Evidence-based medicine and how that relates to official...

Evidence-based medicine and how that relates to official policies about the tolerable

upper level (safety) and approved health effects of

vitamin D. Reinhold Vieth

Professor, Departments of Nutritional Sciences and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

GRASSROOTS HEALTH Sept 20 , 2013

The Childrens’s story HEIDI

Her friend Clara who lived in the city probably suffered from

• Rickets (bone)

• Weak muscles

• Infection-prone

Probable serum 25(OH)D < 25 nmol/L (<10 ng/mL)

Probable serum 25(OH)D > 75 nmol/L (>30 ng/mL)

Vieth 2001. Nutritional Aspects of Osteoporosis, Chapter 17, ed P Burckhardt, RP Heaney, B Dawson-Hughes; Academic Press

Contracted pelvis, in a case of osteomalacia (adult rickets). Normal childbirth would be impossible.

Childhood lack of vitamin D causes rickets

Normal shape of female pelvis

If shadow TALLER than you are tall, you CANNOT make vitamin D

(UV index = 3)

INTRODUCTORY BACKGROUND TO VITAMIN D

Chapter 1

METABOLITE “COMPARTMENT”

Vitamin D3 Normally

Plasma=0-15 nmol/L(Context: 400 IU/quart

milk = 40 nmol/L)

Muscle and

Adipose

Unlimited Storage Capacity in

PLASMA

To Bile

LIVER

25-OHase

KIDNEY

1-α-OHase

7-dehydrocholesterol

UVB light

SKIN


Vitamin D3 Normally


milk = 40 nmol/L)

25(OH)D 2-225 nmol/L

Muscle and

Adipose


PLASMA

To Bile

PLASMA LIVER

25-OHase

KIDNEY

1-α-OHase


UVB light

SKIN


Vitamin D3 Normally


milk = 40 nmol/L)

25(OH)D 2-225 nmol/L

1,25(OH)2D 40-180 pmol/L

24,25(OH)2D Catabolism Excretion

Muscle and

Adipose

Paracrine signaling within tissues

Within Tissues

Possessing 1-OHase

PLASMA


PLASMA

To Bile

PLASMA LIVER

25-OHase

KIDNEY

1-α-OHase


UVB light

SKIN

Intestinal Calcium

Absorption

METABOLITE “COMPARTMENT” Vitamin D3

25(OH)D

CALCITRIOL (Vitamin D hormone)

Within Tissues

Possessing 1-OHase

BLOOD PLASMA

Blood PLASMA

BLOOD PLASMA

Gallagher, 1979; J Clin Invest 64:729

200 1800

Bloo

d Ca

lcitr

iol L

evel

Diet Calcium mg/day

PARACRINE (WITHIN-TISSUE) ACTIONS

25(OH)D

Vitamin D3

1,25(OH)2D Hormone control to increase calcium absorption and bone development (via Calcium)

Pharmacokinetic Features of Vitamin D Metabolites Serum vitamin D rises and falls sharply after a dose.

Within 2-3 days, all of a given dose of vitamin D3 is either stored in tissues, or converted to 25(OH)D.

Serum 25(OH)D rises gradually over time, and if supplies of vitamin D are removed

Half-life = about 2 months. OR 2 weeks*

Serum 1,25(OH)2D is not affected by a vitamin D dose, since its production is stimulated by PTH, and the need for Calcium.

Half-life = 12 hrs.

