertebral fracture or deformity (RR:

0.90, 95% CI: 0.42 to 1.92, Figure A9.5).(89)

February 2014



placebo on new vertebral fracture or deformity


Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of

vertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.

Figure A9.6 presents a meta-analysis of the effects of vitamin D alone on the risk of new

fracture. Based on ten trials with a total of 25,016 participants, there was no statistically

significant effect of vitamin D alone compared with placebo (RR: 1.01, 95% CI: 0.93 to 1.09,

Figure A9.6).(89)

February 2014



placebo on any new fracture


Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of any

fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.

Eight of the 42 RCTs evaluated the effect of vitamin D in combination with calcium

supplementation on the risk of hip, vertebral and any fracture.(122, 156, 157, 162-166)

Pooled data

from eight trials (46,658 participants) showed a statistically significant reduction in the risk of

hip fracture in the population receiving vitamin D plus calcium compared with placebo or no

treatment (RR: 0.84, 95% CI: 0.73 to 0.96, Figure A9.7).(89)

February 2014


Figure A9.7: Meta-analysis of the effects of vitamin D plus calcium supplementation compared

with placebo on new hip fracture: sub-group analysis by history of previous

fracture

Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis

(Review) (89) Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip

fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis

In the subgroup analyses shown in Figure A9.7 by history of prior fracture, there was no

evidence of a statistically significant reduction in effect of calcium plus vitamin D (four trials

with 6,134 participants, RR: 1.02, 95% CI: 0.71 to 1.47), but the pooled data from studies

where a previous osteoporotic fracture was not a selection criterion did show a statistically

significant reduction (four trials with 40,524 participants, RR: 0.81, 95% CI: 0.71 to 0.93,

Figure A9.7). The difference between subgroups did not reach statistical significance (P =

0.24).(89)

In the subgroup analysis by residential status (institution versus community, Figure A9.8),

there was a statistically significant reduction in hip fracture incidence in the institutionalised

residents subgroup (two trials with 3,853 participants, RR: 0.75, 95% CI: 0.62 to 0.92), but

not in the community dwelling group (six trials with 42,805 participants, RR: 0.91, 95% CI:

0.76 to 1.08). However, there was no statistically significant difference between subgroups (P

= 0.17).(89)

February 2014



with placebo on new hip fracture: subgroup analysis by residential status

Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis (Review) (89)

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of hip

fracture and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis

Nine of the 42 RCTs assessed the effects of vitamin D plus calcium supplementation in the

reduction of non-vertebral fractures.(122, 156, 157, 162-167)

Overall, supplementation with vitamin

D plus calcium was not associated with a statistically significant reduction in the incidence of

new non-vertebral fracture compared with placebo (nine trials with 46,781 participants, RR:

0.95, 95% CI: 0.90 to 1.01, Figure A9.9).

February 2014



with placebo on non-vertebral fracture: sub-group analysis by history of previous

fracture


Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of non-


In the subgroup analyses shown in Figure A9.9 by history of prior fracture, there was no

statistically significant reduction in non-vertebral fracture in participants selected on the basis

of prior fracture (four trials with 6,134 participants, RR: 0.93, 95% CI: 0.79 to 1.10, Figure

A9.9), or in participants not selected on the basis of prior fracture (five trials with 40,647

participants, RR: 0.95, 95% CI: 0.90 to 1.01, Figure A9.9). There was no statistically

significant difference between subgroups (P = 0.81).(89)

In the subgroup analysis by residential status (institution versus community: Figure A9.10),

there was a statistically significant reduction in new non-vertebral fracture incidence in the

institutional residents subgroup (two trials with 3,853 participants, RR: 0.85, 95% CI: 0.74 to

0.98), but not in the community dwelling group (seven trials with 42,928 participants, RR:

0.97, 95% CI = 0.91 to 1.02). There was no statistically significant difference between

subgroups (P = 0.09).(89)

February 2014


Figure A9.10: Meta-analysis of the effects of vitamin D and calcium supplementation as

compared with placebo on non-vertebral fracture: subgroup analysis by

residential status

Source: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis

(Review) (89)

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of non-vertebral fractures and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-

analysis.

Three of the 42 trials assessed the effects of vitamin D plus calcium supplementation

compared with placebo or no treatment on the reduction of vertebral fractures.(156, 162, 166)

There was no evidence of a statistically significant preventive effect on clinical vertebral

fractures from the administration of vitamin D plus calcium (three trials with 38,990

participants, RR: 0.91, 95% CI: 0.75 to 1.11, Figure A9.11).

February 2014


Figure A9.11: Meta-analysis of the effects of vitamin D and calcium supplementation compared

with placebo on new vertebral fracture: sub-group analysis by previous fracture


Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate numbers of


Overall, the meta-analyses did not show a statistically significant effect of vitamin D alone on

hip, vertebral, non-vertebral or any fracture. However, there was a statistically significant

reduction in the risk of new hip fracture in the population receiving vitamin D plus calcium

compared with placebo or no treatment. This effect was statistically significant in

institutionalised patients but not in community dwelling patients.

An attempt was made in one of the systematic reviews to evaluate the effect of vitamin D in

the prevention of osteoporosis in younger women (19-49 years old), but no RCTs conducted

among this age group were identified.(108)

In addition, there are currently no identified studies

that have investigated the link between serum 25-(OH)D levels with any outcome measure of

bone health (such as BMD, falls or fractures) in younger adults.

A9.3 Effect of vitamin D supplementation on cancer

Overall cancer risk

The AHRQ systematic review by Chung et al. (2009) included four RCTs(116, 143, 148, 150)

and

two cohort studies(168, 169)

that evaluated the effects of vitamin D on overall cancer risk.(9)

These studies are summarised in Table A9.1. The RCTs evaluated the effects of vitamin D

with or without calcium supplementation on cancer incidence or cancer mortality risk, with a

mean follow-up of four to seven years. In two RCTs(116, 150)

, colorectal cancer was evaluated

as a secondary outcome, the studies being originally designed to evaluate the effects of

vitamin D on fracture risk.

February 2014


Table A9.1: Summary of RCTs from the AHRQ systematic review by Chung et al. (2009)(9)

Study Population Outcome Sample

size Findings Summary of conclusions

Lappe et al.

