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Meta-analysis: Chondroitin for Osteoarthritis of the Knee or Hip

Stephan Reichenbach, MD; Rebekka Sterchi, MD; Martin Scherer, MD; Sven Trelle, MD; Elizabeth Bürgi, PhD; Ulrich Bürgi, MD; Paul A. Dieppe, MD; and Peter Jüni, MD
[+] Article and Author Information

From the University of Bern, Bern, Switzerland; University of Bristol, Bristol, United Kingdom; and University of Göttingen, Göttingen, Germany.


Acknowledgments: The authors thank Gediminas Matulis for translations, Bettina Lässer for bibliographic work, and Malcom Sturdy for database development.

Grant Support: Drs. Reichenbach and Jüni received grants (no. 4053-40-104762/3 and no. 3200-066378) from the Swiss National Science Foundation's National Research Program 53 on musculoskeletal health and Dr. U. Bürgi received a grant from the Swiss Society of Internal Medicine. Dr. Scherer is supported by a Young Investigators' Award of the German Ministry of Education and Research (grant no. 01 GK 0516). Dr. Jüni was a Program for Social Medicine, Preventive and Epidemiological Research senior research fellow funded by the Swiss National Science Foundation (grant no. 3233-066377).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Peter Jüni, MD, Department of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; e-mail, juni@ispm.unibe.ch.

Current Author Addresses: Drs. Reichenbach, Trelle, and Jüni and Ms. Sterchi: Universität Bern, Institut für Sozial und Präventivmedizin, Finkenhubelweg 11, 3012 Bern, Switzerland

Dr. Scherer: Georg-August-Universität Göttingen, Abteilung Allgemeinmedizin, 37099 Göttingen, Germany.

Drs. E. Bürgi and U. Bürgi: Inselspital Bern, Klinik und Poliklinik für Innere Medizin, 3010 Bern, Switzerland.

Dr. Dieppe: Department of Social Medicine, University of Bristol, Whiteladies Road, Bristol, BS8 2PR, United Kingdom.


Ann Intern Med. 2007;146(8):580-590. doi:10.7326/0003-4819-146-8-200704170-00009
Text Size: A A A

Background: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect.

Purpose: To determine the effects of chondroitin on pain in patients with osteoarthritis.

Data Sources: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006.

Study Selection: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions.

Data Extraction: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis.

Data Synthesis: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of −0.03 (95% CI, −0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event.

Limitations: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable.

Conclusions: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

Figures

Grahic Jump Location
Figure 2.
Forest plot of 20 trials comparing chondroitin with control.

I2 = 92% (P < 0.001). The size of the boxes is proportional to the random-effects weights used in the meta-analysis.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Funnel plot of 20 trials comparing chondroitin with control.

Effect sizes on the vertical axis are plotted against their SE on the horizontal axis. Circles indicate individual studies. The dotted line indicates the predicted treatment effect (regression line) from univariable meta-regression by using SE as the explanatory variable. Dashed lines represent the 95% CIs.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Effect sizes according to time of publication.

Effect sizes on the vertical axis are plotted against the publication year on the horizontal axis. Open circles represent studies with fewer than 200 participants, and solid circles represent studies with 200 or more participants. The size of the circles is proportional to the random-effects weights that were used in the meta-regression. The dotted line indicates predicted treatment effects (regression line) from univariable meta-regression by using publication year as the explanatory variable, and dashed lines represent the 95% CIs.

Grahic Jump Location
Grahic Jump Location
Figure 5.
Plot of standardized changes in pain scores in the control group against those in the chondroitin group.

Open circles represent individual studies with fewer than 200 participants, and solid circles represent studies with 200 or more participants. The size of the circles is proportional to the random-effects weights that were used in the meta-analysis. The solid line indicates no difference in changes between the placebo and chondroitin groups. Box plots indicate the interquartile range and median (rectangle) and minimum and maximum changes (error bars).

