Glucosamine Chon Droit in Sulfate Osteoarthritis

GLUCOSAMINE and CHONDROITIN

SULFATE for OSTEOARTHRITIS

By

WorkSafeBC Evidence-Based Practice Group

Dr. Craig W. Martin, Senior Medical Advisor

JUNE 2013

Clinical Services – Worker and Employer Services

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS i

WorkSafeBC Evidence-Based Practice Group June 2013 www.worksafebc.com/evidence

About this report

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

Published: June 2013

About the Evidence-Based Practice Group The Evidence-Based Practice Group was established to address the many medical and policy issues that

WorkSafeBC officers deal with on a regular basis. Members apply established techniques of critical appraisal

and evidence-based review of topics solicited from both WorkSafeBC staff and other interested parties such as

surgeons, medical specialists, and rehabilitation providers.

Cite as WorkSafeBC Evidence-Based Practice Group, Edeer D, Martin CW. Glucosamine and chondroitin sulfate for

osteoarthritis. Richmond, BC: WorkSafeBC Evidence-Based Practice Group; June 2013. Available at:

http:/worksafebc.com/health_care_providers/Assets/PDF/GlucosamineChondroitinOsteoarthritis2013.pdf

Contact Information Evidence-Based Practice Group

WorkSafeBC

PO Box 5350 Stn Terminal

Vancouver BC V6B 5L5

Email [email protected]

Phone 604 279-7417

Toll-free 1 888 967-5377 ext 7417

View other systematic reviews by the Evidence-Based Practice Group online at:

http://worksafebc.com/evidence

http://worksafebc.com/health_care_providers/Assets/PDF/GlucosamineChondroitinOsteoarthritis2013.pdf

http://worksafebc.com/evidence

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS 1


Table of contents

About this report .................................................................................................................................................... i

List of abbreviations ............................................................................................................................................. 2

Background ........................................................................................................................................................... 4

Objective ............................................................................................................................................................... 6

Search Strategy ..................................................................................................................................................... 6

Results ................................................................................................................................................................... 7

Discussion ........................................................................................................................................................... 12

Key messages ...................................................................................................................................................... 13

Summary and conclusions .................................................................................................................................. 15

References ........................................................................................................................................................... 16

Appendix 1 .......................................................................................................................................................... 19

Appendix 2 .......................................................................................................................................................... 20

Additional Resources .......................................................................................................................................... 20



List of abbreviations

ADL Activities of daily living

AFI Algo-functional Index

EBPG Evidence-Based Practice Group

EBM Evidence-based medicine

ES Effect size

GAIT Glucosamine/chondroitin Arthritis Intervention Trial

IA intra-articular

JSN Joint space narrowing

JSW Joint space width

NEJM The New England Journal of Medicine

NHS The National Health Service

LNHPD Licensed Natural Health Products Database

OA Osteoarthritis

QALYs Quality adjusted life years

OARSI Osteoarthritis Research Society International



OMERACT–

OARSI

Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research

Society International

RCT Randomized Controlled Trial

RR Risk Ratio

RTW Return to Work

NSAID Nonsteroidal Anti-inflammatory Drug

SMD Standardized mean difference

VAS Visual Analog Scale

WHO World Health Organization

WM Weighted mean

WMD Weighted mean difference

WOMAC Western Ontario and McMaster Universities Osteoarthritis Index



Background

Osteoarthritis (OA) is a potentially disabling chronic condition and the most common type of arthritis. Arthritis

may emerge in more than a hundred different forms as various rheumatic diseases and conditions, including

OA. In 2010-2011, over 4.6 million Canadians (16.7% of those 15 years and older) reported suffering from

arthritis1 and this figure is expected to reach approximately 7 million in 2031

2. In the same period, the

percentage of Canadians 65 and older with arthritis was 34.1% for males and 52.9% for females3. Amongst the

15% of Canadians living with a disability, one-quarter reported arthritis as the main cause of their disability. In

this disabled group, one-quarter of those aged 25-44 reported not being in the labour force because of their

arthritis2.

With the aging population worldwide, the prevalence of OA is rising. However, the numbers of affected vary

widely depending on the characteristics of the studied population (e.g. age, gender, and ethnicity) and the

joints studied. For some adult populations prevalence estimates approach 20 to 30 percent4. The Arthritis

Society of Canada reports that over 3 million Canadians are affected by OA5 and according to the World

Health Organization (WHO), the number of people suffering from moderate to severe disability due to OA is

43.4 million6.

Osteoarthritis may affect various synovial joints (e.g., hand, foot, knee, hip, and spine). Pain and limited

movement/activity are the most common clinical symptoms. But, there may be further consequences, including

decreased at-work productivity7-8

.

Joint activity is accomplished through a collaborative work. Each of the participating tissues has complex

physiochemical and biomechanical properties. Synovial fluid, articular cartilage, menisci, capsule, synovium,

ligaments and subchondral bone, all have certain roles in joint movement. For example, synovial fluid

lubricants (i.e. lubricin and hyaluronan) ensure an almost friction-free mechanical environment for the articular

cartilage. In case of damage to one component, the other tissues are likely to be affected adversely as well; and

joint degeneration, which leads to OA, may start. Presently, OA is considered as an osteoarticular disease

exhibiting degenerative processes in multiple tissues (articular cartilage, snovium, subchondral bone). During

the course of OA, different joint tissues are at various stages of degeneration or engaged in regenerative and

reparative response. Degradative and synthetic enzyme activities, which normally maintain a balanced

cartilage volume, are shifted. Fibrillation and erosion of articular cartilage, osteophyte formation, subchondral

bone sclerosis, synovial hyperplasia, fibrosis and inflammatory cell infiltration are the pathological changes

observed during the course of OA. Unlike rheumatoid arthritis, OA is not typically characterized by bilateral

joint presentation9-12

.

The current evidence on etiologic and prognostic factors of OA is unclear. Many patient and disease

characteristics (e.g., age, gender, family history, body mass index (BMI), nutrition, injury, smoking,

sports/running, hormones, hyaluronic acid, insulin-like growth factor 1 (IGF-1), bone mineral density, bone

cartilage turnover (measured by cartilage oligometric matrix protein (COMP) or urinary collagen telopeptide

(uCTX)), baseline symptoms and radiologic severity, inflammation, MRI bone marrow lesions) have been

studied. According to a descriptive review on radiologic progression of OA by Cheung et al., except for

malalignment of the knee, atrophic bone response in the hip and generalized OA, which demonstrated strong

association, other factors had moderate to limited strength. Studies on gender, BMI, bone mineral density,

IGF-1, serum COMP, Uctx, initial radiologic severity in predicting OA progress, displayed conflicting

evidence13

. In general, OA is felt to be a condition with a multi-factorial etiology; an “interplay between

systemic and local factors” 14

. When no specific cause is identified, it is referred to as “primary/idiopathic

osteoarthritis”. Primary OA is usually perceived as an ailment of the elderly, though a joint with OA and a

naturally aging joint do not necessarily present identical deterioration10

. If an underlying cause is identified,

then the condition is frequently referred to as “secondary osteoarthritis”. Secondary OA may start at an earlier



age, but is not as prevalent as primary OA. The underlying cause of secondary OA may vary (e.g.,

neurological, metabolic, endocrine, or traumatic). Some conditions leading to secondary OA are congenital

limb or joint deformities, avascular necrosis, acromegaly, ochronosis, and inflammatory joint diseases such as

sepsis, rheumatoid arthritis, and gout. A biomechanical abnormality to the joint or limb may be present15

.

