Efficacy of Chondroitin Sulfate in Patients with Knee Osteoarthritis: A Comprehensive Meta-Analysis Exploring Inconsistencies in Randomized, Placebo-Controlled Trials

INTRODUCTION: There are some controversies about treatment modalities in osteoarthritis (OA), including chondroitin sulfate (CS). The objective of this study was to determine whether CS is effective at alleviating pain and improving function in patients with knee OA and to identify the factors that explain inconsistencies in clinical trial results. METHODS: We conducted a systematic review of randomized, placebo-controlled trials, searching the databases Medline, Cochrane central register for controlled trials and Scopus. Random effects meta-analysis was then performed, using tau(2) and I(2) statistics to assess heterogeneity. The pain and Lequesne index (LI) scores were expressed as standardized mean differences (SMDs), with a 95% confidence interval (CI). Heterogeneity was explored by stratifying the analyses according to pre-specified study-level characteristics and assessing the sources of funnel plot asymmetry. RESULTS: The inclusion criteria yielded 18 trials. Overall, CS significantly but inconsistently reduced pain (SMD: − 0.63; 95% CI: − 0.91, − 0.35; I(2) = 94%) and improved function (SMD: − 0.82; 95% CI: − 1.31, − 0.33; I(2) = 95%). When limiting the analysis to studies with a low risk of bias, the pharmaceutical grade CS of IBSA origin showed a greater reduction in pain (SMD: − 0.25; 95% CI: − 0.34, − 0.16; I(2) = 75%) and function (SMD: − 0.33; 95% CI: − 0.47, − 0.20; I(2) = 53%, p = 0.07) compared with the other preparations (SMD(Pain): − 0.08; 95% CI: − 0.19, + 0.02; I(2) = 20%; SMD(Function): − 0.18; 95% CI: − 0.36, +0.01; I(2) = 0%). Assessing funnel plot asymmetry in the studies with a low risk of bias, we found strong correlations between the treatment effects and study size (pain: r(S) = 0.93; LI: r(S) = 0.86; p < 0.05). Ultimately, there was no residual heterogeneity in the CS effects when the smallest studies were removed from the analyses. CONCLUSION: This new meta-analysis suggests that CS provides a moderate benefit for pain and has a large effect on function in knee OA, however with large inconsistency. The risks of bias, brand and study size were the factors explaining heterogeneity among the clinical trial results. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12325-019-00921-w) contains supplementary material, which is available to authorized users.