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
About this report

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
Phone
Toll-free
craig.martin@worksafebc.com
604 279-7417
1 888 967-5377 ext 7417
View other systematic reviews by the Evidence-Based Practice Group online at:
http://worksafebc.com/evidence

www.worksafebc.com/evidence
June 2013
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

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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

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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

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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 20312. 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
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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 present 15.
Obesity and being overweight are frequently said to influence the development of OA, especially in weightbearing 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 diseasemodification 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

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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 siteexcept 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.

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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 Lequesnes 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, OMERACTOARSI responders rate, risk ratio (RR) was used. Given that no heterogeneity was found, they used a fixedeffects 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 metaanalysis 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
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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 interestthere 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
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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 placebocontrolled 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-totreat 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

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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

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11
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 12week 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 cutoff 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.

June 2013
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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 supplements17, 39. In terms of effectiveness, 3 of the reviewed studies33, 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/metaanalyses. 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.

June 2013
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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 OArelated 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 metaanalysis (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.

June 2013
14
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.

June 2013
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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.

June 2013
16
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.
ODonnell S, Lagac 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-cubeseng.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/oapathophysiology/.
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.

June 2013
17
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-KeepingJoints-in-the-Game.
29.
Natural Standard Professional Monograph - Chondroitin. 2012 [Oct 30, 2012]; Available from:
http://www.naturalstandard.com/.

June 2013
18
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.

June 2013
19
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.
Evidence from well-designed controlled trials without randomization or systematic

reviews of observational studies.
Evidence from well-designed cohort or case-control analytic studies, preferably from

more than 1 centre or research group.
Evidence from comparisons between times or places with or without the intervention.
Dramatic results in uncontrolled experiments could also be included here.
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.

June 2013
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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 guidelines23 guidelines with 51 treatment modalities, of which 20 were more universally
recommendedand 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, placebocontrolled 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:

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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
June 2013
22
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 gain12. 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: Crosssectional 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
June 2013
23
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 healthrelated 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.

June 2013
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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
recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence
following systematic cumulative update of research published through January 2009. Osteoarthritis
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Glucosamine Chon Droit in Sulfate Osteoarthritis

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GLUCOSAMINE and CHONDROITIN

SULFATE for OSTEOARTHRITIS

Clinical Services Worker and Employer Services

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

About this report

Published: June 2013

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

Activities of daily living

Evidence-Based Practice Group

Glucosamine/chondroitin Arthritis Intervention Trial

Joint space narrowing

Joint space width

The New England Journal of Medicine

The National Health Service

Licensed Natural Health Products Database

Quality adjusted life years

Osteoarthritis Research Society International

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research

Randomized Controlled Trial

Nonsteroidal Anti-inflammatory Drug

Standardized mean difference

Visual Analog Scale

World Health Organization

Weighted mean difference

Western Ontario and McMaster Universities Osteoarthritis Index

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

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

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

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

Glucosamine/chondroitin products are not inexpensive.

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

Summary and conclusions

WorkSafeBC Evidence-Based Practice Group

GLUCOSAMINE and CHONDROITIN SULFATE for OSTEOARTHRITIS

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

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

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