Cochrane in CORR^®: Viscosupplementation for the Treatment of Osteoarthritis of the Knee

Importance of the Topic

Osteoarthritis is the most common joint disorder in the world [1]. It affects approximately 15% of adults older than 45 years of age [19], and nearly half of all adults will experience symptomatic osteoarthritis by age 85 [20]. Osteoarthritis is more common than Type 2 diabetes and most forms of cancer [22, 24]. In the United States, osteoarthritis is second only to back pain as a cause of lost productivity [25], and annual total healthcare expenditures related to osteoarthritis are as high as USD 80 billion. This figure is expected to increase during the next decade [27]. The appropriate management of younger patients with mild or moderate osteoarthritis remains a challenging area in the day-by-day clinic and intense research is being conducted [5, 11, 15].

Hyaluronic acid is a glycosaminoglycan molecule made of repeating units of N-acetyl-glucosamine and glucoronic acid [3]. It is one of the main components of normal synovial fluid. Hyaluronic acid functions through antiinflammatory, anabolic, analagesic, and chondroprotective mechanisms [2]. Biomechanically, it may act as a viscoelastic shock absorber, and perhaps as a lubricant in the joint [6]. The synovial fluid in knees with osteoarthritis contains elevated levels of free radicals, inflammatory cytokines, and cleavage enzymes [13], which impair hyaluronic acid function and contribute to the progression of osteoarthritis [3]. Viscosupplementation attempts to restore the biomechanical and biochemical functions of normal synovial fluid through intraarticular injections of hyaluronic acid. This systematic review and meta-analysis examined the effects of viscosupplementation in the treatment of osteoarthritis of the knee.

Upon Closer Inspection

Several preparations of modern commercial hyaluronic acid are currently globally available. They differ mostly by molecular weight, method of production, half-lives, and cost [25]. They are produced either from harvested rooster combs or via bacterial fermentation in vitro [18]. Some can be administered in single-dose regimens, but most require three to five weekly injections [25]. Higher molecular weight hyaluronic acid is suggested to have greater clinical efficacy, but the current literature is inconclusive [17]. This meta-analysis included only randomized controlled trials, and compared 19 different formulations of hyaluronic acid across 76 studies (9847 patients). However, there were few head-to-head trials and firm conclusions about the relative value of each formulation were not possible. Additionally, a diversity of control interventions were utilized, including placebo, intraarticular corticosteroids, nonsteroidal antiinflammatory drugs, physiotherapy, and arthroscopy, which meant that most analyses were based on only a few small trials.

The authors reported no major safety issues for viscosupplementation, but cautioned that the included trials were underpowered to detect rare adverse events [4]. Self-limited (and benign) soft-tissue reactions at viscosupplementation injection sites have been reported in up to 3% of injections [25, 26], and several reports have also described a rare but much more severe acute local reaction known as “pseudosepsis.” Severe acute local reactions typically require arthrocentesis, nonsteroidal antiinflammatories, and intra-articular corticosteroid injections [12]. One study [16] reported a 21% incidence of severe acute local reactions in patients receiving more than one course of treatment, suggesting that patients who desire additional courses should be counseled of their possible increased risk. Future studies should investigate if certain patients are at risk for these reactions, and whether they could safely receive specific formulations [25]. Long-term safety could best be observed in large observational studies modeled after current total joint arthroplasty device registries or pharmaceutical postmarketing “phase-IV” surveillance studies [10, 14, 23].

Take-Home Messages

This Cochrane review found overall benefits to viscosupplementation in comparison to placebo for pain, function, and patient global assessment scores. Several other recent meta-analyses have produced conflicting results [9, 20, 28]. Rutjes et al. [21] found overall no clinically important benefit for pain intensity or frequency of osteoarthritis flares in 89 trials involving 12,667 patients, but high-molecular-weight and cross-linked preparations had greater effects, according to the Rutjes and colleagues study. Campbell et al. [9] reviewed six meta-analyses, and highlighted differences in search strategies, selection criteria, choices of pooled outcome measures and time-points, assessments of study quality, and selection of statistical model. Current clinical guidelines mention poor study quality, publication bias, conflicting results, industry-sponsorship, and unclear clinical significance for their inconclusive recommendations [7, 11, 29].

Based on the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach [8], viscosupplementation for knee osteoarthritis provides a probable pain reduction and improvement of physical function with a low-risk of harm [4, 9, 29]. It is a viable option in younger patients with less severe disease, but further investigations are still required. Future studies should examine whether high molecular weight and cross-linked preparations have superior efficacy, determine long-term outcomes and safety, and include economic analyses [4, 25]. Recurrent methodological limitations related to study heterogeneity, outcome reporting, and bias must be overcome [9, 11, 20, 29].

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