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Therapeutic Effects of Hyaluronic Acid on Osteoarthritis of the KneeA Meta-Analysis of Randomized Controlled Trials
Chen-Ti Wang, MD1; Jinn Lin, MD, PhD1; Chee-Jen Chang, PhD1; Yu-Tsan Lin, MD1; Sheng-Mou Hou, MD, PhD, MPH1
1 Department of Orthopedics (C.-T.W., J.L., and S.-M.H.), Department of Medical Research (C.-J.C.), and Department of Pediatrics (Y.-T.L.), National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan. E-mail address for S.-M. Hou: shengmou@ha.mc.ntu.edu.tw
View Disclosures and Other Information
In support of their research or preparation of this manuscript, one or more of the authors received a grant (DOH89-NH-058) from the Bureau of National Health Insurance, Taiwan. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2004 Mar 01;86(3):538-545
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Background: The magnitude of the therapeutic effects of intra-articular injection of hyaluronic acid on osteoarthritis of the knee is still in question. The aim of this meta-analysis was to elucidate the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for osteoarthritis of the knee.

Methods: We conducted a meta-analysis of twenty blinded randomized controlled trials that compared the therapeutic effect of intra-articular injection of hyaluronic acid with that of intra-articular injection of a placebo to treat osteoarthritis of the knee. The outcome end points were classified into three categories: pain with activities, pain without activities, and function. The outcome measures of the efficacy of hyaluronic acid were the mean differences in the efficacy scores between the hyaluronic acid and placebo groups. The outcome measure of the safety of hyaluronic acid was the relative risk of adverse events.

Results: Intra-articular injection of hyaluronic acid can decrease symptoms of osteoarthritis of the knee. We found significant improvements in pain and functional outcomes with few adverse events. However, there was significant between-study heterogeneity in the estimates of the efficacy of hyaluronic acid. Subgroup analysis and meta-regression analysis showed that lower methodological quality such as a single-blind or single-center design resulted in higher estimates of hyaluronic acid efficacy, that introduction of acetaminophen as an escape analgesic in the trial resulted in lower estimates of hyaluronic acid efficacy, and that patients older than sixty-five years of age and those with the most advanced radiographic stage of osteoarthritis (complete loss of the joint space) were less likely to benefit from intra-articular injection of hyaluronic acid.

Conclusions: This meta-analysis confirmed the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for the treatment of osteoarthritis of the knee. Additional well-designed randomized controlled trials with high methodological quality are needed to resolve the continued uncertainty about the therapeutic effects of different types of hyaluronic acid products on osteoarthritis of the knee in various clinical situations and patient populations.

Level of Evidence: Therapeutic study, Level II-3b (systematic review; nonhomogeneous Level-I studies). See Instructions to Authors for a complete description of levels of evidence.

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    Sheng-Mou Hou
    Posted on April 26, 2004
    Dr. Hou responds:
    National Taiwan University Hospital and National Taiwan University College of Medicine

    To the Editor:

    We appreciate Dr. Bernstein's interest in our article. We have read the meta-analysis conducted by Lo in JAMA. Here are some of our opinions.

    Conducting of a systematic review consists of several steps: Formulating review question, defining inclusion and exclusion criteria, locating studies, selecting studies, assessing study quality, extracting data, analyzing and presenting results, and finally interpreting results. In each step, the reviewers should do their best to answer the review question. Any extrapolation should be avoided.

    In Lo’s(1) and our meta-analyses, we formulated the same question: “is hyaluronic acid effective in the treatment of osteoarthritis of the knee?” However, the steps following the question formulation were somewhat different. For example, Dr. Lo used effect size to summarize the therapeutic efficacy, while we designed our own measure scales in the meta-analysis. The searching date and searching source were also different. Despite the differences, the answer to the review question is still the same: intra- articular hyaluronic acid has therapeutic efficacy compared with intra- articular placebo.

    Lo claimed the effect might be overestimated because of the skewed funnel plot. The therapeutic efficacy, however, is still confirmed in the article because the 95% confidence interval of the pooled effect size does not include zero, which is the same in our analysis. Lo even got a homogeneous effect size in the final pooling, which means the result is highly convincing. Both Lo and we concluded that there is still need for high-quality trials to re-evaluate the therapeutic efficacy of hyaluronic acid. The only difference between Lo’s and our meta-analyses are the funnel plots, which are distorted in Lo’s work but not in ours.

    There are many complex reasons for the distortion of funnel plots, including publication bias, citation bias, language bias, and biased inclusion criteria, etc. Therefore,we would disagree with Dr. Lo that the therapeutic efficacy is overestimated as their comment is based only on a distorted funnel plot. We would also direct Dr. Bernstein to other comments regarding Dr. Lo’s meta-analysis in JAMA (2,3).

    Dr. Bernstein asked another important question-- how to critically appraise the hyaluronic acid trials. We don’t think we can answer this big question clearly in the short reply. Instead, we suggest readers to find some textbook of evidence-based medicine or to search the keyword “evidence-based medicine” (EBM) in the internet searching engine for appraisal guideline of therapy. Only after the appropriate appraisal, we can exactly know whether the results are valid, what the results are, and how the results can help us in the patient care.


    1. Lo, G. H.; LaValley, M.; McAlindon, T.; and Felson, D. T.: Intra- articular hyaluronic acid in treatment of knee osteoarthritis: a meta- analysis. JAMA, 290(23): 3115-21, 2003.

    2. Band, P. A.: Intra-articular hyaluronic acid for treatment of osteoarthritis of the knee. JAMA, 291(12): 1440; author reply 1441-2, 2004.

    3. Moskowitz, R., and Altman, R.: Intra-articular hyaluronic acid for treatment of osteoarthritis of the knee. JAMA, 291(12): 1440-1; author reply 1441-2, 2004.

    joseph bernstein
    Posted on March 06, 2004
    Meta-analyses of the effect of Intra-articular hyaluronic acid
    University of PA

    To the Editor:

    The conclusions reached in the study by Wang, et.al, that "the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for the treatment of osteoarthritis of the knee" was confirmed seems to be in apparent conflict with a paper that appeared in JAMA just a few months ago(1). In that meta-analysis, the authors concluded that "Intra-articular hyaluronic acid has a small effect when compared with an intra-articular placebo. The presence of publication bias suggests even this effect may be overestimated."

    Can the authors please comment on this apparent discrepancy?

    Also, can the authors give us some pointers how we, the readers, can approach these studies critically? It is not hard to imagine that patients (or pharmaceutical representatives) will visit our offices with these studies in hand. References: 1.Grace H. Lo, MD; Michael LaValley, PhD; Timothy McAlindon, MD, MPH; David T. Felson, MD, MPH, "Intra-articular Hyaluronic Acid in Treatment of Knee Osteoarthritis A Meta-analysis". JAMA: 2003;290:3115-3121.

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