Obesity and being overweight are frequently said to influence the development of OA, especially in weight-

bearing joints, such as the knee and hip. Trauma-induced OA usually develops secondary to an acute joint

injury or repetitive/long-term stress to the joint, which are often related to work or sports tasks. In the case of

existing primary OA, new injuries or strains to the joint may aggravate and/or accelerate the course of OA.

Osteoarthritis-affected joints are commonly tender. Patients suffer from morning and/or prolonged fixed body

position stiffness. Swelling and crepitus may also be evident. Generally, pain escalates with increasing activity

throughout the day and many patients need frequent breaks to rest the involved joint16

.

Traditional treatment approaches for patients with OA aim to control clinical symptoms, increase function and

delay surgery. These include pain medications (e.g., acetaminophen, non-steroidal anti-inflammatory drugs

(NSAIDs), corticosteroids, capsaicin), hyaluronic acid injections, recommendations for life style changes (e.g.,

exercise, weight loss, healthy eating, structural/ergonomic adjustments of home and work environment),

physical and massage therapies, braces, and alternative treatments (e.g., acupuncture, yoga, glucosamine and

chondroitin). Although the mechanism of action for glucosamine and chondroitin sulfate are not fully

explained, they have become increasingly popular in the last decade, with global sales of glucosamine

supplements observing a 60% increase from 2003 to 200817

.

Glucosamine is an amino-monosaccharide contributing to the formation of glycosaminoglycans, proteoglycans

and hyaluronic acid, and is found in various human tissues (e.g., tendons, ligaments, synovial fluid, skin, bone,

nails, heart valves, blood vessels, and mucus secretions). It is one of the natural building blocks of articular

cartilage and plays a major role in the structure and functioning of joints. Although not analgesic agents,

glucosamine products are believed to have some anti-inflammatory properties and to delay cartilage

deterioration18-21

. Structure-modifying effects of glucosamine on joint cartilage suggested by radiological

studies22-23

led to its consideration as a disease modifying agent24-25

. An alternative view is that disease-

modification in osteoarthritis should not be studied solely based on radiologic markers (e.g. joint space

narrowing) but should be accompanied with clinical outcomes, such as changes in pain and function26

.

Additional technical information on glucosamine metabolism can be found elsewhere9, 20, 27

.

Chondroitin is a glucosaminoglycan, which has a principle role in maintaining elastic integrity within tissues.

It is found in cartilage and believed to inhibit synovial enzymes that damage cartilage during the course of OA.

Hence, products containing chondroitin sulfate are believed to have positive treatment effects on osteoarthritic

joints28-

29. However, biologic mechanisms explaining the metabolism of orally administrated glucosamine and

chondroitin sulfate are yet to be clarified27, 30

.

Unlike in Europe, where glucosamine and chondroitin sulfate products are treated and regulated as prescription

drugs, in the US and Canada these products are considered dietary supplements and can be purchased over the

counter in various formulations. The number of products in the Canadian market is substantial. For example,

when a “keyword” search is undertaken, the Health Canada Licensed Natural Health Products Database lists

603 glucosamine and 449 chondroitin-based products31

. Similarly, the literature on the topic is also substantial.

For example, a simple database search on Pubmed using these two key words (with no restrictions to study

type) captures a total of 34820 hits32

.

A 2004 review by the WorkSafeBC Evidence-Based Practice Group (EBPG) on glucosamine found level 1

evidence (Appendix 1) for the short and long term effectiveness of glucosamine in treating OA, particularly

OA of the knee and the hip20

. The same report pointed out that the majority of the research was focused on

glucosamine sulfate and there was not sufficient information available on other forms of glucosamine (e.g.,

hydrochloride, chlorhydrate salt, hydroiodide, or combination with herbs, vitamin A, vitamin E, or minerals



including Mg, K, Cu, Zn or Se). The report also noted that most of the primary studies were funded by the

manufacturer of a glucosamine sulfate product.

Objective

The objective of this review was to explore the current literature on effectiveness of glucosamine and

chondroitin sulfate in treating osteoarthritis (OA). We limited our search to systematic reviews/meta-analyses

published from 2004 onwards, and focused on pain, function, mobility, disability, impairment, quality adjusted

life years (QALYs), activities of daily living (ADL), return to work (RTW), and cost, as outcomes of interest.

Search Strategy

The literature search was undertaken on November 21, 2012 and again on May 31, 2013.

We conducted searches on Ovid SP databases (EBM reviews (ACP Journal Club, Cochrane Database of

Systematic Reviews, Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database),

EMBASE, BIOSIS Previews, International Pharmaceutical Abstracts, and Ovid MEDLINE®) using the

keywords glucosamine, chondroitin, sulfate, sulphate, osteoarthritis, OA, osteoarthrosis, arthritis, and

combining these keywords with Boolean operators OR and AND as appropriate.

Inclusion criteria: Only systematic reviews and meta-analyses, published from 2004 onwards, were included.

Study samples of the primary studies were comprised of OA patients (we did not consider a restriction on age,

sex, ethnicity or joint site—except for excluding temporo-mandibular joint) with glucosamine and/or

chondroitin sulfate as the primary treatment modality. Comparisons with placebo, no treatment, or a

comparator were accepted. Primary outcome had to be work-related, e.g. pain, function, mobility, disability,

impairment, quality adjusted life years (QALYs), activities of daily living (ADL), return to work (RTW), and

cost. We only included publications available in English.

Exclusion criteria: Systematic reviews and meta-analyses were excluded if their methodology on selecting and

evaluating the quality of the primary studies was not clearly stated. Publications with primary studies on the

effect of another form of glucosamine or chondroitin (not sulfate form) were excluded. Publications with

primary studies focusing solely on the effect of glucosamine and chondroitin sulfate as a combination or when

used in combination with other treatment modalities were also excluded. Studies on the pharmacological

properties and pharmacokinetics of glucosamine/chondroitin sulfate and studies simply on joint cartilage

structural response to these substances (without clinical outcomes) were also excluded.



Results

We identified 9 systematic reviews/meta-analyses, which examined the efficacy of glucosamine sulfate or

chondroitin sulfate.

Symptom-Modifying Effect of Chondroitin Sulfate in Knee Osteoarthritis: A Meta-Analysis of

Randomized Placebo-Controlled Trials Performed with Structum (Schneider H, 2012)33

This was an industry-funded efficacy study on Structum®, a chondroitin sulfate product. The authors

conducted a meta-analysis. The patients were knee OA patients who used Structum® (1 g daily) for over 3

months. Three studies were included: two trials identified through a database search and an additional

unpublished study obtained from the manufacturer. All three studies were RCTs comparing Structum® with

placebo. The primary outcome of interest was stated as “absolute pain intensity (during activity)”. Secondary

outcomes were Lequesne’s algo-functional Index (AFI) (or other functional assessments) and the rate of

responders according to the Outcome Measures of the Rheumatoid Arthritis Clinical Trials and the

Osteoarthritis Research Society International (OMERACT-OARSI) criteria. There were a number of

inconsistencies in the presentation of results; for example, the name of the first author of the unpublished study

was listed differently in the “characteristics of the studies” table and in the four figures displaying the results of

the meta-analysis. When comparing the change in “pain during activity” at baseline and at the end of the study

(between the intervention and placebo groups) “pain during activity” was measured by visual analog scale

(VAS) and was presented as the weighted mean difference (WMD). For the categorical variable, “OMERACT-

OARSI responders” rate, risk ratio (RR) was used. Given that no heterogeneity was found, they used a fixed-

effects model during the meta-analysis of the 588 patients from the three studies. The treatment effect for

reduction in pain during activity was -5.61 when “study end” was taken as the end-point of the studies.