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References

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Comments

Submit a Comment
Clinical usefulness of chondroitin sulfate
Posted on April 19, 2007
Patrick du Souich
University of Montreal
Conflict of Interest: None Declared

TO THE EDITOR, The report of Reichenbach et al. [1] raises several points. In first place, it confirms that chondroitin sulfate is not an analgesic. As a matter of fact, glycosaminoglycans are not analgesics. In second place, this meta-analysis strongly supports several trials demonstrating that chondroitin sulfate reduces the rate of knee joint space narrowing [2,3]. Finally, this meta-analysis confirms that the incidence of adverse effects caused by chondroitin sulfate is similar to that produced by placebo. Keeping in mind that several double blinded randomized placebo-controlled trials have demonstrated that chondroitin sulfate is superior to placebo for most end-points assessed, that treatment with chondroitin sulfate is associated with a significant decrease in the incidence of joint swelling, effusion, or both [4], and that patients treated with chondroitin sulfate appear to use less NSAIDs [5], the conclusions reached by the authors may not be fully justified. In view of the potential beneficial effects of chondroitin sulfate on joint swelling and space, of its safety and absence of drug-drug interactions, and the lack of safe alternatives for patients multi-medicated for osteoarthritis and other accompanying diseases, e.g. diabetes, hypertension, hyperlipidemia, etc, further studies are warranted before reaching the conclusion that the use of chondroitin in routine clinical practice should be discouraged. 1. Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007;146:580-90. 2. Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P, Uebelhart D. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005;52:779-86. 3. Uebelhart D, Malaise M, Marcolongo R, DeVathaire F, Piperno M, Mailleux E, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12:269-76. 4. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808. 5. Lagnaoui R, Baumevielle M, Begaud B, Pouyanne P, Maurice G, Depont F, Moore N. Less use of NSAIDs in long-term than in recent chondroitin sulphate users in osteoarthritis: a pharmacy-based observational study in France. Therapie. 2006;61 :341-6.

Conflict of Interest:

Research Grant from Bioibérica S.A. No conflict of interest

Interpretation of chondroitin meta-analysis
Posted on April 21, 2007
Harley A Goldberg
Kaiser Permanente, Northern California
Conflict of Interest: None Declared

Interpretation of chondroitin meta-analysis

The meta-analysis by Reichenbach and colleagues(1) is both timely and important. However, we are concerned that the authors' sweeping conclusions are not well grounded in their methodology. Based on data extraction and synthesis, the overall effect size of chondroitin is large (Figure 2, Forest plot) p<0.001, though this conclusion is limited by the presence of heterogeneity among trials (I2=92%). Using meta- regression, the authors identified a subset of trials that provide homogeneity, and stronger methodology, suggesting no effect on pain. The authors accurately state that a meta-regression analysis "should be viewed as hypothesis-generating" and is "observational in nature" yet it is the results of the meta-regression that forms the cornerstone of the article's conclusion. But this conclusion makes no mention of the overall meta- analytic result or limitations, nor the limitations of the meta- regression. The pre-specified "large trial" cut off of 200 participants included five trials, with a summary small-to-moderate effect size of borderline significance. But the authors based their conclusions of "no effect" on only three of these trials (citing, additionally, reporting of intention- to-treat analyses), circumventing the single most important benefit of systematic reviews which discourages a focus on a selective subset of studies. It is of great concern that the author's choice to base their conclusions on only these three studies was almost certainly made without being blinded to these studies' results (since the authors read all of the papers at the outset). Although, in the end, the conclusion that "use of chondroitin in routine clinical practice should therefore be discouraged" may eventually turn out to be true, it is not sufficiently supported by the methodology used here. The data provided by the authors show: a meta-analysis demonstrates large effect size, but is limited by heterogeneity between trials; meta- regression identifying the better trials suggests little or no effect, raising concerns about study quality; these results apply to pain only, and do not address disease progression, which also deserves further study (though the clinical significance of joint-space narrowing is unknown (2)(3). This important analysis needs to be added to the growing evidence on the effect of chondroitin for pain in osteoarthritis, but interpretation of the results should not go beyond what the results themselves allow.

Harley Goldberg, DO Director, Complementary and Alternative Medicine Kaiser Permanente, Northern California

Andrew Avins, MD Division of Research, Northern California Kaiser Permanente General Internal Medicine Section, Department of Medicine, San Francisco VA Medical Center Department of Medicine, University of California, San Francisco Department of Epidemiology and Biostatistics, University of California, San Francisco

1. Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, Dieppe P, Jüni P. Meta-analysis: Chondroitin for Osteoarthritis of the Knee or Hip. Ann Intern Med. 2007;146(8):580-590.