“it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers”

Dietary Calcium

Cir

cula

tin

g 25

(OH

)D

Zone of Healthy Bone

Zone of UnhealthyBone

Calcium Supplementaton

Vita

min

D S

uppl

emen

tato

n or

Sun

shin

e “vitamin D or calcium”

25(OH)D

1,25(OH)2D Made in Multiple Tissues •BONE •BREAST CELLS •PROSTATE CELLS •COLON CELLS •SKIN •LYMPH NODES •BRAIN (CEREBELLUM AND CORTEX) •THYROID TISSUE •PARATHYROID TISSUE •DENDRITIC CELLS •VASCULAR ENDOTHELIUM •MACROPHAGES •PLACENTA

Made in multiple departments for multiple purposes

25(OH)D Cholecalciferol (Vitamin D3)

7-dehydrocholesterol

calcitriol

Cell

mito

Nucleus

Renal secretion of circulating calcitriol services endocrine

requirements of calcium homeostasis Local

Autocrine/Paracrine Effects:

Cell differentiation Reduce replication Immune function

Record Information Issue: Current | All Restrict to: Reviews | Protocols Sort by: Record Title | Match %

Vitamin D supplementation for prevention of mortality in adults Goran Bjelakovic August 2011

Vitamin D supplementation for improving bone mineral density in children Tania M Winzenberg, October 2010

Vitamin D compounds for people with chronic kidney disease requiring dialysis Suetonia C Palmer, October 2009

Vitamin D compounds for people with chronic kidney disease not requiring dialysis Suetonia C Palmer October 2009

Vitamin D for the treatment of chronic painful conditions in adults Sebastian Straube, November 2010

Vitamin D and vitamin D analogues for preventing fractures D for associated with involutional and post-menopausal osteoporosis Alison Avenell, April 2009

Vitamin D for the management of multiple sclerosis Vanitha A Jagannath, December 2010

Calcium and vitamin corticosteroid-induced osteoporosis Joanne Homik, July 2010

Interventions for the prevention of nutritional rickets in term born children Christian Lerch, Thomas Meissner January 2009

Interventions for preventing falls in older people living in the community Lesley D Gillespie, October 2010

Interventions for preventing falls in older people in nursing care facilities and hospitals Ian D Cameron February 2010

THE TOP REVIEW SYSTEM OF EVIDENCE BASED MEDICINE CONCLUDES MULTIPLE BENEFITS OF VITAMIN D

Vitamin D deficiency CAUSES DISEASE PREVENTED IF

25(OH)D Rickets / osteomalacia >25 nmol/L

Proximal-muscle weakness and back pain >25 nmol/L ?

Osteoporosis and fractures >50 nmol/L

(Contentious) Increases risk of: multiple sclerosis, colorectal cancer, breast cancer, diabetes, depression/poor mental status

>75 nmol/L

The „Waddling Gait“ of Osteomalacia

HD11

S.creatinine 2.13 mg/dL (-1.3) S.calcium (corr) 1.50 mmol/L (2.2-2.6) S.phosphate 1.81 mmol/L (0.84-1.45) S.magnesium 0.65 mmol/L (0.7-1.1) 1,25(OH)2D 163 pg/ml (30-70)

25(OH)D 15 nmol/L (>50 or >75 nmol/L) PTH 1082 pg/ml (<65)

62 yr old patient

CKD stage III PAOD stage II arterial hypertension chronic pancreatitis (MRI diagnosis)

Case Presentation Courtesy Prof.Dr.Harald.Dobnig Klinische Abteilung für Endokrinologie und Stoffwechsel Medizinische Universität Graz, Austria

Low 25(OH)D Myopathy Hypovitaminosis D Myopathy Without Biochemical Signs of Osteomalacic Bone Involvement H. Glerup et al Calcif Tissue Int (2000) 66:419–424

FRACTURE-PREVENTION STUDIES WITH VITAMIN D3

Bischoff-Ferrari et alJAMA. 2005;293:2257-2264

72 72

=20 mcg/d

All By Itself, Vitamin D Prevents Fractures

Cumulative probability of any first fracture

One Dose or Placebo pill sent by mail, 100,000 every 4 months

vitamin D (n=1345)

placebo (n=1341)

based on Cox regression; difference between two groups, P=0.04

Trivedi, Doll, and Khaw 2003 BMJ 326:469

The actual data summarized by Bischoff-Ferrari et al AJCN2006

IOM claims that this graph represents the relationship between Serum 25(OH)D and

Bone Mineral Density NB: SAME SCALE as above

50 nmol/L

| NATURE | 7 JULY 2011 | VOL 475: 23

“Guyatt says that much of the current fracas could have been avoided if the IOM panel had been a bit more equivocal in its reporting.”