However, the end-point was different for each study. Two of the studies had 6-month and one had 3-month

follow up periods, until the end of the study. When they repeated the analysis with the data available from all

studies at the 3-month point, the effect size was down to -3.05 and was not statistically significant. They found

a statistically significant pooled effect for Structum® (measured as weighted mean, WM) of -0.73 compared to

placebo; however this was again using the data from the “study end”, which actually represents different time

periods across the three studies. The authors also noted that the “OMERACT-OARSI responders” data was

available directly for only one study and was calculated post-hoc for the other two studies. The overall

conclusion was that Structum® 1 g/day, taken for a 3-6 months period, was effective in the treatment of knee

OA by reducing pain intensity during activity and by improving functionality. All three authors of this meta-

analysis declared a conflict of interest with regards to the funds they received from the industry.

Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network

meta-analysis (Wandel S, 2010)17

Wandel et al. conducted a network meta-analysis34

to study the effect of glucosamine, chondroitin, or their

combination on patients with knee or hip osteoarthritis. The main outcome of interest was joint pain intensity.

The change in minimal width of joint space was the secondary outcome. An extensive literature search was

conducted and only large scale RCTs were selected for the meta-analysis (i.e., at least 100 study subjects in

both the treatment and control arms of a study). The total number of patients from the 10 included studies was

3803. Using a Bayesian random effects model for the pain intensity outcome, they were able to synthesise the

data at multiple time points. They pre-specified the minimal clinically important difference in pain as 0.9 cm



on a 10 cm VAS scale. None of the observed changes in the study were clinically significant. The authors also

checked variation across time points, as well as heterogeneity and consistency between trials; they found no

statistical significance. They used a stratified analysis to test the interactions for some variables (e.g. quality of

the trials, presence/absence of quality control measures, industry funding, joint type, and glucosamine type).

Except for industry funding, tests for interaction were negative. For the trials dependent on industry funding,

the estimated differences between the supplements and placebo were more pronounced (p=0.02 for

interaction). The secondary outcome of interest was change of minimum radiographic joint space. The authors

did not have multiple time points for this variable; hence they used a regular random effects model for the

meta-analysis of this variable. None of the three interventions (glucosamine, chondroitin, or

glucosamine/chondroitin combination) led to a statistically significant difference in joint space narrowing. The

authors also checked safety comparing the odds ratios for adverse events and drop outs/withdrawals due to

adverse events in the intervention and placebo groups. There were no statistically significant differences

between the treatment and placebo groups. It was concluded that compared to placebo, neither glucosamine

nor chondroitin (nor the two combined) had a clinically significant effect on joint pain or narrowing of joint

space in hip or knee OA patients. The authors declared that there were no competing interests with regards to

funding of this network meta-analysis study.

Glucosamine therapy for treating osteoarthritis (Towheed T, 2009)35

This Cochrane review was a systematic review/meta analysis on efficacy and toxicity of glucosamine in

treating OA patients. The authors included RCTs which studied various joints with OA, excluding the

temporo-mandibular joint. Both placebo and comparative studies, either single- or double-blinded were

included. As long as the therapeutic agent was glucosamine alone, all routes of administration were accepted.

Pain, range of motion, functional assessment, and global assessment by the patient and the physician were all

stated as outcomes of interest—there was no main outcome. The authors checked the toxicity of glucosamine,

quantifying this by the number of withdrawals or number of participants reporting adverse outcomes. They

also explored if glucosamine was able to delay the radiologic progression of OA (structural benefit). They

pooled data from primary studies that examined various glucosamine types, administration routes and dosages,

as well as studied OA in various joints. The outcome “reduction in pain” was assessed using different

measurement tools across studies. The authors applied the random effects model for their analysis and reported

on this outcome using standardized mean difference (SMD). The summary SMD for pain reduction was -0.47,

pointing to a significant superior effect of glucosamine. However, heterogeneity was I2 =88%. When they

undertook a post-hoc sensitivity analysis, including only the studies with adequate allocation concealment, the

summary SMD dropped to -0.16 and became insignificant. Nevertheless, the sensitivity analysis results for

Lequesne Index score, WOMAC total score, and joint space reduction continued to display significant positive

effects of glucosamine. When the summary SMDs were computed for WOMAC pain, stiffness, and function

subscale scores, glucosamine remained ineffective compared to placebo in both actual analysis and sensitivity

analysis. The patient and physician global assessments for disease status were compared by only a few studies

and revealed no statistically significant differences between glucosamine and placebo applications. The authors

also undertook a post-hoc subgroup analysis, assessing the effect of glucosamine across various outcomes in

studies using Rotta preparations (a specific brand of glucosamine). For all outcomes, except for the WOMAC

stiffness subscale score, glucosamine showed statistically significant positive effects compared to placebo.

When the authors ran the subgroup analysis on the studies using non-Rotta preparations, the results were the

opposite (no significant difference between glucosamine and placebo). The authors then checked safety

(withdrawals due to toxicity and reports of adverse reactions) and found that glucosamine was as safe as



placebo. In summary, they pointed out that pooled results for studies using adequate concealment or non-Rotta

glucosamine products showed no benefit of glucosamine; whereas for studies using Rotta preparations,

glucosamine was beneficial. They concluded that more research was needed to distinguish the effects of

different glucosamine types (including over-the-counter preparations), dosages, and routes of administration to

understand the mechanism of how glucosamine operates in treating OA, if glucosamine works for all OA

joints, and the patient-specific determinants of radiological progression of OA. They also pointed out that

compared to the past, the trials were not uniformly positive anymore, and this was a research question

worthwhile to investigate in itself. It was stated that this research work received no external funding support.

The authors declared no conflict of interest except for a note that Dr. Towheed was a speaker at a post-meeting

symposium, for which Rotta Pharmaceuticals provided an unrestricted educational grant.