(2007)(148)

Postmenopausal

women taking

either VitD3 1,000

IU +Ca 1,400-1,500

mg/day (n=446) or

Ca 1,400-1,500

mg/day (n=445) or

placebo (n=288)

Incidence of

any cancer

(secondary

endpoint)

Self-reported

(confirmed

in medical

record)

1,180 VitD+ Ca vs.

placebo RR: 0.402

(95% CI 0.2, 82)

Ca vs. placebo RR:

0.532 (0.27,1.03)

Excluding cancers

developed in yr 1

VitD+ Ca RR: 0.232

(0.09 , 0.6)

Completed the

study: 86.8%

Compliance: 85.7%

Association between

use of vitD and Ca and

reduced risk of cancer.

Logistic regression

does not take into

account censoring and

may affect the validity

of the results

Chlebowski

et al.

(2007)(143)

Postmenopausal

women receiving

either VitD 400 IU

+ Ca 1g vs. placebo

Participants were

allowed to use up to

600 IU (1,000 IU

later) and 1,000 mg

Ca/day in addition

to study drugs)

Medical

records

(blinded

investigators)

36,282 Breast cancer HR:

0.96 (0.86 , 1.07)

Several subgroups

evaluated

Age 70-79 yrs HR:

1.08 (0.82 , 1.43)

Baseline VD ≥

600IU 1.34 (1.01 ,

1.78

Compliance 60-63%

Authors mention

association between

higher calcium and

lower risk.

No association

between lower breast

cancer risk and higher

serum vitamin D levels

after adjusting for

body mass index

(BMI) and physical

activity in addition to

other variables (nested

case control).

Wactwaski-

Wende et al.

(2006)(116)

Postmenopausal

women receiving

either VitD 400 IU

+ Ca 1 g vs.

placebo

Participants were

allowed to use up to

600 IU (1,000 IU

later) and 1,000 mg

Ca/day in addition

to study drugs

Incidence of

any cancer

Secondary

endpoint

Self-reported

(confirmed

in medical

record)

36,282 Any cancer HR: 0.98

(0.91, 1.05) VitD vs.

placebo

Compliance: ~ 60%

No association

between VitD + Ca

and cancer vs. placebo.

Use of VitD and/or Ca

in addition to study

drugs may have biased

the results towards the

null.

Trivedi et

al.

(2003)(150)

Elderly men and

women taking

either vitamin D3

100,000 IU every

four months

equivalent to ~ 800

IU/day) or placebo

Incidence of

any cancer

Cancer

mortality

Self-reported

2,686 Any cancer RR 1.09

(95% CI: 0.86, 1.36)

Overall cancer

mortality RR 0.86

(98% CI: 0.61, 1.20)

Completed the

study: 76.5%

Compliance rate:

76%

No association

between VitD + Ca

and cancer vs. placebo

Lappe et al. (2007) conducted a four-year RCT designed to compare the effects of vitamin D3

(1,000 IU/day) plus calcium (1,400-1,500 mg/day) to a placebo and the same dose of calcium

alone, on the risk of fractures. Treatment effects on the risk of any type of cancer was a

secondary endpoint.(148)

The study included 1,179 healthy postmenopausal women (> 55

years old) without any known cancer, chronic kidney disease, or metabolic bone disease. All

women were white with a mean age of 66.7 ± 7.3 years and a mean baseline 25-(OH)D level

of 71.8 ± 20.3 nmol/L.(148)

Baseline characteristics by study group were not provided and the

authors did not mention if they were comparable, especially with regards to cancer risk

factors. An intention-to-treat (ITT) analysis with logistic regression was used. Cox

proportional hazards analysis was not used as, according to the authors, the assumption of a

February 2014


constant hazard ratio was not satisfied by their data. The authors did not, however, provide

additional information on how the violation occurred.(148)

A total of 1,024 of 1,180 (86.8%) subjects completed the study with treatment adherence

being 85.7% in the vitamin D and calcium group and 74.4% in the calcium group. Cancer

was diagnosed in 20 of 288 (6.9%) patients in the placebo group, 17 of 445 (3.8%) in the

calcium group, and 13 of 446 (2.9%) in the vitamin D and calcium group over four years of

follow-up. There was a 60% decrease in cancer risk with vitamin D and calcium compared to

placebo (unadjusted RR: 0.402, 95% CI: 0.20, 0.82) and a trend to risk reduction with calcium

compared with placebo (RR: 0.532, 95% CI: 0.27, 1.03). Excluding the cancer cases

diagnosed during the first year, the RR for vitamin D and calcium was 0.232 (95% CI: 0.09,

0.60) and 0.587 (95% CI: 0.29, 1.21) for calcium alone.(148)

The study by Lappe et al. (2007) had some limitations which included the use of logistic

regression to analyse time-to-event data, which may have led to bias since losses-to-follow-up

and censoring was not taken into account. In addition, demographic characteristics by study

group were not provided and the authors did not provide comment on whether the two groups

were comparable.

The RCT by Wactawski-Wende et al. (2006) was part of the Women’s Health Initiative

(WHI) study, which compared the effects of vitamin D (400 IU/day) and calcium (1,000

mg/day) to placebo on the risk of hip fractures (primary outcome), colorectal cancer

(secondary outcome), and other types of cancer.(116)

Women in both study groups were

allowed to take up to 600 IU/day of vitamin D (later increased to 1,000 IU) and up to 1,000

mg of calcium/day in addition to the study drug. The women included in the vitamin D and

calcium study had been participating for a year in a component of the WHI trial in which

women were randomised to either:

dietary interventions through a low-fat diet high in fruits and vegetables;

postmenopausal hormone therapy;

a combination of the two; or

placebo and usual diet.(170)

The effect of vitamin D plus calcium on overall cancer and colorectal cancer was evaluated

based on an ITT time-to-event analysis using a Cox proportional hazards model. A total of

36,282 postmenopausal women, 50 to 79 years old, without a history of hypocalcaemia or

renal calculi, not using corticosteroids or > 600 IU/day of vitamin D, were included (18,176 in

the vitamin D plus calcium group and 18,106 in the placebo group). The results were

stratified by age, colorectal cancer history, and hormone therapy/dietary modification study

group assignment. The mean follow-up was 7 ± 1.4 years. Treatment compliance was low in

both groups, at approximately 60%. This study reported that there was no statistically

significant difference in the overall risk of cancer with vitamin D plus calcium compared to

placebo (HR: 0.98, 95% CI: 0.91, 1.05). There were 1,634 cases (1.28% per year) in the

combination group and 1,655 (1.30%/ per year) in the placebo group. Despite being a large

study, the fact that vitamin D plus calcium intake in addition to the study drug was allowed, as

well as a relatively low compliance rate, may have contributed to the lack of a statistically

significant difference between the study groups.