2. Hunter DJ, Zhang YQ, Tu X, et al. Change in joint space width: Hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheum 2006;54:2488-95.

3. Spector TD, Dacre JE, Harris PA, Huskisson EC. Radiological progression of osteoarthritis: an 11 year follow up study of the knee. Ann Rheum Dis. 1992 Oct;51(10):1107"“1110.

Conflict of Interest:

None declared

Raw Material Quality - Chondroitin Confounder?
Posted on April 27, 2007
Michael D. Levin
Health Business Strategies
Conflict of Interest: None Declared

In their meta-analysis of the literature on chondroitin for OA of the knee or hip, the authors correctly observed that their study is "limited by the quality of the included trials". They further disclosed that "several relevant variables were poorly reported" and that "most trials had poor methodological quality or inadequate reporting".

One critically important poorly controlled relevant variable in this review (and in others involving therapeutic uses of dietary ingredients) deserves comment. As an expert who reviews analytical results for a variety of dietary ingredients and dietary supplements, I have found that the authenticity, potency and purity of many dietary ingredients is highly variable. Simply put, raw material quality is an under-recognized confounder in clinical trials. For example, ConsumerLab.com recently reported that 73% of all products tested containing chondroitin failed potency testing . Between 1% and 8% of the labeled amount of chondroitin was found in three products, and none could be detected in a fourth. Unfortunately, there are several different analytical tests that are used commercially to measure the presence of chondroitin, some of which are more specific than others. Non-specific analytical methods, such as size exclusion chromatography, provide unreliable results. Specific methods, such as enzymatic HPLC, are far more appropriate. Agreement on analytical methodologies remain a challenge for this industry, and, in my experience, most clinicians are simply not aware of this problem.

This raises the simple question: did the products used in these studies contain therapeutic doses of chondroitin? If not, what conclusions can be drawn from these studies? And what are the implications for future research?

Michael D. Levin Health Business Strategies Clackamas, OR 97015

ConsumerLab.com, Product Review: Joint Supplements, 4/11/07

Conflict of Interest:

None declared

Chondroitin sulfate in the treatment of osteoarthritis- shouldn't we contemplate yet?
Posted on April 30, 2007
Tamás Bárdos
PTE Orthopedic Surgery, Pecs, Hungary
Conflict of Interest: None Declared

According to market researches only in the US $1 billion is spent yearly on musculoskeletal dietary supplements. Several distinct studies have focused on measuring the efficacy of these agents alone or in combination but still no clear conclusion has been made.

In a recent meta-analytic review of Reichenbach et al. (1) a thorough search was performed to determine the value of chondroitin alone in controlling osteoarthritic complaints. Only the few solid, large sample- sized studies were examined and negligible or no benefit of chondroitin was found, and the more precise preparation and larger sample size the study was based upon the less advantage chondroitin delivered. As a straight forward conclusion the authors discourage use of chondroitin in routine clinical practice.

The responding editorial in the journal, however, straight away commented and obscured the conclusion. (2) No severe adverse effects of chondroitin is reported to date, hence the conclusion: there is "no harm in encouraging them (the patients) to continue taking it as long as they perceive a benefit".

We have reservation about the responsibility of an editorial comment on studies of such importance. Not only it is questionable to disagree on the result of a well-executed meta-analytic paper without evidence-based data form the literature, but might also be misleading for clinicians having unconditional trust in reputable papers and its editors.

One of the most cited recent multicenter clinical trial is the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) (3). The study found that chondroitin in combination with glucosamine may have beneficial effect only in the subgroup of patients with moderate-to-severe osteoarthritic knee pain but not with mild pain.

"Milestone" study with fairly high number of participants and of high level of evidence was conducted previously for glucosamine sulfate (sponsored by Rottapharm- European patent holder) (4) The three-year-long study demonstrated a good effect in the joint space narrowing. Thus far it is the only publication able to convince us about the benefit of dietary supplements -in this case glucosamine sulfate- in osteoarthritic pain.

Having such significant financial impact on health care budget doctors in the musculoskeletal discipline have enormous responsibility in recommending any of the dietary supplements.