The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review

and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate (Hochberg MC, 2008)36

The authors undertook a systematic review and meta-analysis of the RCTs on the treatment of patients with

knee osteoarthritis with chondroitin sulfate, published between 1996 and 2000. They searched for placebo-

controlled trials. The outcome of interest was the rate of joint space width decline, as measured by the change

in minimum joint space width (mm/year). They included trials with at least 52 weeks of duration and which

had studied orally administered chondroitin sulfate at 800 mg per day. They identified three studies in their

database search and an additional one in the abstract presentations at the 2006 annual meeting of American

College of Rheumatology. The study sample sizes (46 to 622), the techniques used for knee radiographs

(weight-bearing AP radiographs vs. radiographs in Lyon-Schuss position with knee flexion), and the duration

of the trials (52 weeks vs. 24 months) were different; however, heterogeneity testing revealed I2=0%. Hence,

the authors used a fixed effects model to pool data across studies for the meta-analysis. In order to maintain

data on the joint space decline for a similar period of time, the authors assumed that the decline rate was

constant over time for the 24-month studies, and divided the recorded data in half in order to obtain the

corresponding value for 12 months. This approach may have affected the observed effect sizes. The authors

reported a summary effect size (as a standardized mean difference) of 0.26 in the annual rate of decline in

minimal joint space width (p<0.0001). They concluded that orally administrated chondroitin sulfate (800 mg

daily) had a small, but significant effect on slowing the rate of decline in joint space narrowing. The authors

acknowledged funding support from Bioberica S.A., a company manufacturing chondroitin sulfate.

Meta-analysis: Chondroitin for Osteoarthritis of the Knee or Hip (Reichenbach S, 2007)37

The authors undertook a meta-analysis to determine the effects of chondroitin on osteoarthritic knee or hip

pain. After searching standard databases (e.g., Cochrane, MEDLINE, EMBASE, CINAHL) and additional

sources they identified 291 potentially eligible articles. For the analysis, they selected 22 RCTs. Two studies

were only available as abstracts, without sufficient data to calculate effect sizes, thus only 20 studies were

included in their analysis. For pain-related outcomes, effect sizes were calculated at the end of the trial by

dividing the differences in mean values of the treatment and control groups (placebo or with no treatment) by

the pooled standard deviation (SD). An effect size of 0.30 was considered the minimum value for clinical

relevance. They found major differences amongst the studies in terms of allocation concealment, intention-to-

treat analysis and sample size. They also noted that the newer publications showed smaller effect sizes

compared to the older publications. When all 20 RCTs were all included (summary effect size= -0.75)

heterogeneity was too high (I2=92%); therefore they restricted the analysis to the three RCTs which were larger



in sample size (covering 40% of the patients included in all 20 trials) and had utilized an intention-to-treat

analysis approach. The summary effect size on pain improvement obtained based on these three trials was -

0.003 and was not statistically significant. This corresponded to only a 0.6 mm change in pain on a 10cm VAS

scale. The authors stated that there were few trials that studied the effect of chondroitin on joint space

narrowing and the pooled estimate of effect sizes was small (0.12 and 0.24 for minimum and mean joint space

width, respectively). The authors also stated that the larger benefit of chondroitin observed in earlier studies

might have been related with a higher proportion of patients with low-grade OA in those studies. They

concluded that a clinically relevant benefit of chondroitin for the patients with advanced OA was unlikely. The

authors declared no potential conflict of interests.

Glucosamine for pain in osteoarthritis (Vlad SC, 2007)38

The objective of this meta-analysis was to identify factors contributing to the large heterogeneity existing

amongst glucosamine trials on knee or hip osteoarthritis, which had relief of pain as their outcome of interest.

The authors included 15 glucosamine trials. The summary effect size from the meta-analysis (glucosamine

compared to placebo) was 0.35. Heterogeneity (as measured by I2) was substantial at 0.80, suggesting that

much of the variation in outcome was not due to chance. Therefore, the authors stated that pooling of the

results may not be appropriate to reflect the true effect of glucosamine and undertook a subgroup analyses to

find out which study characteristics better explained the differences in effect size. They explored study design,

study subjects, and markers of industry involvement in funding/authorship. They quantified I2 separately for

different factors. In terms of glucosamine type, they reported that glucosamine hydrochloride was not effective

(pooled effect size= 0.06). In terms of study design, they found that only allocation concealment was related

with the large heterogeneity. Although not statistically significant, the authors also found a decreasing trend in

effect sizes in glucosamine studies throughout the last three decades. They reported that 11 studies with

industry involvement had a pooled effect size of 0.47 (I2 = 0.81), whereas 4 non-industry funded trials had a

pooled effect size of 0.05 (I2 = 0). In a post-hoc analysis, the authors looked into the industry-funded trials

more closely and compared the effect sizes in the 8 trials funded by Rottapharm (effect size=0.57) with the 3

trials funded by other companies (effect size= 0.22). This difference was not statistically significant (p=0.27).

The authors concluded that substantial heterogeneity amongst the glucosamine trials was likely due to

differences in glucosamine preparations, poor allocation concealment and industry involvement. The authors

listed NIH grants as the funding source for this meta-analysis.

Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis

of randomised placebo-controlled trials (Bjordal JM, 2007)39

This study was not merely on glucosamine and chondroitin sulfate. It explored the efficacy of commonly used

pharmacotherapeutic agents for osteoarthritic knee pain (i.e., oral and topical NSAIDs, opioids, paracetamol

(acetaminophen), steroid injections, glucosamine and chondroitin sulfate). The primary outcome was the

change in intensity of overall pain and was quantified as the best mean difference of change (in mm VAS) in

the intervention group over the control (placebo) group through different time points. The authors provided

separate tables for 7 different intervention types (two of which were glucosamine and chondroitin). They

outlined the characteristics of the studies included in each group, e.g., number of patients, quality of the

methodology, mean baseline pain in mm VAS, and time points for outcome measurements. There were 7 trials

included for glucosamine and 6 trials for chondroitin sulfate, whereas the table for oral NSAIDs included 25

trials. The authors were interested in the maximum effect time points and in evaluating efficacy compared to



patient-centered outcome thresholds. They analyzed the efficacy of each intervention type compared to these

thresholds in a 1 to 4 week period and at 6-, 8-, and 12-week time points. In 1-4 weeks, for glucosamine

sulfate, they reported the best mean difference of change in pain (as measured by VAS) was 4.7 mm at 4

weeks and for chondroitin sulfate 3.9 mm at 3.6 weeks. Neither glucosamine nor chondroitin sulfate passed the

patient-centered outcome mean threshold for “minimal perceptible improvement”, which was set as 9.7 mm

VAS. In contrast, oral NSAIDs passed this threshold at 2.3 weeks (10.2 mm change in VAS), and topical

NSAIDs passed it at 1.6 weeks (11.6 mm VAS). The only intervention which passed the mean threshold for

“slight improvement” was steroid injections (14.5 mm change in VAS, at 1.5 weeks). On the 6-, 8-, and 12-

week time point graph, both glucosamine and chondroitin sulfate displayed a trend of progress towards the end

12-week time point. However, by 12 weeks, glucosamine sulfate did not pass the mean threshold “minimal

perceptible difference” and was stated to be ineffective in relieving pain. For chondroitin sulfate, which was

the only intervention that barely passed this threshold by 12 weeks, the authors pointed out that 5 of the 6 trials

in this intervention group were funded by pharmaceutical companies, and the only trial without industry

funding had not reported perceptible improvement in pain intensity by week 12. Based on their findings, the

authors concluded that paracetamol, glucosamine sulphate, and chondroitin sulphate are not effective for pain

relief for knee OA in the short term within a month, and topical NSAIDs and intra-articular steroid injections

only offer limited pain relief over placebo in this short term. They also pointed out the potential patient

selection bias for the NSAID trials and large dropout rates for the opioid trials. Their general conclusion was

that the efficacy of common pharmacological interventions for short-term pain relief in osteoarthritis of the

knee was limited (if any). The authors did not report any conflict of interest or external funding in addition to a

grant from the Norwegian Research Council.