The RCT by Trivedi et al. (2003) (150)

evaluated the effect of vitamin D3 (100,000 IU every

four months) compared to placebo on the risk of fracture and overall mortality in 2,686 men

February 2014


and women, 65 to 85 years old, selected from the Doctors Study Register in the UK.(150)

Cancer incidence was a secondary outcome. The two groups were comparable with regards to

demographic characteristics with a mean participant age of 74 ± 4.6 years. The mean calcium

intake of 742 mg/day at four years did not differ between the study groups. The compliance

rate was approximately 76% and did not differ between the study groups. There were 188

(14%) cancer cases reported in the treatment group and 173 (13%) in the control group. After

a follow-up of five years, there were no statistically significant differences between the study

groups with regards to both incidence of cancer (RR: 1.09, 95% CI: 0.86, 1.36) and overall

cancer mortality (RR: 0.86, 98% CI: 0.61, 1.20).

In addition to the three RCTs, there were two cohort studies identified in the AHRQ

systematic review by Chung et al. (2009)(9)

. Both studies used participants of the Third

National Health and Nutrition Examination Survey (NHANES III), which included a national

sample of non-institutionalised subjects in the US.(168, 169)

Both evaluated the association

between baseline serum 25-(OH)D and rate of cancer mortality over a mean follow-up of

eight years. Therefore, the effect of vitamin D intake on cancer mortality was not directly

evaluated. Moreover, there was limited adjustment for potential confounders that may have

affected serum vitamin D levels in the analysis (e.g. adjustment for calcium intake was not

done in these studies).

The first study by Freedman et al. (2007)(168)

included 16,818 men and women over the age of

17. A cox proportional hazards analysis adjustment for age, ethnicity and smoking was used.

Baseline serum 25-(OH)D was divided into quintiles and the rate of cancer mortality over

eight years of follow-up was compared among the quintiles. The mean age varied between 40

and 45 years depending on the baseline 25-(OH)D. In total, there were 536 deaths due to

cancer but no association between baseline 25-(OH)D and cancer mortality over the eight

years of follow-up.(168)

The second study by Melamed et al. (2008)(169)

evaluated the association between baseline 25-

(OH)D and overall mortality. Cancer mortality was a secondary endpoint, along with

mortality due to cardiovascular disease, infectious disease, or external causes. Participants

included men and women over the age of 20 who were given both a baseline 25-(OH)D

measurement and a physical examination. The baseline serum 25-(OH)D was divided into

quartiles and the rate of cancer mortality over eight years of follow-up was compared among

quartiles. A total of 13,331 participants were included with a mean age of 42 to 46 years,

depending on the baseline 25-(OH)D quartile. In total, 424 deaths due to cancer occurred but

no association was found between baseline 25-(OH)D levels and cancer mortality over the

eight-years of follow-up.(169)

Colorectal cancer

Only two RCTs (116, 150)

were identified that evaluated the effects of vitamin D with or without

calcium supplementation on risk of colorectal cancer and colorectal adenocarcinoma in men

and women aged 50 years and older (Table A9.1). In both RCTs, colorectal cancer was

evaluated as a secondary outcome, the studies being originally designed to evaluate the effects

of vitamin D on fracture risk. The two RCTs reported no association between vitamin D with

or without calcium and the incidence of colorectal cancer or colorectal adenocarcinoma, with

a mean follow-up of five to seven years.(116, 150)

However, despite not finding an association

between vitamin D use and the risk of colorectal cancer, the WHI RCT found that subjects

with higher baseline serum 25-(OH)D had a lower risk of colorectal cancer (P for trend:

0.02).(116)

February 2014


Despite the inconsistent findings of the two RCTs, authors of the 2011 AHRQ report

calculated pooled ORs for risk of cancer per 10 nmol/L increase in serum 25-(OH)D, with

adjustment for as many potential confounders as possible. An inverse (and thus protective)

association was found between high vitamin D levels and reduced risk of colorectal cancer.

Similarly, a more recent meta-analysis performed by Touvier et al. (2012)(109)

observed a

significant inverse association between increases of 100 international units per litre (IU/L) in

serum 25-(OH)D and reduced risk of colorectal cancer.(109)

Therefore, despite the evidence from prospective cohort studies supporting the protective

effect of high serum vitamin D levels in reducing the risk of colorectal cancer, RCTs

establishing the same association are still lacking.

Breast cancer

The review by Chung et al. (2009)(9)

identified two RCTs(143, 150)

that assessed the effects of

vitamin D, with or without calcium, on the risk of breast cancer. Similar to the trials

evaluating the efficacy of vitamin D in colorectal cancer, the RCTs were originally designed

to evaluate bone health outcomes. Neither of the RCTs (mean follow-up of five and seven

years) showed an association between vitamin D and breast cancer risk. In the study by

Chlebowski et al. (2008)(143)

, a higher baseline vitamin D level was not associated with a

decrease in breast cancer risk after adjusting for BMI and physical activity, in addition to

other variables (nested case-control analysis).

Prostate cancer

No RCTs evaluating the effects of vitamin D supplementation, with or without calcium, on

prostate cancer risk were identified. However, the AHRQ systematic review by Chung et al.

(2009)(9)

identified 11 nested case-control studies that evaluated the association between

baseline serum vitamin D levels and prostate cancer risk.(171-181)

Prostate cancer risk was a

secondary outcome in most of these studies. Sample sizes ranged from 61 to 749 subjects

with mean ages between 44 and 68 years. Follow-up periods ranged from two to 16 years.

The results obtained in the observational studies were inconsistent. One study found an

increased risk of prostate cancer (OR: 1.7; 95% CI: 1.1, 2.4) in subjects with higher serum

vitamin D levels (25-(OH)D 80 nmol/L) vs. lower levels (40-49 nmol/L).(171)

Another study

found a protective effect of vitamin D but only in men younger than 52 years (OR 3.5; 95%

CI: 1.7, 7.0; ≤ 40 nmol/L vs. > 40 nmol/L)(172)

. A third study reported that the lowest risk of

prostate cancer is associated with the normal average serum concentration of 25-(OH)D (40–

60 nmol/l).(181)

The remaining eight observational studies did not find a significant

association between serum vitamin D and prostate cancer risk.(9)

A9.4 Effect of vitamin D supplementation on cardiovascular disease

Four publications related to two RCTs(142, 145, 147, 150)

evaluated the effects of vitamin D, with

or without calcium, on the development of cardiovascular disease. However, both RCTs were

originally designed to evaluate the effect of vitamin D on fractures (compared to placebo).