GAIT team continues research in narrowing of the joint spaces, and soon will provide proof for us -clinicians- as whether dietary supplements such as chondroitin and/or glucosamine sulfate is to be recommended to patients with osteoarthritis. In the meantime, we believe, one should refrain from communicating obvious suggestions.

Reference List

(1) Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007;146:580-590.

(2) Felson DT. Chondroitin for pain in osteoarthritis. Ann Intern Med. 2007;146:611-12.

(3) Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New Engl J Med. 2006;354(8):795-808.

(4) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001; 357:251-56.

Conflict of Interest:

None declared

Chondroitin Sulfate Meta-Analysis: The Jury is Not Yet Out
Posted on May 15, 2007
Jean-Pierre Pelletier
OA Research Unit, Research Centre University of Montreal Hospital Centre, Notre-Dame Hospital
Conflict of Interest: None Declared

The recent meta-analysis of Reichenbach et al (1) on chondroitin sulfate (CS) raises a number of issues related to clinical trials on osteoarthritis (OA). The authors acknowledge that the studies reported in this review are highly heterogeneous in quality, which obviously imposes serious uncertainties to the accuracy of the conclusions drawn in the review. This drawback has also plagued other meta-analyses in the same field.

With regard to the evaluation of the effect of CS on OA symptoms, the review brings up the issue of the great heterogeneity of the patient population included in the studies. It is known that patient response to treatment may vary in relation to the severity of disease. It is again acknowledged by the authors that the limitation to fully explore this dimension of the trials may have impacted the findings and quality of the analysis. The recent study by Clegg et al (2) very elegantly demonstrated in OA trials that the severity of symptoms could dramatically impact patient response to treatment with agents such as CS and glucosamine hydrochloride together (patients with more severe symptoms being more responsive). Interestingly, these findings are somewhat contradictory to the conclusions of the present meta-analysis.

From a structural point of view and as suggested by the authors, attention should be given to most recent expert trials exploring the disease modifying properties of CS. Two of these long-term (two years) studies (3, 4) were realized under optimal conditions and inclusive of over 900 patients including placebo controls. In these trials, the primary outcomes were met, providing strong scientific evidence to support the DMOAD effects of CS.

As the quality of trials improves and important issues are addressed, it will become easier to draw firm conclusions on the therapeutic effectiveness of OA drugs including CS. As outlined, the number of significant limitations imposed on this meta-analysis and the fact that, as per the findings of the review, a clinically relevant effect of CS in patients with lower grade OA cannot be excluded, indicate that the jury is not yet out. With recent high-quality trials pointing toward a beneficial effect of CS on OA structures and symptoms alone or in combined treatment, the conclusions of the present review seem premature.

Jean-Pierre Pelletier MD, Professor of Medicine, Head - Arthritis Centre "“ University of Montreal, Head - Arthritis Division "“ University of Montreal Hospital Centre (CHUM), Director - Osteoarthritis Research Unit - Research Centre "“ CHUM, Chairholder - Chair in Osteoarthritis - University of Montreal

1. Reichenbach S, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007;146:580-90.

2. Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795- 808.

3. Michel B, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee. A randomized, controlled trial. Arthritis Rheum. 2005;52:779-86.

4. Kahan A. STOPP (STudy on Osteoarthritis Progression Prevention): a new two-year trial with chondroitin 4&6 sulfate (CS). Accessed at www.ibsa- ch.com/eular_2006_amsterdam_vignon-2.pdf on 18 September 2006.

Conflict of Interest:

Consultant for Bioiberica, Spain.

Meta-analysis: Chondroitin for Osteoarthritis of the Knee or Hip - Authors' response
Posted on June 12, 2007
Sven Trelle
University of Bern, Institute of Social and Preventive Medicine
Conflict of Interest: None Declared