Glucosamine Long-Term Treatment and the Progression of Knee Osteoarthritis: Systematic Review of

Randomized Controlled Trials (Poolsup N, 2005)40

To explore the structural and symptomatic efficacy and safety of glucosamine in knee OA, the authors

conducted a systematic review and meta-analysis of glucosamine studies published through August 2004, as

identified through bibliographic databases (Medline, EMBASE, Biosis, EBM reviews and the Cochrane

Library). Initially, 17 clinical trials were identified. However, after applying inclusion/exclusion criteria only 2

placebo-controlled RCTs were retained for meta-analysis. The main outcome of interest was disease

progression, which was measured using joint space narrowing. Instead of using a continuous variable, such as

“standardized mean difference”, the authors employed a dichotomized variable arbitrarily set to a 0.5 mm cut-

off level for the joint space width. They compared the proportion of patients with more than 0.5 mm narrowing

in the glucosamine and placebo groups. Glucosamine displayed a preventative effect in terms of disease

progression. The pooled relative risk in the meta-analysis was 0.46 and the authors did not find significant

heterogeneity between the two studies. Based on WOMAC index findings, glucosamine was found to be more

effective than placebo for symptom-related outcomes, such as pain and function. There was a high drop-out

rate for both of the trials (in both the treatment and placebo groups), though the authors did not mention this

issue as a potential limitation of their study (likely because both of the primary trials reported analyzing data

using an intent-to-treat approach). In their conclusion, the authors referred to the sparse data on the long-term

use of glucosamine for knee OA and called for new studies. No information was disclosed regarding funding

of the study or the authors’ conflict of interest declaration.



Discussion

We reviewed 8 systematic reviews/meta-analyses, which explored the effect of glucosamine and chondroitin

sulfate for treating OA of various joints (excluding the temporomandibular joint). Although our outcome of

interest was not limited to pain relief, it was the primary outcome of interest in most of the studies we

reviewed17, 33, 37-39

. Out of these 8 studies, 3 focused on the efficacy of chondroitin33, 36-37

, 3 on glucosamine35, 38,

40 and 2 included both supplements

17, 39. In terms of effectiveness, 3 of the reviewed studies

33, 36, 40 reported

glucosamine and/or chondroitin to have positive effects on osteoarthritic joint structure or OA-related

symptoms; whereas, 517, 35, 37-39

stated that these agents were no more effective than placebo.

Our review had some limitations. First of all, we did not search for unpublished systematic reviews/meta-

analyses. This may introduce concerns regarding publication bias. Also, our search was limited to publications

in English, which may have introduced a language bias. Since there is a vast amount of descriptive literature

on the topic and many research studies appear to lack proper methodology (e.g., being uncontrolled, not having

sufficient sample sizes and follow up periods with well-defined end-points, not applying blindness, not

reporting adverse effects/drop outs) we limited our inclusion criteria to systematic reviews/meta-analyses

published in peer-reviewed journals. The choice of English language was arbitrary as per our own language

barriers. Primary studies, which were analyzed in the systematic reviews/meta-analyses we reviewed, in

general, had not controlled for factors such as severity of OA, or treatment approaches such as exercise, weight

control, rest, and heat/cold applications. Also, some argue that the “sulfate” part of glucosamine and

chondroitin products contributes to the efficacy observed in some of the studies. It is not yet clear if this is true,

and if so, how much of the effect is from the “sulfate” part of these agents is yet to be well understood.



Key messages

- The etiology of osteoarthritis is multifactorial in nature and is not entirely due to aging. Some of the

risk factors believed to be associated with development of OA include female gender, genetic

predisposition, obesity, and prior injuries to the joint.

- With the ever-increasing average age of working populations it is likely that more people with OA will

be employed in the future and they may seek compensation and treatment entitlements through OA-

related workers’ compensation claims.

- Information on the pathophysiology of OA, treatment approaches including non-pharmacological

treatments (e.g., weight loss, exercise, or muscle strengthening) are drawing increasing attention, and

treatment modalities directed at the OA joint are improving. New treatments, such as biotherapies,

growth factors, and meniscal implants are being explored.

- Nutritional products like glucosamine and chondroitin are considered pharmacological treatment

modalities, being categorized in the same group as topical and systemic NSAIDs, intraarticular

steroids or hyaluronate injections.

- In Canada, glucosamine and chondroitin are not prescription drugs and are available over the counter.

In the last decade, the demand for these products has increased.

- Only glucosamine and chondroitin products that pass assessment by Health Canada on safety,

effectiveness, and quality are listed in the Licensed Natural Health Products Database (LNHPD).

- Effects of glucosamine and/or chondroitin have been studied mostly in primary OA patients. It is not

yet clear if the efficacy conclusions drawn based on these studies also apply to secondary OA, for

which work-related traumas and repetitive injuries likely play a larger role.

- Similarly, glucosamine and/or chondroitin have been studied mostly in knee or hip OA patients.

Hence, drawing generalized conclusions for all OA-affected joints (e.g., hand, wrist, shoulder, and

ankle) may not be appropriate at present, given the state of the literature.

- There is a range of glucosamine and chondroitin products sold on the market. Their purity,

recommended dosage and administration routes vary. When these readily available products are used

for research studies, it becomes difficult to compare results from different studies or to conduct a meta-

analysis (since the products are not standardized).

- In addition, it is evident from some of the meta-analyses undertaken that the primary studies display

heterogeneity in terms of study sample size, administration of the glucosamine and/or chondroitin

sulfate agents (type, route, dosage), studied joints affected by OA (e.g., knee, hip), studied outcomes

and how they are measured (various measurement tools), use of different effect size measures for

efficacy, and reporting of funding support from the industry.

- Since OA is a slowly-progressing disease, long-term studies are needed to observe disease

modification or adverse effects of the treatment agents used. For long-term studies, high drop-out rates

and patient loss to follow up are significant issues.



- Long-term studies on adverse effects or drug interactions of glucosamine and chondroitin sulfate are

sparse.

- Caution should be exercised when reading the results from efficacy studies on

glucosamine/chondroitin use in OA patients, as selective involvement of the industry in this research

may bias these results/conclusions.

- Glucosamine/chondroitin products are not inexpensive.

- Clinical effectiveness of glucosamine and/or chondroitin sulfate is not yet clear. Observed positive

effects in some studies might be due to the natural course of osteoarthritis, regression to the mean, or

the placebo effect.

- Effectiveness of glucosamine and chondroitin sulfate as a combination therapy is not supported by the

current research evidence.



Summary and conclusions

In a 2004 review on glucosamine the WorkSafeBC Evidence-Based Practice Group (EBPG) reported level 1

evidence (Appendix 1) for the short and long term effectiveness of glucosamine in treating OA, particularly

OA of the knee and the hip. However, in recent years, studies with better methodology and without industry

involvement have been conducted. Although research is ongoing and not yet conclusive, as per the currently

available evidence-based information, glucosamine and chondroitin sulfate (as singular products) are not

feasible treatment options for OA. Currently, OA patients are likely to benefit from a personalized treatment

approach, which uses a set of modalities, including non-pharmacological, pharmacological, and surgical, as

appropriate. Coverage decisions for the use of glucosamine and chondroitin sulfate products amongst this set

of modalities for work-related OA will require a case by case management decision. Summaries of other useful

publications on the topic can be accessed through the attached Appendix 2.