Vitamin D Beyond Bone Muscle Bone Cardiovascular

Brain & Nerves Immune

Vitamin D Beyond Bone

Serum 25-hydroxyvitamin D status as a determinant of MULTIPLE SCLEROSIS outcome following acute

demyelination in children Banwell et al 2011 www.thelancet.com/neurology Vol 10 May 2011

MS ADS

Disease OUTCOME

150

120

90

60

30

0

INIT

IAL

PRES

ENTA

TIO

N

Seru

m 2

5-hy

drox

yvia

tmin

D (n

mol

/L)

The Big New Randomized Clinical Trials

VITAMIN D ZERO (Placebo)

VITAMIN D 2000 IU/day

Fish Oil ZERO (Placebo)

5000 people

5000 people

Fish Oil 1000 mg/day

5000 people

5000 people

THE VITAL STUDY: Cancer and Heart Disease

Cost = $30,000,000

PLACEBO

VITAMIN D 3000 IU/day

as 100,000 IU once Monthly

2525 people

2525 people

THE VIDA STUDY: Heart Disease, Respiratory Disease, Fractures

Cost = $6,000,000

Vitamin D deficiency is a nutritional inadequacy that :

CAUSES DISEASE PREVENTED IF 25(OH)D

Rickets / osteomalacia >25 nmol/L

Proximal-muscle weakness and back pain >25 nmol/L ?

Osteoporosis and fractures >50 nmol/L

(Contentious) Increases risk of: multiple sclerosis, colorectal cancer, breast cancer, diabetes, depression/poor mental status

>75 nmol/L

WHAT IS “NORMAL” FOR 25(OH)D ?

Chapter 2

World Distribution of Nonhuman Primates

Regions shaded white are the natural habitat of non-human primates

from; Primate Behavior: Field studies of monkeys and apes. I DeVore 1965

Old-World Primates

Humans exposing full skin surface

to Sunshine’s

UVB

Winter 43o N

Latitude

“Normal” 0

40

120

160

Vitamin D Status in Primates and Early Humans

Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000

80 80

Physiological adult intake

Blood Levels when taking 1000 IU/day

Northern People Taking

4000 IU/day

Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL

Luxwolda and Muskiet , Brit J Nutrition 2011

Ancestry Other South Asian European East Asian African

Seru

m 2

5(O

H)D

(nm

ol/l)

120

100

80

60

40

20

0

1. Traditional culture

2. Modern Africans

Are “Normal” serum 25(OH)D levels healthy?

100 nmol/L = 40 ng/mL

50 nmol/L

Rickets/osteomalacia range

Gozdzik et al, BMC Public Health 2008, 8:336

WHY NOT GET ON WITH GIVING MORE VITAMIN D?

BECAUSE THERE IS RISK OF TOO MUCH

Paraphrasing Paraclesius:

“anything that actually works, will be harmful if the dose is high enough”

Why is vitamin D toxic? Because it works.

Paraphrasing Paraclesius:

“anything that actually works, will be harmful if the dose is high enough”

Difficulties in Establishing Policy • Perception that Government

is Paternalistic • Resistance to “mandatory

medication” • Risk of Overriding Individual

choice • Clinical vs. population

approaches • Professionals in nutrition

focus on the clinical (supplementation) approach

• WHO ambivalence/opposition

• Desire for Natural, “Green” foods.

TH Tulchinsky 2004 European Journal of Public Health, Vol. 14 : 226-228

TERAD3 Ag BLOX Rodenticide…with the low hazard benefits of Vitamin D3. TERAD3 Ag kills anticoagulant-resistant rats and mice…

Might the Fear of similar Problems Underlie Vitamin D Health Policy?

