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

Context People sometimes use chondroitin preparations to prevent hip or knee damage and pain. Contribution This systematic review summarized data from 20 trials that compared the effects of chondroitin with either placebo or no treatment in patients with hip or knee osteoarthritis. Recent high-quality trials showed chondroitin had minimal or no effect on joint pain. Effects on joint space were inconclusive. Few adverse events were reported. Implication Chondroitin probably does not prevent or reduce joint pain in people with osteoarthritis. The Editors Pharmacologic therapy for osteoarthritis consists mainly of analgesics and nonsteroidal antiinflammatory drugs. Although these are the most commonly prescribed agents for this condition, they may cause serious gastrointestinal and cardiovascular adverse events and do not affect the underlying structural cartilage damage (1, 2). A disease-modifying therapy would be more beneficial. Attempts have been made to influence cartilage loss in osteoarthritis by administering such cartilage constituents as chondroitin (38). Chondroitin is a highly hydrophilic, gel-forming polysaccharide macromolecule. Its hydrocolloid properties convey much of the compressive resistance of cartilage. Despite its large molecular size, ingested chondroitin is partially absorbed in the intestine (912) and some of it may reach joints (9, 13). Oral chondroitin for treating osteoarthritis has become widespread (14). A previous meta-analysis demonstrated moderate to large effects on symptoms (4) but questioned the quality of the included studies. Recently published large-scale trials of high methodological quality (3, 8) found conflicting results. We performed a systematic review and meta-analysis of all available randomized, controlled trials to determine the effects of chondroitin on pain and joint space width and to explore whether reported beneficial effects could be explained by biases affecting individual trials or publication bias. Methods Literature Search We searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), and CINAHL (1982 to 2006) using a combination of keywords and text words related to osteoarthritis; these were combined with generic and trade names of the various preparations of chondroitin plus a validated filter for controlled clinical trials (15). Appendix Table 1 shows the details of the search. We used similar strategies to identify previously published systematic reviews and meta-analyses. In addition, we manually searched conference proceedings and textbooks, screened reference lists of all papers, retrieved reports citing relevant articles through Science Citation Index (1981 to 2006), and contacted trialists and content experts. Finally, we searched 4 clinical trial registries (www.clinicaltrials.gov, www.controlled-trials.com, www.actr.org.au, and www.umin.ac.jp/ctr) to identify ongoing trials. The last update of searches was performed on 30 November 2006. Appendix Table 1. Search Strategy* Trial Selection We included randomized or quasi-randomized, controlled trials in patients with osteoarthritis of the knee or hip, which compared chondroitin with placebo or with no intervention. Trial groups given low doses (<400 mg/d administered orally) were excluded. No language restrictions were applied. Two reviewers independently evaluated reports for eligibility. Disagreements were resolved by discussion. Quality Assessment Two of 3 reviewers independently assessed concealment of treatment allocation, blinding, and adequacy of analyses (16). Concealment of allocation was considered adequate if the investigators responsible for patient selection were unable to suspect before allocation which treatment was next. Analyses were considered adequate if all recruited patients were analyzed in the group to which they were originally allocated, regardless of the treatment received (intention-to-treat principle). Because there is debate about how to handle missing data in the analyses of continuous outcomes (17), we did not assess whether the methods that were used were appropriate. Appendix Table 2 shows additional details regarding quality assessment. Disagreements were resolved by discussion with a third reviewer and subsequent consensus. Appendix Table 2. Methodological Characteristics of Included Trials* Outcome Measures The prespecified primary end point was pain at the end of the trial or at a maximum of 3 months after termination of chondroitin therapy (whichever came first). When an article provided data on more than 1 pain scale, we referred to a previously described hierarchy of pain-related outcomes (18) and extracted the outcome that was highest on this list. Global pain took precedence over pain on walking and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores. If a trial report provided data on global pain scores and WOMAC pain subscores, we only recorded data on global pain scores. Secondary end points were changes in minimum and mean radiographic joint space width and, as measures of drug safety, the number of patients experiencing any adverse event, patients who withdrew because of adverse events, and patients experiencing any serious adverse events (19). Data Collection Data regarding publication status, trial design, patient characteristics, treatment regimens, outcome methods, results, and funding were extracted in duplicate on a standardized form. When necessary, means and measures of dispersion were approximated from figures in the reports. For crossover trials, we extracted data from the first period only because of a possible carry-over effect of chondroitin. If effect sizes could not be calculated, we contacted the authors for additional data. Disagreements were resolved by discussion with a third reviewer and subsequent consensus. Statistical Analysis Whenever possible, we used results from an intention-to-treat analysis. Effect sizes were calculated by dividing the differences in mean values at the end of the trial across treatment groups by using the pooled SD (20). Appendix Table 3 shows the formulas that were used. If some required data were unavailable, we used the approximations described in Appendix Table 4 (21, 22). An effect size of 0.30 may be considered minimally clinically relevant. On the basis of a median pooled SD in trials that assessed pain by using a visual analogue scale (VAS) (2.1 cm on a 10-cm VAS), this effect size corresponds to a difference in pain scores of 0.6 cm (on a 10-cm VAS) between chondroitin and placebo groups. Appendix Table 3. Equations* Appendix Table 4. Calculation of Effect Sizes* We used standard random-effects meta-analysis (23) and calculated the I2 statistic, which describes the percentage of total variation across trials that is attributable to heterogeneity rather than to chance (24). I2 values of 25%, 50%, and 75% correspond to low, moderate, and high between-trial heterogeneity. We investigated the association between trial size and treatment effects in funnel plots by plotting effect sizes on the vertical axis against their SES on the horizontal axis (25). We assessed asymmetry by the asymmetry coefficientthe difference in effect size per unit increase in SE (26). We then performed analyses stratified by the following trial characteristics: concealment of allocation, use of a placebo control, patient blinding, adequacy of analyses in accordance with the intention-to-treat principle, trial size, funding, route of administration, length of follow-up, and differences in the use of cointerventions in the trial groups. We used a prespecified cutoff of 200 randomly assigned patients to distinguish between small-scale and large-scale trials and a cutoff of 26 weeks to distinguish between short-term and long-term trials. Univariable random effects meta-regression models (27) were used to examine whether effect sizes were affected by these factors. In addition, the following 3 continuous variables at trial level were included in univariable meta-regression: chondroitin dosage (in trials with oral administration), treatment duration, and length of follow-up. To explore whether small effect sizes might be explained by unusually high effects in the placebo group, we used an approach analogous to plots used by L'Abb and colleagues (28) and plotted changes in pain scores in the control group against changes in pain scores in the chondroitin group, which were standardized by the pooled SD (20). Finally, we restricted the analysis to large-scale placebo-controlled trials (200 randomly assigned patients) with an intention-to-treat analysis. Differences in changes in minimal and mean joint space width were pooled by using original units in millimeters. To explore the magnitude of effects on the width of the joint space, we expressed these differences as effect sizes, dividing the pooled estimates in millimeters by the median pooled SD of 1.3 mm found for minimal and mean joint space width. We performed analyses by using Stata, version 9.2 (Stata Corp., College Station, Texas). Role of the Funding Sources Drs. Reichenbach and Jni 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. Brgi 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 Jni is a senior research fellow in the Program for Social Medicine, Preventive and Epidemiological Research funded by the Swiss National Science Foundation (grant no. 3233-066377). The funding agencies had no role in study design, data collection, data synthesis, data interpretation, writing the report, or the decision to submit the manuscript for publication. None of the authors is affiliated with or funded by any manufacturer of a c