No statistically significant association between vitamin D, with or without calcium

supplementation, and cardiovascular outcomes were found in the two RCTs. The first RCT

by Trivedi et al. (2003)(150)

evaluated the effect of vitamin D3 (100,000 IU every four months)

compared to placebo on fractures and overall mortality in 2,686 men and women, aged 65 to

85 years old, selected from the Doctors Study Register in the UK.(150)

The mean calcium

intake at four years of 742 mg/day did not differ between the study groups. The authors

February 2014


reported non-significant estimates favourable to vitamin D alone: an RR of 0.90 (95% CI:

0.77 to 1.06) for incidence of CVD and an RR of 0.84 (95% CI: 0.65 to 1.10) for CVD

mortality. Therefore, after a follow-up of five years, there was no statistically significant

difference between the study groups with regards to several cardiovascular outcomes and

cardiovascular death (Table A9.2).(150)

Three studies were analyses derived from the WHI trial, which randomised 36,282

postmenopausal women to daily supplementation with 400 IU vitamin D plus calcium or

placebo.(142, 145, 147)

The cardiovascular outcomes evaluated were secondary endpoints. One

of the WHI study analyses evaluated the effect of vitamin D supplementation on the

development of hypertension and detected no effect.(145)

In the study by Hsia et al. (2007)(147)

,

vitamin D plus calcium had no overall effect on a composite measure of coronary artery

disease mortality or myocardial infarction, or on the incidence of stroke, coronary

revascularisation, heart failure, angina, or transient ischemic attack. Therefore, no statistically

significant association between vitamin D, with or without calcium, and cardiovascular

outcomes was observed. The authors concluded that there was no evidence of increased or

decreased risk in cardiovascular outcomes with vitamin D and calcium.(142, 147)

Table A9.2: Summary of RCTs evaluating the effect of vitamin D, with or without calcium, on

cardiovascular disease

Study Population Outcome Sample

size Findings

LaCroix et

al.

(2009)(142)

Margolis

et al.

(2008)(145)

Hsia et al.

(2007)(147)

Postmenopausal

women receiving

either VitD 400

IU + Ca 1 g vs.

placebo

Participants were

allowed to use up

to 600 IU (1,000

IU later) and

1,000 mg Ca/day

in addition to

study drugs

Cardiovascular

outcomes and

mortality

Self-reported and

confirmed in

medical records

36,282 MI: 1.05 (0.91, 1.20)

Coronary artery bypass graft or PCI:

1.08 (0.98, 1.22)

Hospitalised for heart failure: 0.95

(0.83, 1.10)

Angina: 1.08 (0.94, 1.24)

Stroke: 0.95 (0.82, 1.10)

TIA: 1.16 (0.95, 1.42)

Composite (stroke, TIA):1.02 (0.91,

1.15)

Cardiac composite (MI, CHD, death,

CABG, or PCI): 1.08 (0.99, 1.19)

Cardiac composite (MI or CHD

death): 1.04 (0.92, 1.18)

Cardiovascular death: 0.92 (0.77,

1.07)

Coronary heart disease death: 1.01

(0.79, 1.29)

Cerebrovascular death: 0.89 (0.62,

1.29)

Trivedi et

al.

(2003)(150)

Elderly men and

women taking

either VitD3

100,000 IU every

four months

equivalent to ~

800 IU/day) or

placebo

Cardiovascular

outcomes

(secondary

endpoint)

From death

certificate or self-

reported in

questionnaire

Multiple outcomes

evaluated

2,686 Cardiovascular disease (CVD) HR

0.90 (95% CI: 0.77, 1.06)

Ischemic heart disease (IHD) HR 0.94

(95% CI: 0.77, 1.15)

Cerebrovascular disease: HR 1.02

(95% CI: 0.77, 1.36)

CVD death: HR 0.84 (95% CI: 0.65,

1.10)

IHD death: HR 0.84 (95% CI 0.56,

1.27)

Cerebrovascular disease death: HR

1.04 (95% CI: 0.61, 1.77)

February 2014


A9.5 Effect of vitamin D supplementation on type 2 diabetes

The 2012 HTA identified three RCTs that evaluated the effect of vitamin D supplementation

on diabetes outcome measures in healthy adults(139, 144, 182)

. An analysis of data derived from

the WHI study showed that supplementation (400 IU/day plus calcium) had no effect on the

incidence of diabetes over a seven-year follow-up.(144)

Another study that enrolled 104 adults

(mean age 52 to 53 years) found that vitamin D supplementation (equivalent of 2,857 IU/day

without calcium) for six months had no effect on serum levels of glycated haemoglobin.(139)

A third study using the same dose of vitamin D observed no effect on blood glucose at one or

two years.(182)

Overall, the results suggest that supplementation with vitamin D has no effect

on the incidence of diabetes or diabetes markers in adults. However, the overall quality of the

evidence is low due to the small number of studies and intermediate outcome measures in the

two smaller studies.

Although not directly evaluating the effects of vitamin D supplementation, a recent systematic

review and meta-analysis evaluating the effect of vitamin D levels on type 2 diabetes was

performed up to August 2012 by Khan et al. (2013)(183)

. It included 18 prospective studies,

comprising 210,107 participants, reporting association of circulating or dietary vitamin D with

incident type 2 diabetes, metabolic syndrome and insulin resistance (IR) outcomes. The

included studies collected a total of 15,899 metabolic events during a median follow up of 10

years (range 3-22 years). The RR for individuals in top versus bottom thirds of baseline

vitamin D were 0.81 (95% CI 0.71, 0.92); 0.86 (95% CI 0.80, 0.92); and 0.84 (95% CI 0.64,

1.12) for type 2 diabetes, metabolic syndrome and IR outcomes, respectively. Findings were

generally consistent across various study-level characteristics.

Another systematic review and meta-analysis conducted by Forouhi et al. (2012)(184)

included

new data from two previously unpublished studies, the European Prospective Investigation

into Cancer (EPIC)-Norfolk study(184)

, which is a nested case-cohort study, and the Ely

prospective study(185)

. The systematic review included 11 prospective studies (3,612 cases

and 55,713 non-cases) on the association between serum 25-(OH)D concentration and

incident type 2 diabetes published until January 2012. The authors performed a meta-analysis

combining available evidence with results from the EPIC-Norfolk and Ely studies. In the

EPIC-Norfolk, baseline 25-(OH)D was lower among incident type 2 diabetes cases (mean

[SD] 61.6 [22.4] nmol/L; N=621) vs non-case sub-cohort participants (mean 65.3 [23.9]

nmol/L; N=826). There was an inverse association between baseline 25-(OH)D and incident

type 2 diabetes in multivariable-adjusted analyses: HR 0.66 (95% CI: 0.45, 0.97), 0.53 (95%

CI: 0.34, 0.82), 0.50 (96% CI: 0.32, 0.76), comparing consecutive increasing 25-(OH)D

quartiles with the lowest. In the Ely study (185)

, 37 incident type 2 diabetes cases were

identified among 777 participants. In meta-analysis shown in Figure A9.12, the combined RR

of type 2 diabetes comparing the highest with lowest quartile of 25-(OH)D was 0.59 (95% CI:

0.52, 0.67). Therefore, these findings demonstrate an inverse association between circulating

25-(OH)D and incident type 2 diabetes.

