A Cochrane review included 76 studies. Follow-up periods varied between day of last injection and 18 months. Forty trials included comparisons of hyaluronan/hylan and placebo, 10 trials included comparisons of intra-articular (IA) corticosteroids, 6 trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), 3 trials included comparisons of physical therapy, 2 trials included comparisons of exercise, 2 trials included comparisons of arthroscopy, 2 trials included comparisons of conventional treatment, and 15 trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses.
A systematic review included 22 studies with a total of 2 949 subjects. The sample size ranged from 24 to 408. Seven RCTs provided data on an intention-to-treat basis. Seventeen studies were sponsored by industry. Overall, the studies found a small effect for hyaluronic acid compared with placebo (ES 0.32, 95% CI 0.17–0.47, p<0.001). The forest plot showed two outlier studies with an ES greater than 1.5; both used the highest molecular weight hyaluronic acid. After removal of the 3 RCTs using the highest molecular weight hyaluronic acid, the effect decreased (ES 0.19, 95% CI 0.10–0.27, p<0.001). There was evidence of publication bias (asymmetrical funnel plot and Egger test p=0.07). Unpublished studies showed a non significant ES for hyaluronic acid compared with placebo (ES 0.07, 95% CI -0.15–0.28). Statistically significant heterogeneity was detected (p<0.001) for the meta-analysis of all studies. After removing the 3 RCTs (n=252) using the highest molecular weight hyaluronic acid heterogeneity was no longer statistically significant (p=0.58).
Comment: The quality of evidence is downgraded by inconsistency (variability in results across studies) and by potential reporting bias.