Background: Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra- articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment.
Methods: We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events.
Results: Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. Patients who received the intervention experienced a reduction in pain during movement: the mean difference on a 100-mm visual analogue scale was –3.8 mm (95% confidence interval [CI] –9.1 to 1.4 mm) after 2–6 weeks, –4.3 mm (95% CI –7.6 to –0.9 mm) after 10–14 weeks and –7.1 mm (95% CI –11.8 to –2.4 mm) after 22–30 weeks. However, this effect was not compatible with a clinically meaningful difference (expected to be about 15 mm on the visual analogue scale). Furthermore, the effect was exaggerated by trials not reporting an intention-to-treat analysis. No improvement in knee function was observed at any time point. Even so, the effect of hyaluronic acid on knee function was more favourable when allocation was not concealed. Adverse events occurred slightly more often among patients who received the intervention (relative risk 1.08, 95% CI 1.01 to 1.15). Only 4 trials explicitly reported allocation concealment, had blinded outcome assessment and presented intention-to-treat data.
Interpretation: According to the currently available evidence, intra- articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit–risk ratio. Osteoarthritis affects about 10% of the population
over 55 years of age. Of those, one-quarter are severely disabled.1 The condition is characterized by degeneration of the articular cartilage and subsequent subchondral bone changes. The underlying mechanisms remain unknown, but the glycosaminoglycan–proteoglycan matrix may play a major role.
Hyaluronic acid, a glycosaminoglycan, is widely used for the treatment of osteoarthritis of the knee. A survey of 2 general practices in the United Kingdom showed that about 15% of patients with osteoarthritis received intraarticular treatment with glucosamine sulfates. The costs of such treatment are significant. At present, 1 syringe of hyaluronic acid costs at least Can$130 (US$110). The treatment of knee osteoarthritis is covered by the US
Medicare program but not by provincial formularies in Canada. In Austria (which has 8 million inhabitants) more than 10 million euros (approximately US$12 million or Can$15 million) is spent by social insurance programs annually for hyaluronic acid preparations (excluding the cost of application).
Hyaluronic acid has beneficial effects in vitro.4 Because of its viscoelastic quality, it may replace synovial fluid. Furthermore, it may reduce the perception of pain. Beneficial molecular and cellular effects have also been reported. Hyaluronic acid is frequently applied by intra-articular injection, but the evidence concerning its clinical relevance is conflicting. The European League against Rheumatism (EULAR) recommends the intra-articular application of hyaluronic acid as “category 2” evidence (at least 1 controlled study without randomization).5 The American College of Rheumatology recommends intra-articular hyaluron therapy for patients with no response to nonpharmacologic therapy and simple analgesics. In contrast, other specialists have concluded that “hyaluronate sodium is not efficacious” in the treatment of osteoarthritis.7 The first state-of-the-art systematic review and meta-analysis was published recently, and its authors concluded “that intra-articular hyaluronic acid, at best, has a small effect.”
We performed a systematic review and meta-analysis of the effect of intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee. In contrast to previous metaanalyses on this subject, we used a different approach to data synthesis and interpretation: instead of analyzing a composite effect size over time, we allocated trial data, when possible, to 3 outcome groups that we assumed would be relevant for patients with osteoarthritis. We specifically looked at pain at rest, pain during exercise and joint function as distinct outcomes, measured repeatedly over time. In addition, we assessed adverse events and the impact of both trial quality and molecular mass of the product. This analysis allows us to provide important additional insight into the effects of intra-articular administration of hyaluronic acid for the treatment of osteoarthritis of the knee. variation due to unexplained heterogeneity: I2 = (Q – df)/Q.14 A value of less than 20% is consistent with little variability between studies, and 20% to 50% can be considered to represent a moderately large degree of variation. Regression methods were used to assess the presence of publication bias.
We used multivariate meta-regression analysis to assess whether an effect had been influenced by allocation concealment (blinding of randomization, yes versus no or unclear), blinded outcome assessment (blinded treating physician, patient and outcome assessor, explicitly reported versus not explicitly reported or unclear) and intention-to-treat analysis (explicitly reported versus not explicitly reported or unclear). We repeated the analyses for only those trials that fulfilled all 3 criteria.
We assessed the impact of the molecular mass of the hyaluronic acid on efficacy. We used molecular mass as an ordinal category and then collapsed categories of molecular mass into 2 categories (≤900 kDa and > 900 kDa) and repeated the analysis.