February 2014


Figure A9.12: Meta-analysis of the effects of serum 25-(OH)D on incident type 2 diabetes

Source: Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the EPIC-Norfolk cohort and updated meta-analysis of prospective studies(184)

The sizes of the boxes for individual studies are inversely proportional to the variances of log RRs, and horizontal lines represent 95% CI.

All analyses were performed using Stata/SE10.1 (Stata, College Station, TX, USA)

The systematic review by Mitri et al. (2011)(186)

examined the association between serum

vitamin D status and incident type 2 diabetes, and the effect of vitamin D supplementation on

glycaemic outcomes. It included eight longitudinal cohort studies and 11 RCTs published

until February 2011. In the meta-analyses of four observational studies shown in Figure

A9.13, vitamin D intake >500 IU/day decreased the risk of type 2 diabetes by 13% (RR: 0.87,

95% CI: 0.76-0.99) compared with vitamin D intake<200 IU/day.

Figure A9.13: Meta-analysis of the effects of higher vitamin D intake as compared to lower

vitamin D intake on incident type 2 diabetes

Source: Vitamin D and type 2 diabetes: a systematic review(186) Horizontal lines represent 95% CI. All analyses were performed using Comprehensive Meta-Analysis version 2.2.050 (Biostat, Englewood,

NJ, USA)

Figure A9.14 shows the combined data from seven longitudinal studies that found that a

serum 25-(OH)D concentration > 25 ng/mL (62.5 nmol/L), compared with a concentration <

February 2014


14 ng/mL (35 nmol/L), was associated with a statistically significant reduction in the

incidence of type 2 diabetes at 1.3 to 22 years (43%, 95% CI: 24%, 57%).

Figure A9.14: Meta-analysis of the effects of higher blood 25-(OH)D as compared with lower

blood 25-(OH)D on incident type 2 diabetes

Source: Vitamin D and type 2 diabetes: a systematic review(186)

Horizontal lines represent 95% CI. All analyses were performed using Comprehensive Meta-Analysis version 2.2.050 (Biostat, Englewood,

NJ, USA)

In post hoc analyses from eight trials among participants with normal glucose tolerance at

baseline and in three small underpowered (n=32 to 62) trials of patients with established type

2 diabetes, there was no effect of vitamin D supplementation on glycaemic outcomes. In two

trials among patients with baseline glucose intolerance, vitamin D supplementation improved

insulin resistance. The authors of the review did not perform meta-analysis on any of the 11

included RCTs because the trials were too heterogeneous. The authors concluded that

vitamin D may play a role in type 2 diabetes; however, to better define the role of vitamin D

in the development and progression of type 2 diabetes, high-quality observational studies and

RCTs that measure serum 25-(OH)D concentration and clinically relevant glycaemic

outcomes are needed.(186)

In summary, vitamin D status at baseline in apparently healthy adults is inversely associated

with future risks of type 2 diabetes and metabolic syndrome. However, reliable evidence

from adequately dosed randomised trials of vitamin D supplementation is needed to confirm

the observational findings.

A9.6 Effect of vitamin D supplementation on the risk of obesity

The 2012 HTA published by Washington State Health Care Authority(27)

reported that there

were no observational studies which assessed the association between vitamin D status and

the presence or risk of obesity; however, two RCTs were identified that evaluated the effect of

vitamin D supplementation on body weight or development of obesity(141, 146)

. The study by

Caan et al. (2007)(146)

was derived from the WHI trial and enrolled only postmenopausal

women. It included 22,827 participants who were not obese at baseline. The authors reported

that over a seven-year follow-up, slightly less weight gain was observed among the non-obese

participants who were randomised to vitamin D, although the prescribed dose of vitamin D

was relatively low (400 IU/day): –0.08 kg (95% CI: –0.23 to 0.06) for normal-weight

individuals and –0.09 kg (95% CI: –0.22 to 0.04) for overweight individuals. The RCT by

Daly and Nowson (2009)(141)

enrolled Caucasian men (N=167). Participants were, on average,

middle-aged (mean age 61 years) and mildly overweight (BMI 26.2). Men were randomised

to the treatment group of 400 IU/day of vitamin D3 added to milk. No effect on weight

February 2014


change over a two-year period was observed, and, in fact, neither group exhibited meaningful

weight changes. Therefore, these two fair-quality studies did not demonstrate an effect in

middle-aged to older non-obese adults.(27)

There was one RCT that compared the effects of two hypocaloric diets in overweight or obese

women which found that the diet associated with greater weight loss also led to greater

vitamin D intake and a greater mean increase in serum 25-(OH)D levels.(187)

However, no

conclusions about causality can be drawn from this study.

A9.7 Effect of vitamin D supplementation on multiple sclerosis

The 2012 HTA did not identify any RCTs that examined the effect of vitamin D

supplementation on the incidence of MS.

A9.8 Effect of vitamin D supplementation on mood disorders

The 2012 HTA published by Washington State Health Care Authority(27)

identified three

RCTs (4,625 participants) that evaluated the effect of vitamin D on mental health in

unselected populations (all postmenopausal women or elderly adults).(140, 149, 188)

The three

RCTs were rated as fair- to good-quality; the overall body of evidence was considered to be

of moderate quality. Baseline serum 25-(OH)D was not reported for the overall study group

in any of these trials. A wide range of supplementation regimens were used across the trials,

from 400 IU/day vitamin D plus calcium to 1,370 IU/day vitamin D alone. Follow-up ranged

from 6 months to 5 years. Overall, supplementation had no effect on the mental component

score of the SF-12 Health Survey questionnaire(140, 149)

, the Profile of Mood States

questionnaire(188)

, or the General Health Questionnaire(140)

. The World Health Organization

Well-Being Index and the Patient Global Impression Improvement Scale was also assessed in

a subgroup of 118 participants and no treatment effect of vitamin D was apparent.(140)

A9.9 Effect of vitamin D supplementation on all-cause mortality

Two good quality studies provided evidence for all-cause mortality. Trivedi et al. (2003)(150)

evaluated the effect of vitamin D3 100,000 IU every four months (approximately 833 IU/day)

for five years in 2,686 men and women, aged 65 to 85 years old. Approximately 28% of

participants had CVD at baseline. The RR of all-cause mortality favoured supplementation

but was not statistically significant (RR: 0.88, 95% CI: 0.74 to 1.06). A second report

analysed data from the WHI study, which randomised 36,282 postmenopausal women to daily

supplementation with 400 IU vitamin D plus calcium or placebo for seven years.(142)

The HR

for all-cause mortality was 0.91 (95% CI: 0.88 to 1.01).

