A Risk-Benefit Assessment of Injections of Hyaluronan and its Derivatives in the Treatment of Osteoarthritis of the Knee

Abstract

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.

Hyaluronic acid inhibits mRNA expression of proinflammatory cytokines and cyclooxygenase‐2/prostaglandin E2 production via CD44 in interleukin‐1‐stimulated subacromial synovial fibroblasts from patients with rotator cuff disease

“…Although HA is widely used in the treatment of OA, [12][13][14] the nature of its anti-inflammatory mechanism remains poorly understood. 11 Similarly, a clinical benefit of HA in rotator cuff disease was demonstrated by Shibata et al, 15 although little is known about its anti-inflammatory effect in the disease.…”

“…11 Intraarticular HA injection is used to treat knee OA, and its therapeutic efficacy has been verified. [12][13][14] In rotator cuff disease, Shibata et al uniquely demonstrated that HA injection is an effective conservative procedure, 15 although the mechanism of its anti-inflammatory effect is not fully understood.…”

Rheologic Behavior of Osteoarthritic Synovial Fluid after Addition of Hyaluronic Acid: A Pilot Study

“…The advantage of cross-linkage seems mainly to increase the stability and residence time of the VS in the joint. However, other studies suggest the noncross-linked VS effect is comparable with that of the cross-linked system [27,43], and to date, no definitive conclusion has been reached regarding any advantage of cross-linkage on the clinical benefit [2,27,29,33,52,59]. Therefore, techniques aimed at investigating variations of HA (concentration and molecular weight) and rheologic changes attributable to VS are needed to better understand its mechanisms of action and to determine possible differences between different HA commercial formulations.…”

Tratamento medicamentoso da osteoartrose do joelho

“…Existem no mercado vários preparados de ácido hialurônico e as suas diferentes propriedades reológicas são dependentes basicamente de seus pesos moleculares (8) . Com um peso molecular de 6x10 6 daltons (Da), as propriedades viscoelásticas do Hylan G-F 20 são similares às do líquido sinovial de adultos jovens saudáveis (3) ; três injeções semanais são comprovadamente seguras e superiores em eficácia em relação ao placebo (infiltração com solução salina ou artrocentese) (9,10) com analgesia de até seis meses.…”