As correctly pointed out by Goldberg and Avins, our meta-analysis was hampered by the limited quality of included trials and the heterogeneity of their results. Therefore, the interpretation of the meta-analysis of all trials was difficult and the investigation of potential sources of heterogeneity mandatory (1). The restriction of the analysis to large- scale high-quality trials covering 40% of patients was not based on subjective judgment, but on results from stratified analyses and corresponding interaction tests. All explored factors were pre-specified before initiating our systematic review. The three factors associated with treatment effects, concealment of allocation, intention-to-treat analysis and sample size, are known to be associated with bias (2,3). The cut-off of 200 patients used to explore the influence of trial size was specified in a grant proposal submitted to and funded by the Swiss National Research Programme 53 on musculoskeletal health (http://www.nfp53.ch/e_module.cfm?kati=6), which was initiated in 2004 before four of the five large-scale trials became available. The only trial in more than 200 patients that was already available in 2004 (4) showed a large effect of chondroitin, which was incompatible with the effects found in any of the subsequent large-scale trials. It lacked adequate concealment of allocation, did not have a placebo control and failed to perform an intention-to-treat analysis.

It is joint pain, which leads patients with osteoarthritis to seek medical help. We believe therefore that pain reduction should be the primary objective in osteoarthritis trials (5). Contrary to Goldberg and Avins' notion, we addressed radiographic joint space narrowing in a secondary analysis and found clinically irrelevant effects of chondroitin. We agree with Pelletier that the STOPP trial (6) and the study by Michel et al. (7) met the primary endpoint in terms of joint space narrowing. However, the difference in mean changes of joint space narrowing in favor of chondroitin of 0.14 and 0.12mm are evanescent, corresponding to an effect size of merely 0.1 standard deviation units. We disagree with Pelletier that Clegg et al (8) provided robust evidence for an association between severity of symptoms and treatment response in patients receiving a combination of chondroitin and glucosamine. The results referred to by Pelletier origin from one of a multitude of subgroup analyses and might be explained by chance alone. As addressed in our discussion, there might be a role of chondroitin for patients with low-grade osteoarthritis, but this needs to be evaluated in large-scale trials performed independently from manufacturers.

We agree with Levin that pharmaceutical quality is important in evaluations of food supplements. However, the three large-scale high- quality trials, which showed no effect, either had evaluated the capsules for purity, potency, and quality (8) or used an established preparation manufactured by the trial sponsor, which is approved and monitored by the Swiss drug approval agency (6,7).

Sven Trelle, Stephan Reichenbach, and Peter Jüni

University of Bern

Institute of Social and Preventive Medicine

Division of Clinical Epidemiology & Biostatistics

Finkenhubelweg 11

3012 Bern, Switzerland

1. Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ. 1994;309:1351-5. [PMID: 7866085]

2. Jüni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001;323:42-46. [PMID: 11440947]

3. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta- analyses. Ann Intern Med. 2001;135:982-9. [PMID: 11730399]

4. Nasonova VA, Alekseeva LI, Arkhangel'skaia GS, Davydova AF, Karmil'tseva EA, Kogan KM, et al. [Results of the multicenter clinical trial of structum preparation in Russia]. Ter Arkh. 2001;73:84-7. [PMID: 11806217]

5. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage. 1996;4:217-43. [PMID: 11048620]

6. Kahan A. STOPP (STudy on Osteoarthritis Progression Prevention): a new two-year trial with chondroitin 4&6 sulfate(CS). Accessed at http://www.ibsa-ch.com/eular_2006_amsterdam_vignon-2.pdf on 18 September 2006.

7. Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005;52:779-86. [PMID: 15751094]

8. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808. [PMID: 16495392]

Conflict of Interest:

None declared

How solid are the results of the meta-analysis by Reichenbach et al. and its conclusions?
Posted on November 30, 2007
Andreas G. Helg
Institut Biochimique SA
Conflict of Interest: None Declared

Reichenbach et al. (1) aimed in their recent meta-analysis at the examination of the effects of chondroitin sulfate on pain in patients with knee (or hip) osteoarthritis. They found for chondroitin sulfate a pooled effect size of "“0.75 (95 % CI, "“0.99 to "“0.50) corresponding to a large symptomatic effect. They, however, noted a high degree of between-trial heterogeneity (I2 of 92 %, p < 0.001). In order to identify factors that correlate with observed effects they thus performed univariable meta- regression analyses. These analyses showed that 4 factors, concealment of allocation (adequate or unclear), intention-to-treat analysis (yes or no/unclear), number of patients (≤ 200 or >200), and year of publication (as continuous variable) were associated with treatment effects. From these findings they concluded that trials of better quality (with adequate concealment of allocation and intention-to-treat analysis) gave smaller effects, and that observed effects decreased with time (year of publication) as with time quality of trials improved. Accordingly, they argued that their analysis can be restricted to 3 of the most recent trials which were homogenous with respect to the factors they associated with heterogeneity and included 40 % of all patients. From the pooled effect size of these 3 trials they finally concluded that the symptomatic benefit of chondroitin sulfate is minimal or inexistent.