Evidence was also available from a Cochrane Review with pooled data from 50 RCTs (94,148

participants) to assess the effect of vitamin D supplementation on mortality in adults.(117)

The

studies were not analysed according to population or indication. Overall, the review found

that vitamin D decreased mortality (RR: 0.97, 95% CI: 0.94 to 1.00).

A9.10 Effect of vitamin D supplementation on maternal and neonatal outcomes

The Cochrane review by De-Regil et al. (2012)(113)

examined whether vitamin D alone or in

combination with other micronutrients given during pregnancy improved maternal and

neonatal outcomes. It included six RCTs (total of 1,023 women), five of which were

published in the 1980s(189-193)

and one in 2009(194)

. Five RCTs compared the effects of

vitamin D alone versus no supplementation/placebo(189-192, 194)

and one trial compared the

effects of vitamin D and calcium versus no supplementation(193)

. The outcomes measured in

February 2014


these studies were pre-eclampsia, gestational diabetes, serum vitamin D levels, baby birth

weight and adverse events.

The study by Marya et al. (1987)(193)

reported that: women who received 1,200 IU of vitamin

D along with 375 mg of elemental calcium per day were as likely to develop pre-eclampsia as

women who received no supplementation (RR: 0.67; 95% CI: 0.33 to 1.35).

Data from four trials involving 414 women consistently showed that women who received

vitamin D supplements had higher concentrations of vitamin D in serum at term than those

women who received no intervention or a placebo; however, the magnitude of the response

was highly heterogeneous.(189-191, 194)

Data from three trials involving 463 women suggested that women who receive vitamin D

supplements during pregnancy less frequently had a baby with a birth weight below 2,500

grams than those women receiving no treatment or placebo; statistical significance was

borderline (RR: 0.48; 95% CI: 0.23 to 1.01).(189, 191, 192)

Only the study by Yu et al. (2009) assessed the safety of vitamin D supplementation during

pregnancy. There were no significant differences in adverse side effects, including nephritic

syndrome, stillbirths or neonatal deaths, between women who received vitamin D

supplements in comparison with women who received no treatment or placebo.(194)

In addition to the six included trials, three publications based on two RCTs(195-197)

are

published post the Cochrane review by De-Regil et al. (2012). The AViDD trial by Baqui and

colleagues (2013)(196)

evaluated the effect of high-dose vitamin D3 supplementation (35,000

IU/week till delivery) administered prenatally during the 3rd

trimester on maternal and

neonates (assessed by measuring cord blood 25-(OH)D concentration). It included 160

pregnant women from Bangladesh randomised to either a placebo group (N=80) or

intervention group (N=80). Mean maternal 25-(OH)D concentration was significantly higher

in the intervention group at term when compared to placebo (134 vs. 38 nmol/L; P < 0.001).

Similarly, neonates serum 25-(OH)D concentration was also significantly higher in the

mothers who received vitamin D supplementation compared with the placebo group (cord

blood: 103 vs. 39 nmol/L; P < 0.001). More importantly, there were no reported adverse

events (e.g. hypercalcemia) due to the administration of the relatively high dose of vitamin D

supplementation in pregnant women.

The same research team performed a preceding pilot trial in Dhaka, Bangladesh (N=28

pregnant women) and found that 3rd

trimester regimens of 14,000 IU/week (≈2000 IU/day)

and 35,000 IU/week (≈5000 IU/day) led to mean 25-(OH)D concentrations of 76 nmol/L (rise

of 36 nmol/L) and 98 nmol/L (rise of 57 nmol/L), respectively, following 10 weeks of

supplementation (until delivery).(195)

The recent study by Soheilykhah et al. (2013)(197)

evaluated the effects of three different doses

of vitamin D on insulin resistance (IR) during pregnancy. This was an un-blinded RCT (thus

potential high risk of bias) done on 120 women (during the first trimester of pregnancy until

delivery). The pregnant women were randomised to three groups receiving three different

doses of vitamin D (200 IU/day, 50,000 IU/month and 50,000 IU/2 weeks). The increase in

the mean serum 25-(OH)D concentration was greatest in the 50,000 IU/2 weeks group (from

7.3 to 34.1 ng/ml) when compared to the 50,000 IU/month group (increased from 7.3 to 27.23

ng/ml) and the 200 IU/day group (increased from 8.3 to 17.7 ng/ml) (P < 0.001). The mean

differences of insulin and IR before and after intervention in the 200 IU/day and the 50,000

February 2014


IU/2 weeks were significant (P = 0.01, P = 0.02). This study shows that supplementation of

pregnant women with 50,000 IU vitamin D every two weeks improved IR significantly.

There are no systematic reviews of RCTs evaluating the effects of vitamin D supplementation

(or serum levels of vitamin D concentration) on the risk of gestational diabetes. The

systematic review and meta-analysis performed by Poel et al. (2012)(198)

was based on the

analyses of results from seven cross-sectional or case control studies and included no RCTs.

The authors of this review found that serum 25-(OH)D < 50 nmol/L was significantly

associated with gestational diabetes.(198)

In summary, vitamin D supplementation up to 5000 IU/day (35,000 IU/week) in the third

trimester of pregnancy is considered to be safe and increases serum vitamin D concentrations

≥ 80 nmol/L in virtually all mothers and newborns. However, the role and clinical

significance of vitamin D supplementation, as well as the significance of optimal serum 25-

(OH)D concentration (levels exceeding 80 nmol/L), in pregnancy remains unclear. There are

currently six RCTs in progress that are further evaluating the clinical significance of vitamin

D during pregnancy.