References

1. Arthritis Alliance of Canada. Newsletter. 2013 [cited May 29, 2013]; April 2013:[Available from:

http://www.arthritisalliance.ca/docs/newsletters/201304%20AAC%20Newsletter.pdf.

2. O’Donnell S, Lagacé C, McRae L, Bancej C. Life with arthritis in Canada: a personal and public

health challenge Chronic Diseases and Injuries in Canada. 2011;Vol 31(3):135-6.

3. PHAC (Public Health Agency of Canada). The Chronic Disease Infobase (Arthritis data by gender,

65+ for Canada). 2013 [June 3, 2013]; Available from: http://66.240.150.17/cubes/data-cubes-

eng.html.

4. Neogi T. OARSI Primer / Chapter 1 - Epidemiology of OA Osteoarthritis Research Society

International (OARSI); 2010 [cited May 21, 2013]; Available from:

http://primer.oarsi.org/print/book/export/html/2.

5. The Arthritis Society of Canada. Osteoarthritis. 2013 [May 21 2013]; Available from:

http://www.arthritis.ca/page.aspx?pid=941.

6. WHO. World Report on Disability 2011. WHO, 2011.

7. Dibonaventura M, Gupta S, McDonald M, Sadosky A. Evaluating the health and economic impact of

osteoarthritis pain in the workforce: results from the National Health and Wellness Survey. BMC

Musculoskelet Disord. 2011;12:83. Epub 2011/04/30.

8. Zhang W, Koehoorn M, Anis AH. Work productivity among employed Canadians with arthritis.

Journal of occupational and environmental medicine / American College of Occupational and

Environmental Medicine. 2010;52(9):872-7. Epub 2010/08/28.

9. Coluet J, Vinatier C, Merceron C, Pot-vaucel M, Guicheux J, et al. From osteoarthritis treatments to

future regenerative therapies for cartilage. Drug Discovery Today. 2009;14(19-20):913-25.

10. Ling SM. Osteoarthritis: Pathophysiology. The John Hopkins Arthritis Center; 2012 [cited May 21,

2013]; Available from: http://www.hopkinsarthritis.org/arthritis-info/osteoarthritis/oa-

pathophysiology/.

11. Poole AR. OARSI Primer / Chapter 3 - The Normal Synovial Joint. Osteoarthritis Research Society



12. Salter DM. OARSI Primer / Chapter 4 - Pathology of OA. Osteoarthritis Research Society



13. Cheung PP, Gossec L, Dougados M. What are the best markers for disease progression in

osteoarthritis (OA)? Best practice & research Clinical rheumatology. 2010;24(1):81-92. Epub

2010/02/05.

14. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clinics in geriatric medicine. 2010;26(3):355-69.

Epub 2010/08/12.



15. Tile M. Osteoarthritis (Discussion paper prepared for The Workplace Safety and Insurance Appeals

Tribunal). Ontario: The Workplace Safety and Insurance Appeals Tribunal; 2008 [Sep 30, 2011];

Available from:

http://www.wsiat.on.ca/tracITDocuments/MLODocuments/Discussions/osteoarthritis.pdf.

16. NIH (National Institutes of Health) Information Clearinghouse. Osteoarthritis. 2010 [updated July

2010; cited Nov 2, 2012]; NIH Publication No. 10-4617]. Available from:

http://www.niams.nih.gov/Health_Info/Osteoarthritis/default.asp.

17. Wandel S, Juni P, Tendal B, Nuesch E, Villiger PM, Welton NJ, et al. Effects of glucosamine,

chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ.

2010;341:c4675. Epub 2010/09/18.

18. Kelly GS. The Role of Glucosamine Sulfate and Chondroitin Sulfates in the Treatment of

Degenerative Joint Disease. Alternative Medicine Review. 1998;3(1).

19. Natural Standard Professional Monograph - Glucosamine. 2012 [Nov 6, 2012]; Available from:

http://www.naturalstandard.com/.

20. Martin CW. GLUCOSAMINE: Review of its effectiveness in treating knee osteoarthritis. WCB

Evidence Based Practice Group, 2004 January 2004. Report No.

21. Fajardo M, Di Cesare PE. Disease-modifying therapies for osteoarthritis : current status. Drugs &

aging. 2005;22(2):141-61. Epub 2005/03/01.

22. Rovati LC, Girolami F, Persiani S. Crystalline glucosamine sulfate in the management of knee

osteoarthritis: efficacy, safety, and pharmacokinetic properties. Therapeutic advances in

musculoskeletal disease. 2012;4(3):167-80. Epub 2012/08/02.

23. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the

osteoarthritis progression: A meta-analysis. Rheumatology International. 2010;30(3):357-63.

24. Bijlsma JW, Knahr K. Strategies for the prevention and management of osteoarthritis of the hip and

knee. Best practice & research Clinical rheumatology. 2007;21(1):59-76. Epub 2007/03/14.

25. Herrero-Beaumont G, Rovati LC, Castaneda S, Alvarez-Soria MA, Largo R. The reverse glucosamine

sulfate pathway: Application in knee osteoarthritis. Expert Opinion on Pharmacotherapy.

2007;8(2):215-25.

26. Abadie E, Ethgen D, Avouac B, Bouvenot G, Branco J, Bruyere O, et al. Recommendations for the use

of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.

Osteoarthritis Cartilage. 2004;12(4):263-8. Epub 2004/03/17.

27. McAlindon TE. Nutraceuticals: Do they work and when should we use them? Best Practice and

Research: Clinical Rheumatology. 2006;20(1):99-115.

28. Brown DA. Natural Products on Deck: Keeping Joints in the Game. Pharmacy Times2011 [Nov 19,

2012]; Available from: http://www.pharmacytimes.com/news/Natural-Products-on-Deck-Keeping-

Joints-in-the-Game.

29. Natural Standard Professional Monograph - Chondroitin. 2012 [Oct 30, 2012]; Available from:

http://www.naturalstandard.com/.



30. Jackson CG, Plaas AH, Sandy JD, Hua C, Kim-Rolands S, Barnhill JG, et al. The human

pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in

combination. Osteoarthritis Cartilage. 2010;18(3):297-302. Epub 2009/11/17.

31. Health Canada – Licensed Natural Health Products Database. [updated Sep 27, 2012Oct 30, 2012];

Available from: http://webprod3.hc-sc.gc.ca/lnhpd-bdpsnh/.

32. U. S. National Library of Medicine – National Institutes of Health/PubMed. [Oct 30, 2012]; Available

from: http://www.ncbi.nlm.nih.gov/pubmed.

33. Schneider H, Maheu E, Cucherat M. Symptom-modifying effect of chondroitin sulfate in knee

osteoarthritis: A meta-analysis of randomized placebo-controlled trials performed with Structum. Open

Rheumatology Journal. 2012;6(1):183-9.