Quart J Med 1948, Volume 17 : 203-228 Minimum 46000 IU/d for weeks.

Vitamin D3 Poisoning by Table Sugar. DOSE: 1.7 MILLION UNITS/DAY FOR 7 MONTHS!

Reinhold Vieth PhDb, Tanya R Pinto BScb, Bajinder S Reen MDa, and Min M Wong MDa

Lancet 2002 359: 672

June 1999, a 29-year-old man admitted to emergency with symptoms of:

extreme right-sided flank pain conjunctivitis (a sign of dehydration)

increased thirst vomiting in acute renal failure anorexia fever, chills

Initially treated with steroids and discharged: presumed gastroenteritis

Vitamin D3 Poisoning by Table Sugar. DOSE: 1.7 MILLION UNITS/DAY FOR 7 MONTHS!

Lancet 2002 359: 672

October 1999, his 63-year-old father was admitted to emergency with similar complaints.

He was also in acute renal failure, and no history of stones.

Calcium VERY HIGH 3.82 mmol/L (normal, 2.20-2.65 mmol/L), 25(OH)D HIGH 1555 nmol/L (normal 20-80 nmol/L) 1,25(OH)2D NEAR NORMAL 151 pmol/L (normal, 30-140 pmol/L). Elevated “free” 1,25(OH)2D causing toxicity.

Vit D

For Vitamin D.

POTENTIAL “MECHANISMS OF TOXICITY”: Traditional:

1. Amplification or mimicking of the 1,25(OH)2D signal to intestine and bone: initially raises urine calcium, later raises serum calcium

New? Phenomena

2. “High” bolus (annual) doses increase number of falls and fractures

3. “U-shaped risk curves” evident in some epidemiological studies

VITAMIN D A MODERN EXAMPLE OF THE

FORTIFICATION VS SUPPLEMENTATION

DILEMMA

Canada Total Vitamin D intakes from food (fortification) and supplements (non-prescription):

VERY VERY FEW CANADIANS CONSUME THE VIT D RDA.

0

200

400

600

800

1000

1200

95%ile`

5%ile Median

15

30

10

0

20

Vita

min

D C

onsu

mpt

ion

(mcg

/day

)

5

Vita

min

D C

onsu

mpt

ion

(IU/d

ay)

25

Estimated average

requirment

DO DOSAGE RECOMMENDATIONS FOR VITAMIN D MAKE SENSE?

NEW 2011 USA/Canada IOM POLICY FOR VITAMIN D

Vitamin D mcg/day (10 mcg = 400 IU)

Risk

of

harm

(ex

cess

)

Risk

of

harm

(in

adeq

uacy

)

RDA NOAEL

15-20 100 250 1250

UL

EAR

LOAEL

UF

Traditionally

CALCIUM

Related

Purpose, to deliver >50 nmol/L 25(OH)D

VITAMIN D INTAKE RECOMMENDATIONS:

IOM VS ENDOCRINE SOCIETY

RISKS/BENEFITS FOR GOVERNMENT POLICY: “Political Controversy”

18-19th Century Breakthroughs

• Lind and scurvy 1747 • Lemon juice (vit C) in Royal

Navy, 1796 • Davy isolates sodium,

potassium, calcium, magnesium, sulphur, boron, 1807

• Chatin shows iodine prevents goiter, 1850

• Eijkman publishes Thiamine deficiency cause of beriberi, 1897

TH Tulchinsky MD MPH Braun School of Public Health

Preventing Goiter and Iodine Deficiency Disorders

• 1917, high % US draftees rejected - goiter

• 1922-27, goiter rates fall from 39% to 9% by statewide prevention programs

• 1924, Morton’s Iodized Salt (N America)

• 1979, Iodization mandatory in Canada • 1980s, WHO - universal iodization of

salt • Many countries achieved iodization


Cost Comparison: Supplementation vs Fortification

Source: World Bank, 1994

0

1

2

3

4

Iron

Suppl Fort

Iodine Vit A

US

Dol

lars

Annual Per Capita US$ Cost of Interventions

Suppl Fort Suppl Fort


Evidence-Based Decision with vitamin D:

Is it Realistic to demand Perfect Evidence?