A9.11 Effect of vitamin D supplementation on children and adolescents

One large RCT by Kumar et al. (2011)(199)

evaluated the effect of supplementation in young

children. The RCT demonstrated that a high dose of vitamin D (1400 IU/day) over a six-

month period improved most anthropometric measures in low-birthweight infants in India, but

health outcomes were not affected. Loss to follow-up was high. No relevant studies

evaluating the non-skeletal effects of vitamin D supplementation on growth-related outcome

measures in older children and adolescents were identified.

February 2014


APPENDIX 10 – Review of the effectiveness of supplementation in patients with chronic disease

The 2012 Hayes, Inc. HTA for the Washington State Health Care Authority(27)

identified three

systematic reviews and 16 RCTs (18 publications) that evaluated the effect of vitamin D

supplementation on disease-related outcomes in patients with chronic disease:

obesity

poor musculoskeletal health;

cancer;


type 2 diabetes;

multiple sclerosis;

depression and other mood disorders; and

all-cause mortality.

A10.1 Effect of vitamin D supplementation on obesity

The 2012 HTA included eight RCTs involving 32,111 randomised participants with a BMI >

25 kg/m2 (146, 200-206)

. Study quality was generally good in the analyses involving > 400

participants but was fair in smaller studies (which had dropout rates exceeding 20% and no

ITT analysis). Participants were generally in early middle age and more women than men

were included. Vitamin D dosage varied from 300 IU/day to 5714 IU/day, with most

participants also receiving calcium supplementation. Overall, there was no effect on weight-

related outcomes or cardiometabolic outcomes, including weight or other measures of obesity,

blood pressure, or glycemia measures. No studies analysed the effect on blood pressure

according to baseline values. However, additional large trials using doses in the higher range

could change these results, especially with the analysis of baseline measures of blood pressure

and glycemia. Evidence relating to mortality or cardiovascular events in obese individuals is

lacking.

A10.2 Effect of vitamin D supplementation on poor musculoskeletal health

A recent review evaluated vitamin D supplementation for patients with osteoporosis.(125)

The

report included 17 RCTs with patients selected on the basis of a diagnosis of osteoporosis or

indirect evidence of poor musculoskeletal health (such as a history of vertebral fracture).

Study participants (N=2,547 in total across the 17 RCTs) were generally vitamin D deficient.

The evidence suggests that inactive vitamin D at doses of 800 to 1400 IU/day is not effective

for improving bone health in patients who have a history of fracture. Two RCTs evaluated

vitamin D3 plus calcium in patients with a history of fracture consistent with osteoporosis.

The effect on BMD at different sites varied widely; where positive effects were observed,

they were very small. In contrast, three RCTs comparing active vitamin D (calcitriol or

synthetic analogs) with control found it to be effective in maintaining or improving BMD.

Two RCTs found that active vitamin D was more effective than inactive vitamin D for

maintaining or improving BMD and/or reducing fractures and falls. Four RCTs found that

active vitamin D was less effective than bisphosphonates and one RCT found that active

vitamin D was less effective than hormone replacement therapy. However, five RCTs

showed that active vitamin D as an add-on to either bisphosphonate or hormone replacement

therapy was more effective than bisphosphonates or HRT alone, suggesting that active forms

February 2014


of vitamin D may improve the effectiveness of some pharmaceutical treatment for poor bone

health.

A10.3 Effect of vitamin D supplementation on cancer

One systematic review evaluated vitamin D in cancer patients.(126)

The review identified three

RCTs (total N=1273), all of which involved patients with advanced prostate cancer. The

RCTs were considered to be of fair quality, although two were subject to bias because of early

stopping based on interim analysis. The results relating to overall survival were conflicting

and pooled estimates were imprecise.

A10.4 Effect of vitamin D supplementation on cardiovascular disease

The 2012 HTA report by WA Health Care Authority identified a systematic review by

Witham et al. (2009)(110)

that evaluated the effect of vitamin D supplementation on blood

pressure (BP). It included 11 RCTs involving participants (< 545 participants in total) with

hypertension, defined as systolic blood pressure (SBP) > 140 mmHg and diastolic blood

pressure (DBP) > 90 mmHg.(27, 110)

Inactive vitamin D (D2 or D3) doses fell within the range

of 800 to 2,000 IU/day. The authors performed a meta-analysis of the difference in blood

pressure change and found a small beneficial effect: –3.6 mmHg (95% CI: –8.0 to 0.7; Figure

A10.1) for SBP and –3.1 mm Hg (95% CI: –5.5 to 0.6; Figure A10.2) for DBP. The authors

cited evidence suggesting that a reduction in SBP of 3 mmHg would correspond to 10%

reduction in cardiovascular deaths on a population level.(27)

Figure A10.1: Meta-analysis showing the effects of vitamin D on systolic blood pressure

Source: Effect of vitamin D on blood pressure: a systematic review and meta-analysis (110)

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate mean difference in

systolic blood pressure and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall

meta-analysis.CI, confidence interval, SD, standard deviation, WMD, weighted mean difference.

February 2014


Figure A10.2: Meta-analysis showing the effects of vitamin D on diastolic blood pressure

Source: Effect of vitamin D on blood pressure: a systematic review and meta-analysis (110)

Diamonds display meta- analysis results centred on pooled estimates and extending to 95% CI. Squares and lines indicate mean difference in

diastolic blood pressure and 95% CI for individual studies. The size of the boxes is proportional to the weight of each study in the overall meta-analysis.CI, confidence interval, SD, standard deviation, WMD, weighted mean difference.

Subgroup analysis suggested a greater effect on SBP in trials using inactivated vitamin D (D2

or D3) than in trials using activated vitamin D (calcitriol or synthetic analogues) (-6.18

mmHg, 95% CI: -12.32 to -0.04 vs +0.71 mmHg, 95% CI: -4.81 to 6.23; Figure A10.1).

However, the difference in the effect between the two trial subgroups was not significant.(27,

110) Therefore, the meta-analysis performed by Witham et al. (2009)

(110) suggested a small but

potentially clinically meaningful reduction in SBP associated with vitamin D

supplementation, and an uncertain effect on DBP, in patients with hypertension.

Two RCTs evaluated vitamin D in patients with congestive heart failure. An RCT (N=93

evaluable patients) comparing vitamin D3 (2000 IU/day) plus calcium with calcium plus

placebo found no difference in physiological measures at 9 months and no difference in

cumulative survival at 15 months.(137)

However, this study was considered to be of poor

quality and there was a substantial withdrawal of sicker patients. Another RCT (N=105)

randomised patients with chronic heart failure to two administrations of 100,000 IU of

vitamin D2 at baseline and 10 weeks, or placebo, in order to assess the effect on function and

quality of life.(136)

At 20 weeks, there was no difference in measures of function (according to

the Functional Limitations Profile or six-minute walk time) but a significant difference

favouring vitamin D2 in quality of life (assessed using the Minnesota Living with Heart

Failure Questionnaire).

