Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: A systematic review and meta-analysis

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Abstract

Objective

To assess the relative efficacy of intra-articular hyaluronic acid (IAHA) in comparison with non-steroidal anti-inflammatory drugs (NSAIDs) for knee osteoarthritis (OA).

Methods

We searched Medline, EMBASE, Google Scholar, ISI Web of Science, and Cochrane Database from inception until February 2013. Randomized controlled trials comparing HA with NSAIDs for knee OA were included if they reported at least one pain outcome. Two reviewers abstracted data and determined quality. Outcomes included pain, function, and stiffness. Random-effects meta-analyses were performed.

Results

Five trials (712 participants) contributed to the pain analysis. Both groups showed improvement from baseline. The analysis found an effect size (ES) of −0.07 (95% CI: −0.24 to 0.10) at trial end, favoring neither treatment. There were no statistically significant differences between the groups at 4 and 12 weeks in function [ES = −0.08 (95% CI: −0.39 to 0.23)] or stiffness [ES = 0.03 (95% CI: −0.27 to 0.34)] analyses based on two trials. Injection site pain was the most common adverse event reported in the HA group, and gastrointestinal adverse events were more common in the NSAIDs group.

Conclusion

This meta-analysis suggests that IAHA is not significantly different from continuous oral NSAIDs at 4 and 12 weeks. Our study detected no safety concerns; however, the included trials had only a short follow-up duration. Given the favorable safety profile of IAHA over NSAIDs, this result suggests that IAHA might be a viable alternative to NSAIDs for knee OA, especially for older patients at greater risk for systemic adverse events.

Introduction

Osteoarthritis (OA) is one of the most common disabling joint disorders in adults [1]. Approximately one in every seven adults suffers from this condition over their lifetime, with 9% of the US population affected by the age of 60 [2]. Furthermore, by the year 2030, arthritis is predicted to affect up to 25% of the US adult population and limit activity in 9.3% [3]. Osteoarthritis is also economically burdensome due to the high prevalence, growing treatment expenditures, and substantial indirect costs of the disease. National studies in industrialized countries have appraised the economic impact of arthritis as 1.5–2.5% of their respective Gross National Products (GNP) [4].

Osteoarthritis poses a treatment dilemma to both physicians and patients as no disease-modifying treatments exist, and the few available symptomatic therapies present efficacy and safety challenges. Oral treatments, such as NSAIDs or acetaminophen, have known risks of systemic adverse events including gastrointestinal or cardiovascular (in case of NSAIDs) abnormalities [5], [6], [7]. In this light, local treatments appear to be preferable, especially in older patients with comorbidities, among whom OA is most prevalent.

Intra-articular hyaluronic acid (IAHA) preparations are locally administered OA treatments that are considered to be devoid of the bulk of systemic adverse events. Various in vitro and in vivo studies suggest several possible mechanisms of action for IAHA [8], [9]. The main physiological effect of exogenous hyaluronic acid in OA remains unknown however, and relevant data from humans are scarce [10]. Beginning in 1997, the US Food and Drug Administration (FDA) has approved six IAHA devices for the use in knee OA, one of the most common OA sites. Nonetheless, the efficacy of HA in the treatment of OA has not been definitively confirmed.

Several meta-analyses have examined the effects of IAHA in the treatment of knee OA compared with placebo and with intra-articularly injected corticosteroids and found inconclusive results [11], [12], [13], [14], [15], [16], [17], [18], [19]. Three meta-analyses found HA to be more efficacious than IA placebo [11], [12], [13], three found it to be marginally efficacious [14], [15], [16], and two found it to be no better than IA placebo [17], [18]. Although NSAIDs are among the most efficacious and widely used treatments for knee OA, no meta-analysis has been performed to assess these medications against IAHA, which is considered to have a more favorable safety profile. The objectives of this study were to systematically evaluate the relative efficacy of IAHA for symptomatic knee OA in comparison with NSAIDs.

Section snippets

Selection of trials

We performed an electronic literature search for citations comparing the efficacy of intra-articular hyaluronic acid with oral non-steroidal anti-inflammatory drugs in the management of knee OA. We searched Medline, EMBASE, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to April 2013. The key terms osteoarthritis, osteoarthrosis, gonarthrosis, degenerative arthritis, knee, hyaluronic acid (and the trade names for hyaluronic acid), hyaluronate,

Trials

Our electronic literature search produced 677 studies and our search of the unpublished literature yielded 50 citations (Fig. 1). Of these studies, 543 were excluded after title and abstract screening. Full reports were retrieved for 184 studies, and 179 of those studies were excluded because they were not considered relevant to our primary study questions. Four published randomized clinical trials fulfilled our inclusion criteria [26], [27], [28], [29]. From the unpublished literature search,

Discussion

This study identified five trials comparing IAHA with NSAIDs for treating knee OA. Based on the findings of our meta-analysis, in patients with knee OA, IAHA injections demonstrated no statistically significant difference in efficacy to that of continuous oral NSAIDs at 4 weeks, 12 weeks, and end of the trial. Both treatments displayed moderate improvement from baseline. Effect sizes for pain, function, and stiffness showed no statistically significant differences between the two treatment

Conclusion

This meta-analysis showed that IAHA injection was not statistically significantly different in terms of efficacy for symptomatic knee OA from continuous oral NSAIDs at 4 weeks, 12 weeks, and end of the trial. Given the favorable safety profile of IAHA over NSAIDs, this result suggests that IAHA may be a viable alternative to NSAIDs in knee OA care, especially for older patients at greater risk for systemic adverse events. Studies evaluating the synergistic effect of the two treatments remain of

Acknowledgments

Dr. Bannuru is supported by a F32 HS021396 grant from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. We would like to thank the Tufts Medical Center Division of Rheumatology for their review and critical feedback.

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    Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that no authors received financial support for the submitted work; T.E. McAlindon declares associations with the following companies: Croma, Sanofi-Aventis Novartis, and EMD Serono. R.R. Bannuru, E.E. Vaysbrot, and M.C. Sullivan declare no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

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