This approach is debatable. Indeed, even the author of the editorial (2) rose the question whether it was reasonable to select 3 large-scale trials and not summarize all of the evidence.

We asked ourselves whether the authors did not miss out any analyses or disregard any factors in their considerations. In particular, we wondered whether there was really no relation between observed effects and duration of follow-up. This question is crucial as 2 out of the 3 selected trials were long-term trials with a duration of follow-up of 24 months or more carried out primarily to verify the structure-modifying properties of chondroitin sulfate.

Considerations regarding the duration of follow-up:

We, therefore, carried out additional univariable meta-regression analyses using the same data, estimations of effect sizes, and methods as in the publication of Reichenbach et al. (1) and in the appendices thereof. These analyses revealed an association between effect size and duration of follow-up as a continuous variable (p = 0.04), i.e. the longer the duration of the trials the smaller the observed effects. In particular, also stratified analyses indicated an association between effect size and duration of follow-up when the cutoff between short- and long-term trials was set to 12 months (p = 0.04 for ≤ 12 months vs > 12 months) instead of 6 as was done by Reichenbach et al. (1). Thus, there exists an association between the duration of follow-up and observed effects that cannot be ignored in the context of such a meta-analysis.

This finding is not surprising. Also Scott et al. (3) observed that the NSAIDs they examined did not reduce pain more efficaciously than placebo after 1 year. Furthermore, in most long-term trials conducted to provide evidence of a structure-modifying effect, the investigated drug was not superior to placebo at the end of follow-up with respect to pain reduction (4"“9). Whether in long-term trials clinically significant symptomatic improvements and structure-modification actually can be demonstrated concomitantly remains unclear (9, 10, 11).

A dependence of the treatment effects on the duration of follow-up could also be observed in the STOPP trial (5), 1 out of the 3 trials selected by Reichenbach et al. (1). In this trial pain on VAS and WOMAC pain subscores had decreased significantly more in the group with active treatment than in the placebo group after 1, 3, 6, and 9 months. The largest difference between groups was observed after 6 months and corresponded to an effect size of "“0.23 (SE = 0.08) for VAS and "“0.21 (SE = 0.08) for WOMAC pain subscores (intention-to-treat analysis). We would like to note that a duration of follow-up of 6 months actually corresponds to the trial duration recommended by regulatory authorities (12) for the assessment of the symptom modifying properties of symptomatic slow-acting drugs in osteoarthritis (SYSADOAs) like chondroitin sulfate.

We do not comprehend why the authors had not noticed the association between observed effects and duration of follow-up indicated above and why they did not mention that 2 out of the 3 trials they selected were long- term trials which were actually carried out to verify the structure- modifying properties of chondroitin sulfate, and not to assess its symptomatic effects. Moreover, we cannot understand why they did not take into account the superiority of chondroitin sulfate during the first 9 months in the STOPP trial, and why they did not consider or at least discuss the possibility of assessing the symptomatic effects independently of the duration of follow-up of the trials and in accordance with regulatory requirements (12) after 6 months.

The authors restricted their meta-analysis to 3 trials that they considered to be homogenous, in particular with respect to the factors they associated with between-trial heterogeneity. With the identification of an additional factor associated with between-trial heterogeneity, the duration of follow-up, this approach, however, can no longer be sustained as 2 of the 3 selected trials are completely different from the remaining one with respect to the newly identified factor.