A10.5 Effect of vitamin D supplementation on type 2 diabetes

The 2012 HTA identified a total of 12 RCTs involving individuals with abnormal blood

glucose (frank diabetes, impaired glucose control, or insulin resistance). Eight of the RCTs

(with a total of 707 patients) were identified from two systematic reviews(111, 112)

, one of

which conducted a meta-analysis. An additional four RCTs (297 randomised participants)

were selected involving patients with frank type 2 diabetes, abnormal blood glucose and high

risk of type 2 diabetes or gestational diabetes.(127-130)

Trial quality was considered to be fair.

Active vitamin D or very high doses of inactive vitamin D were used in these trials, most of

which did not combine calcium with vitamin D. No studies showed harmful effects.

Among 11 trials that reported measures of glycemia (fasting plasma glucose or HbA1C) or

insulin resistance, the estimates of differences in change between vitamin D and control

February 2014


groups consistently favoured vitamin D but ranged from negligible in magnitude and

statistically non-significant, to uncertain because of very wide confidence intervals, to

statistically significant but small in magnitude. Evidence from 6 RCTs evaluating an effect

on insulin resistance was inconsistent. Three trials were consistent in showing no effect on

blood pressure. A single trial found no effect on albuminuria. Evidence relating to other

outcomes, such as weight control or renal function, was insufficient.

A10.6 Effect of vitamin D supplementation on multiple sclerosis

The Cochrane review by Jagannath et al. (2010)(114)

evaluated the effect of vitamin D on MS

and included a single RCT by Burton et al. (2010)(134)

. The trial included 49 patients with MS

and was conducted over 52 weeks. Patients were treated with escalating doses of vitamin D

plus calcium (N=25) compared with control (N=24). All of the patients were permitted to

continue personal use of supplements. The trial provided some evidence of the potential

benefit of high vitamin D doses on the reduction of annualised relapse rate, Expanded

Disability Status Scale (EDSS) scores, and suppression of T-cell proliferation. There were no

adverse events reported over the study period. However, the authors of the review judged the

included RCT to be a low powered trial with a potential high risk of bias (due to the lack of

allocation concealment and blinding), thus limiting the evidence on the use of vitamin D in

MS.

Three publications based on two RCTs(131, 207, 208)

were published after the 2010 Cochrane

review. The small study by Soilu-Hanninen et al. (2012)(131)

evaluated the effectiveness and

safety of vitamin D3 in conjunction with interferon β-1b (IFNB) in patients with MS. This

was a double-blind placebo-controlled trial that recruited 66 MS patients randomised to either

vitamin D supplementation or placebo. The authors reported a median change in the primary

outcome measure of T2 Burden of Disease (BOD) on MRI scan5 of 287 mm

3 in the placebo

group and 83 mm3 in the vitamin D group (P=0.105). In addition, serum levels of 25-(OH)D

increased two-fold from a mean of 54 (range 19-82) nmol/L to 110 (range 67-163) nmol/L in

the vitamin D group (with 84% of patients reaching a serum 25-(OH)D level >85 nmol/L in

the vitamin D group vs 3% in the placebo group (P<0.0001)). Patients in the vitamin D group

showed fewer new T2 lesions (P=0.286) and a significantly lower number of T1 enhancing

lesions (P=0.004), as well as a tendency to reduced disability accumulation (P=0.071) and to

improved timed tandem walk (P=0.076). There were no significant between-group

differences in adverse events or in the annual relapse rate. The authors of the study concluded

that vitamin D3 in conjunction with IFNB reduces MRI disease activity in MS.(131)

The

authors of this study did not evaluate the effect of vitamin D supplementation alone on the

same primary outcomes.

The two publications by Kampman and colleagues (based on one RCT)(207, 208)

evaluated the

effects of high dose of vitamin D supplementation (20,000 IU/week) on the prevention of

bone loss and on reducing the risk of relapses and disease progression in patients with MS.

Participants were randomised to either vitamin D (20,000 IU/week) plus calcium (500

mg/day) or placebo. Median serum 25-(OH)D concentration increased from 55 nmol/L at

baseline to 121 nmol/L following 96 weeks of vitamin D supplementation.(207, 208)

There was

no significant difference between groups in annualised relapse rate, EDSS, MS functional

composite components, grip strength or fatigue.(208)

This trial also evaluated the effect of

5 T2-weighted magnetic resonance imaging (MRI) scan shows the total number of lesions (lesion load) and

BOD. These are hyperintense lesions, meaning that they appear as bright spots on the MRI image.

February 2014


vitamin D supplementation on percentage change in BMD at the hip, the spine, and the

ultradistal radius over the 96-week period. There was no significant percentage change in

BMD between groups at any site. BMD decreased at the hip by 0.7% in the treatment group

(95% CI: -1.6 to 0.2) and 1.4% in the placebo group (95% CI: -2.3 to -0.4).(207)

Therefore, in

this small RCT, supplementation with 20,000 IU vitamin D3 weekly did not result in

beneficial effects on the measured MS-related outcomes and did not prevent bone loss.

However, this study was not powered to address clinical outcomes as none of the results were

suggestive of an effect in this sample population of MS patients.

Due to the conflicting results and small quantity of data, the overall body of evidence is

considered to be of low quality and firm conclusions cannot be drawn.

A10.7 Effect of vitamin D supplementation on mood disorders

Two RCTs of vitamin D supplementation were identified in individuals with mood disorders. (209, 210)

However, both studies did not meet the inclusion criteria due to small sample size

(<20 patients), short follow-up interval (< 3 months), and/or lack of calcium only or placebo

control group. One study of 15 individuals with seasonal affective disorder showed that

vitamin D plus calcium improved symptoms after one month, whereas phototherapy did

not.(209)

The other study of 180 women with premenstrual syndrome reported that calcium

plus vitamin D was comparable to hormone therapy, but neither treatment had more than a

very small effect on symptoms, compared with placebo, after two months.(210)

A10.8 Effect of vitamin D supplementation on all-cause mortality

The literature search did not identify any relevant data on all-cause mortality in patients with

chronic disease.

MBS Reviews VITAMIN D TESTING REPORT...February 2014 MBS Reviews – Vitamin D Testing Review Report...

Documents

Transcript of MBS Reviews VITAMIN D TESTING REPORT...February 2014 MBS Reviews – Vitamin D Testing Review Report...