A risk-benefit assessment of injections of hyaluronan and its derivatives in the treatment of osteoarthritis of the knee.

Hyaluronan is critical for the homeostasis of the joint as an organ, in part, because it provides the rheological properties (viscosity and elasticity) of the synovial fluid. These properties depend upon both the concentration and the molecular weight of the hyaluronan in the synovial fluid. In osteoarthritis, the hyaluronan is both smaller in size and lower in concentration. Thus, it is rational and physiologically meaningful to treat osteoarthritis with viscosupplementation, i.e. injection of material designed to increase the rheological properties of the synovial fluid. It is important, though, to assess the risks and benefits of such a physiological treatment. There are various products on the market for viscosupplementation. These include hyaluronan preparations of relatively low molecular weight (Hyalgan and ARTZ), a hyaluronan preparation of intermediate molecular weight, but still lower molecular weight than that of the hyaluronan in normal healthy synovial fluid (Orthovisc), and a cross-linked hyaluronan (a hylan) of high molecular weight (Synvisc). The evidence from in vitro and in vivo models of osteoarthritis and from clinical trials to date suggests that efficacy, as would be expected by mechanistic reasoning, depends strongly upon molecular weight. The available evidence indicates that these products differ little in the incidence and severity of adverse events (about 2 to 4%, almost always local swelling, and with no adverse sequelae). All are very well tolerated in comparison to nonsteroidal anti-inflammatory drug therapy, although direct comparisons are few. The only potentially serious adverse event is joint infection, which is rare and directly dependent upon the number of injections, among other factors. No infection has been related to contamination of any of the products. In summary, treatment with low molecular weight preparations of hyaluronan seems to be effective. However, viscosupplementation with hyaluronan preparations may have slightly higher risk and less benefit than viscosupplementation with hylans, because the relatively lower molecular weight hyaluronan preparations require more injections which may incur higher costs and theoretically an increased chance of infection. Viscosupplementation with hylans is clearly effective, and the available evidence suggests that the benefits almost certainly outweigh the risks.

The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone.

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.