In addition to the association between treatment effects and year of publication revealed already by the authors, we also found an association between duration of follow-up and year of publication (p = 0.02) as well as between the number of patients and the year of publication (p = 0.0003), i.e. trials became longer and larger with time. Thus, the decrease in observed effects with the year of publication may not only be due to an increase of quality of trials with time as concluded by Reichenbach et al. (1), but also to the increase in duration of follow-up with time. This conclusion is likely to be more plausible as there exists a causal link between duration of follow-up, number of patients, and time (year of publication): The duration of follow-up increased with time because in recent years the primary goal of most trials with chondroitin sulfate was the assessment of the structure-modifying properties of this drug. In accordance with regulatory requirements (12), such trials, however, demand a longer duration of follow-up and much larger numbers of patients as observable effects are small and larger numbers of drop-outs need to be accounted for.

Other aspects:

Reichenbach et al. (1) stated in their publication that they contacted the authors of the trials that they included into their meta- analysis. Unfortunately, we could not deduce from the respective text passages in their publication whether they actually contacted the authors systematically in order to gather missing information"“what would be more appropriate"“or only if they could not calculate an effect size. We tried to get in touch with the authors of the trials included in the meta- analysis in order to verify whether they had indeed been contacted. By the time of completion of this letter we had obtained an answer from 9 of these authors responsible for a total of 12 out of the 20 trials included in the meta-analysis. No one of the authors who had responded to our inquiry had been contacted by any of the authors of the meta-analysis.

In their meta-analysis Reichenbach et al. (1) applied a most recent definition of intention-to-treat to distinguish between trials with and trials without such an analysis. The definition of intention-to-treat, however, has changed with time. In particular, patients who had been enrolled in a trial, but not received any treatment, i.e. whether any unit of the examined drug, nor placebo, previously were excluded from ITT analyses what is not the case anymore today. In addition to the trials with an intention-to-treat analysis according to the definition given in the meta-analysis the publications of the following trials provided results of intention-to-treat analysis in accordance with the definitions and standards applicable at the time of their release: Bourgeois et al. (13), Bucsi and Poór (14), Malaise et al. (15), Pavelka et al. (16), and Mazières et al. (17, 18). In all these trials missing data were completed according to the last observation carried forward method.

The publication by Malaise et al. in Litera Rheumatologica (15) was a proceeding of the EULAR congress 1998. The full paper was published 2004 in Osteoarthritis and Cartilage by Uebelhart et al. (19). The authors, however, only refer to the proceeding which had not yet contained all methodological details and results.

The authors also had included the 2 most recent trials which by the time of publication of the meta-analysis had been available only in form of abstracts (5, 18). These abstracts did not provide all methodological details and results. In particular, the abstract by Kahan (5) also did not contain any results regarding the symptomatic effect of chondroitin sulfate. Additionally, the authors of these abstracts belong to those who had not been contacted by the authors of the meta-analysis in order to complete missing information.

The 4 circumstances described in the last 4 paragraphs are crucial with respect to the factors which the authors associated with between- trial heterogeneity, and thus with respect to the restriction of the meta- analysis to 3 trials. If based on the above summarized circumstances they had judged some trials differently with respect to concealment of allocation or intention-to-treat analysis the correlations between observed effects and these factors might have resulted differently.

Conclusion:

We hold that the approach pursued by the authors is not robust. In particular, the meta-analysis cannot be restricted to only 3 trials. Furthermore, because of correlations between many of the analyzed factors, sustainable conclusions may not be drawn from the results of univariable analyses based on data extracted solely from publications, but only from multivariate meta-regression analyses based on data verified in collaboration with the authors of the underlying publications. Additional factors such as pain at baseline, radiographic stage of osteoarthritis, and time adjusted drop-out rates also need to be looked at carefully.

Note regarding effects of chondroitin sulfate on joint space narrowing (JSN):

The authors of the meta-analysis wrote that they found differences in changes between chondroitin sulfate and placebo corresponding to small effect sizes. We would like to point out that the calculation of effect sizes is not meaningful to assess the structure-modifying properties of chondroitin sulfate as the progression of JSN was virtually halted in the groups with active treatment and as, therefore, the differences between groups essentially reflect the natural progression of osteoarthritis in the placebo groups. By claiming that the effect sizes are small the authors of the meta-analysis are actually saying that the natural progression of osteoarthritis (the numerator) is slow (small) and that the measurement error (the denominator) is large. The latter fact is known and is compensated for by a larger number of patients and a duration of follow -up of at least 2 years (12).