34. Li T, Puhan MA, Vedula SS, Singh S, Dickersin K, Ad Hoc Network Meta-analysis Methods Meeting

Working G. Network meta-analysis-highly attractive but more methodological research is needed.

BMC medicine. 2011;9:79. Epub 2011/06/29.

35. Towheed T, Maxwell L, Anastassiades TP, Shea B, Houpt JB, Welch V, et al. Glucosamine therapy

for treating osteoarthritis. Cochrane Database of Systematic Reviews. 2009(4).

36. Hochberg MC. Structure-modifying effects of chondroitin sulfate in knee osteoarthritis: an updated

meta-analysis of randomized placebo-controlled trials of 2-year duration. Osteoarthritis Cartilage.

2010;18 Suppl 1:S28-31. Epub 2010/04/20.

37. Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. Meta-analysis: chondroitin for

osteoarthritis of the knee or hip. Annals of internal medicine. 2007;146(8):580-90.

38. Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis. Arthritis &

Rheumatism. 2007;56(7):2267-77.

39. Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Short-term efficacy of pharmacotherapeutic

interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials.

European Journal of Pain. 2007;11(2):125-38.

40. Poolsup N, Suthisisang C, Channark P, Kittikulsuth W. Glucosamine long-term treatment and the

progression of knee osteoarthritis: systematic review of randomized controlled trials. The Annals of

pharmacotherapy. 2005;39(6):1080-7. Epub 2005/04/28.



Appendix 1

WorkSafeBC Evidence-Based Practice Group levels of evidence (adapted from 1,2,3,4)

1 Evidence from at least 1 properly randomized controlled trial (RCT) or systematic review

of RCTs.

2 Evidence from well-designed controlled trials without randomization or systematic

reviews of observational studies.

3 Evidence from well-designed cohort or case-control analytic studies, preferably from

more than 1 centre or research group.

4 Evidence from comparisons between times or places with or without the intervention.

Dramatic results in uncontrolled experiments could also be included here.

5 Opinions of respected authorities, based on clinical experience, descriptive studies or

reports of expert committees.

References

1. Canadian Task Force on the Periodic Health Examination: The periodic health examination. CMAJ.

1979;121:1193-1254.

2. Houston TP, Elster AB, Davis RM et al. The US Preventive Services Task Force Guide to Clinical

Preventive Services, Second Edition. AMA Council on Scientific Affairs. American Journal of Preventive

Medicine. May 1998;14(4):374-376.

3. Scottish Intercollegiate Guidelines Network (2001). SIGN 50: a guideline developers' handbook. SIGN.

Edinburgh.

4. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian

Task Force on Preventive Health Care. CMAJ. Aug 5, 2003;169(3):207-208.



Appendix 2

Additional Resources

OARSI Recommendations

Osteoarthritis Research Society International (OARSI) developed recommendations for the management of hip

and knee osteoarthritis1. OARSI Recommendations Part 1 (2007)

2 included a critical appraisal of existing

treatment guidelines—23 guidelines with 51 treatment modalities, of which 20 were more universally

recommended—and a systematic review of the existing evidence (through January 2006). The meta-analysis

found glucosamine sulfate and chondroitin sulfate to have an effect in the management of OA pain compared

with placebo or active control. With sensitivity analysis that included the more recently published studies, the

authors reported that “treatment with glucosamine sulphate remained superior to placebo while treatment with

glucosamine hydrochloride was not” and also, “following the addition of the new data on chondroitin sulphate

from the GAIT study to the results of the earlier RCTs; treatment with chondroitin sulphate was no longer

superior to placebo”. OARSI Recommendations Part 2, published in 20083, included evidence-based, expert

consensus guidelines. The recommendations regarding glucosamine and chondroitin sulfate (# 18 and #19)

were: “Treatment with glucosamine and/or chondroitin sulphate may provide symptomatic benefit in patients

with knee OA. If no response is apparent within 6 months treatment should be discontinued” and “In patients

with symptomatic knee OA glucosamine sulphate and chondroitin sulphate may have structure-modifying

effects while diacerein may have structure-modifying effects in patients with symptomatic OA of the hip”.

OARSI Recommendations Part3 (2010)4 addressed the changes in evidence from the period of January 2006 to

the end of January 2009 and stated that “[Effect size] for pain relief from [intra-articular] hyaluronic acid,

glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was

greater heterogeneity of outcomes and more evidence of publication bias”.

GAIT Studies

The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was a turning point for the research on the

treatment of OA with glucosamine and chondroitin sulfate. The main reason for this was its being a

methodologically sound multicentre study, relying on a large sample size (n=1583). This randomized, placebo-

controlled trial was funded by the US National Center for Complementary and Alternative Medicine

(NCCAM) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

To our knowledge, three research papers were published using data from the GAIT study. The first one was by

Clegg et al., published in NEJM in 20065, which inflamed the debate on the efficacy of gucosamine and

chondroitin in the treatment of knee OA. The Clegg study was among the primary studies included in four of

the systematic reviews/meta-analyses6-9

we reviewed in this report. Two years later, Sawitzke et al. conducted

an ancillary study with a subset of the original sample to examine the structural response in cartilage to these

supplements10

. The third study, published in 2010 by the same team, was to measure long-term effects and

safety of glucosamine and chondroitin in the original sample11

. The short summaries of the three GAIT studies

are as follows:



Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis (Clegg D,

2006)5. A total of 1583 patients were randomized to 5 groups; glucosamine, chondroitin sulfate, both

glucosamine and chondroitin sulfate, celecoxib, or placebo. The outcome of interest was improvement in knee

pain over 24 weeks, as measured by a 20% decrease from the baseline pain value (measured by summed score

for the WOMAC pain subscale). They reported that glucosamine and chondroitin sulfate, either in

combination or alone, were not effective in reducing OA knee pain in the overall study sample. However,

when they stratified data into two subgroups based on baseline pain scores (moderate-to-severe or mild), the

combination of glucosamine and chondroitin sulfate became statistically significantly effective for the

moderate-to-severe pain group. The authors acknowledged that this result should be confirmed with future

studies.

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo

taken to treat osteoarthritis of the knee: 2-year results from GAIT (Sawitzke AD, 2010)11

. A subset of 662

patients from the original GAIT study (meeting the criteria of Kellgren/Lawrence (K/L) grade 2 or 3 changes

and with baseline joint space width of at least 2mm) were followed for 24 months, while they continued with

the treatment assignments to which they were originally randomized. The primary outcome of interest was

similar to the original study, a 20% reduction in WOMAC pain score. In the 24-month period, none of the four

treatment options reached a statistically (and clinically) significant reduction in pain compared to placebo.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from

the glucosamine/chondroitin arthritis intervention trial (Sawitzke AD, 2008)10

The third publication of the GAIT study was from an ancillary study, where the rate of joint space width (JSW)

loss over 2 years was explored in a sample of 581 knees, from 357 patients. Inclusion required K/L grade 2 or

3 changes determined on a standard AP radiograph of the knee in weight-bearing position. In the placebo

group the mean change in JSW was expected to be 0.4 mm. The authors used a mixed-effects model regression

analysis and did not find any significant differences in mean JSW loss over 2 years between the treatment

groups and the placebo group. They concluded that “no therapy resulted in predefined thresholds for either

statistically significant or clinically meaningful structural modification”. They also acknowledged

shortcomings of their study, such as the small number of knees qualified for the study, less than anticipated

JSW loss during the study period, and variability of JSW measurement across study sites.