1. Personal care decisions (flexible and possibly only during sickness).

2. Physician care of patient (flexible and possibly only during sickness).

3. Government Health policy: for all society and for years to come.

1

2

Zero Evidence

The shades of grey of health/medical decisions

3 Certainty = “Causality” = RCT only

Metaanalysis of RCT’s

Policy is slow to adapt because it demands the Ultimate in Evidence: RCT + meta-analysis

Primary vs 2o outcomes

Potential

Effect for

DRUG

RCT

“Evidence

Based

Medicine”

Relative Dose Difference

PLACEBO TREATMENT

CLASSIC DRUG CLINICAL TRIAL •Recruit persons currently at high risk of a disease event

•Treat existing condition

•High likelihood to show effect in an individual.

Res

pons

e O

utco

me

X

Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484

•Recruit Healthy persons at low risk

•Prevent a currently- non-existing future condition

•Low likelihood to show effect in an individual

Potential For Non-

Index Nutrition

RCT

RDA TREATMENT

CLASSIC NUTRIENT CLINICAL TRIAL

Relative Dose Difference R

espo

nse

Out

com

e

Relative Dose Difference

X

Y

White response curve is

the “index”, classic

effect of the

nutrient.

Green represents a new, putative

effect.

Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484

For Vitamin D.

THINK ABOUT THE OPTIONS: •Change the BEHAVIOR of society to consume an ideal diet

•Change diets through FORTIFICATION

•Advise all of society to take a SUPPLEMENT

•Health is a responsibility of:

1 THE INDIVIDUAL take a supplement

2 HEALTH PROFESSIONALS advise a supplement or PRESCRIPTION

3 GOVERNMENT POLICY Fortification (mandatory/optional)

Evidence-Based Decision with vitamin D:

An example of how IOM has used key evidence.

“Risk of vitamin D deficiency osteomalacia in bone maintenance”

KEY TEACHING POINT

What does this minimal risk actually mean in IOM context????

IOM report states on pg 15-7 “Data from the work of Priemel et al. (2010) have been used by the committee to support a serum 25OHD level of 50 nmol/L as providing coverage for at least 97.5 percent of the population.”

“Our data … strongly argue that in conjunction with a sufficient calcium intake, the dose of vitamin D supplementation should ensure that circulating levels of 25(OH)D reach this minimum threshold (75 nmol/L or 30 ng/mL) to maintain skeletal health”

The key Figure from Priemel et al 2010: The IOM Report claims that based on the figures below, 25(OH)D > 50 nmol/L prevents osteomalacia in

97.5% of people (i.e. claim is Risk< 2.5%). Below is the evidence they specify for that.

7 o’malacia 22 OK Risk = 7/28=25%



THE IOM JUSTIFIES 50 nmol/L because if 25(OH)D> 50 nM (20 ng/mL) then only about 1% of the population had

evidence of Osteomalacia bone disease.

7 o’malacia 22 OK

Risk = 7/28 =25%



Does the use of the evidence by the IOM make sense to you?

QUESTIONS COMMONLY ASKED AFTER GIVING A TALK LIKE THIS:

1. So tell me, how much vitamin D I should be taking.

2. Should I be worried about taking vitamin D?

3. How can the IOM justify its way of making recommendations?

4. How much vitamin D do you (RV) take? 5. Why are policy makers so conservative?

Decision Theory: Pain of a unit of loss =

2 X the Pleasure of a unit of win

-1 0 +1 +2

degree of wrong or correct

1 -

-2 -

Evidence-based medicine and how that relates to official...

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