• Anne W S Rutjes, Peter Jüni, Bruno R da Costa, Sven Trelle, Eveline Nüesch, and Stephan Reichenbach.
• Institute of Social and Preventive Medicine, University of Bern, Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland.
• Ann. Intern. Med. 2012 Aug 7;157(3):180-91.

BackgroundViscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.PurposeTo assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis.Data SourcesMEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources.Study SelectionRandomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis.Data ExtractionPrimary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression.Data SynthesisEighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, -0.37 [95% CI, -0.46 to -0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of -0.03 (CI, -0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of -0.11 (CI, -0.18 to -0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]).LimitationsTrial quality was generally low. Safety data were often not reported.ConclusionIn patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.Primary Funding SourceArco Foundation.

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