Placebo effect in OA

A study published by Zhang et al.3 reported a meta-analysis of RCTs on OA to explore the placebo effect and

its determinants. Patients from 184 active treatment/placebo, 3 active treatment/placebo/ untreated control, and

11 active treatment/untreated control trials were included. The placebo effect was defined as the overall change

from baseline in the placebo group and was presented as effect size (ES). It was compared to the ES from the

untreated control group. Statistical pooling for the meta-analysis was undertaken as appropriate and potential

determinants of placebo effect were checked via multiple regression analysis. The main outcome of interest

was ES for pain. They also studied the placebo effect for other outcomes. While they found moderate placebo

effect (ES 0.43 to 0.51) for subjective outcomes (e.g., pain, stiffness, and self-reported function), they found

placebo to be ineffective in objective outcomes, e.g., joint space narrowing. The placebo effect for pain was

listed as 0.48 for the trials where the active treatment was glucosamine, and 0.42 where the active treatment



was chondroitin. The authors argued that the observed placebo effects were likely to be real (rather than being

due to “regression to the mean” or “natural remission of the disease”) because they had included an untreated

control group for this meta-analysis. The authors declared no conflict of interest and acknowledged an

unrestricted grant from a private company (IDEA AG, Munich) amongst other grants they received from

research agencies.

Cost-Effectiveness

There are a few studies on the cost-effectiveness of glucosamine and chondroitin sulfate. The only HTA report

we were able to find was by Black et al. and was published in 2009. According to this report, if anything, the

cost-effectiveness of glucosamine sulfate was inconclusive due to the uncertainty related to the “magnitude

and duration of QoL gain”12

. The other two studies we were able to find on the cost-effectiveness of

glucosamine sulfate13

and on chondroitin sulfate14

were both industry-funded studies, by Rottapharm, and

IBSA Institut Biochimique, respectively. Both of these studies found the products to be cost effective for the

treatment of knee OA.

Reports on Work-related Osteoarthritis

Evaluating the health and economic impact of osteoarthritis pain in the workforce: results from the

National Health and Wellness Survey (Dibonaventura M, 2011)15

The authors conducted a population-based study to evaluate the impact of OA pain on utilization of healthcare

resources and related costs, and on productivity at work. They used data from the 2009 National Health and

Wellness Survey. They studied two groups; one group (n=2173), who reported suffering from OA pain in the

last month, and the comparative group (n=37599), who did not report having OA or had not suffered from OA

pain in the last month. They found significant differences between the two groups in terms of demographics.

The OA-pain group was older and held more women. As well, more co-morbid health problems and a trend

towards obesity were present in this group. The variables of interest were compared between the two groups,

with and without OA pain. Regarding impaired productivity at work, the authors used presenteeism and

absenteeism as a measure and found both to be significantly higher in the OA-pain group (p<0.0001). The

economic burden was assessed using the direct (health provider, ER and hospitalization) costs and indirect

costs (any cost related to lost productivity). Both direct and indirect costs were statistically significantly higher

in the OA-pain group (p<0.00001). The authors acknowledged the limitations of their study as: being based on

self report, not having any information from a medical claims data source (specifically, for prescribed

pharmacotherapy which has not been reported by the patients), not being able to take into account the type of

employment and the site (joint) of the OA pain, and extrapolation of 6-month data to 1 year in order to

estimate the annual costs. The authors underlined that the relationship they found between OA pain and

productivity pointed only to an association, not to causality. They concluded that even with the attached

limitations, this study was important to point to the fact that OA pain is not confined to the elderly population,

but is also a problem for the working-age population; and has an impact on the quality of life, work

productivity, and healthcare resource utilization of workers.

In another recent paper, Impact of self-rated osteoarthritis severity in an employed population: Cross-

sectional analysis of data from the national health and wellness survey16

. Dibonaventura et al. analysed the

same data from the 2009 National Health and Wellness Survey, this time including all people who reported a

diagnosis of OA, without a limitation to those who suffered from OA pain in the last month. Hence, the



number of people in the OA (n=4876), and non-OA cohorts (comparator group, n=34896) in the 2012 study

were different from their 2011 study, summarized above. This time they were interested in the effect of

severity of OA on various outcomes, such as pain-related interference in work activities, lost productivity,

health-related quality of life, and direct/indirect costs. Lost productivity was measured by absenteeism,

presenteeism, overall work impairment, and activity impairment. Presenteeism seemed to be the primary

source of work impairment. Those in the severe OA pain category displayed higher decrease in work

productivity compared to moderate-, mild-, and no-pain categories. The same trend was observed with health-

related quality of life and cost. The effects on the physical components of HRQoL were greater than the effects

on the mental components and were not only statistically, but also clinically, significant (greater than 3 point

differences between groups).

Work Productivity among Employed Canadians with Arthritis (Zhang W, 2010)17

Zhang et al. used the 2005 Canadian Community Health Survey to compare work productivity of people with

arthritis to the productivity of healthy people. The data was extracted for people between the ages 25 to 64,

who were employed the week before they participated in the survey and had filled in valid information

regarding their work activities and chronic health conditions. The sample size was 55,714. After testing the

variables for descriptive statistics, they studied the relationships of four “chronic condition status” categories

(1- no chronic condition, 2-arthritis only, 3-any chronic condition other than arthritis, 4-arthritis plus any other

chronic conditions) to “absenteeism” and “presenteeism”. When the characteristics of people in these four

groups were compared, statistically significant differences were observed. For example, the frequency of

presenteeism was 21% in the “arthritis only” and 3.1% in the “no chronic condition” groups. During the

multivariate analysis for associations, they accounted for confounders, such as age, sex, socioeconomic and job

characteristics. The association (presented as adjusted OR) between presenteeism and “arthritis only”,

compared to “no chronic condition”, was 8.02 and for “arthritis plus any other chronic conditions”, it was up to

16.72. The authors noted that people with arthritis had similar odds of absenteeism compared to healthy people

(no chronic disease group); whereas they had higher odds for reduced productivity at work, even after

controlling for the other chronic conditions. They acknowledged the limitations of their study, including:

reliance on self-report, not being able to tell if there was a group of people who had already left their jobs

altogether due to arthritis (therefore, not contributing to the frequency of absenteeism), and the use of

“education level” (instead of personal income) to determine socioeconomic characteristics. The authors

mentioned cross-sectional/snap-shot character of their study and pointed out the need for a longitudinal study

design.



References

1. OARSI (Osteoarthritis Research Society International). Treatment Guidelines. 2013 [May 16, 2013];

Available from:

http://www.oarsi.org/index2.cfm?section=Publications_and_Newsroom&content=OAGuidelines.

2. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI

recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of

existing treatment guidelines and systematic review of current research evidence. Osteoarthritis

Cartilage. 2007;15(9):981-1000. Epub 2007/08/28.

3. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI

recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based,

expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-62. Epub 2008/02/19.

4. Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI

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Glucosamine Chon Droit in Sulfate Osteoarthritis

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