Andreas G. Helg, PhD, Institut Biochimique SA, Via del Piano, CH-6915 Pambio-Noranco, Switzerland.

Florent de Vathaire, Research Director, University of Paris XI, Director of the INSERM UNIT 605, Institut Gustave Roussy, 39 Rue Camille Desmoulins, F-94805 Villejuif, France

1. Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007;146:580-90.

2. Felson DT. Editorial: chondroitin for pain in osteoarthritis. Ann Intern Med. 2007;146:611-2.

3. Scott DL, Berry H, Capell H, Coppock J, Daymond T, Doyle DV, et al. The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial. Rheumatology. 2000;39:1095-101.

4. Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P, et al. Chondroitin 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005;52:779-86.

5. Cited in the meta-analysis as: Kahan A. STOPP (STudy on Osteoarthritis Progression Prevention): a new two-year trial with chondroitin 4&6 sulfate (CS). Assessed at www.ibsa- ch.com/eular_2006_amsterdam_vignon-2.pdf on 18 September 2006. Updated reference: Reginster JY, Kahan A, Vignon E. A two-year prospective, randomized, double-blind, controlled study assessing the effect of chondroitin 4&6 sulfate (CS) on the structural progression of knee osteoarthritis: STOPP (STudy on Osteoarthritis Progression Prevention). Program Book of the ACR/ARHP Annual Scientific Meeting; 10"“15 November 2006; Washingtion, DC: Abstract L42.

6. Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005;52:2015-25.

7. Lequesne M, Maheu E, Cadet C, Dreiser RL. Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip. Arthritis Rheum. 2002;47:50-8.

8. Dougados M, Nguyen M, Berdah L, Mazières B, Vignon E, Lequesne M; ECHODIAH Investigators Study Group. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the chondromodulating effect of diacerein in OA of the hip. Arthritis Rheum. 2001;44:2539-47.

9. Brandt KD, Mazzuca SA. Lessons learned from nine clinical trials of disease-modifying osteoarthritis drugs. Arthritis Rheum. 2005;52:3349- 59.

10. Bruyere O, Reginster JY, Giacovelli G, Barbetta B, Rovati LC, Pavelka K. Clinical significance of the long-term symptom-modifying effects of glucosamine sulfate: comment on the article by Brandt and Mazzuca (9). Arthritis Rheum. 2006;54:2339-41.

11. Brandt KD, Mazzuca SA. Author reply to (10). Arthritis Rheum. 2006;54:2341-3.

12. Committee for Proprietary Medicinal Products, The European Agency for the Evaluation of Medicinal Products: Human Medicines Evaluation Unit. Points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis. 1998 (CPMP/EWP/784/97).

13. Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz JL, Rozenberg S. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthritis Cartilage. 1998;6 Suppl A:25-30.

14. Bucsi L, Poór G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 1998;6 Suppl A:31-6.

15. Malaise M, Marcolongo R, Uebelhart D, Vignon E. Efficacy and tolerability of 800 mg oral chondroitin 4&6 sulfate in the treatment of knee osteoarthritis: a randomised, double-blind, multicentre study versus placebo. Litera Rheumatologica. 1999;24:31-42.

16. Pavelka K, Manopulo R, Bucsi L. Double-blind, dose-effect study of oral chondroitin 4&6 sulfate 1200 mg, 800 mg, 200 mg and placebo in the treatment of knee osteoarthritis. Litera Rheumatologica. 1999;24:21-30.

17. Mazières B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol. 2001;28:173-81.

18. Mazières B, Hucher MMH, Zam MMZ. Chondroitin sulfate in the treatment for knee osteoarthritis: a randomized, double blind, multicenter, placebo-controlled trial. Ann Rheum Dis. 2006;65(Suppl II):398 (abstract). Full paper: Mazières B, Hucher M, Zaïm M, Garnero P. Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2007;66:639-45.

19. Uebelhart D, Malaise M, Marcolongo R, DeVathaire F, Piperno M, Mailleux E, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12;269-76.

Conflict of Interest:

Andreas G. Helg is employed by IBSA Institut Biochimique SA, a Swiss manufacturer and distributor of a chondroitin prescription drug. Florent de Vathaire is consulting IBSA Institut Biochimique SA as a biostatistician.

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