Copyright © 2004 by The Journal of Bone and Joint Surgery, Inc.

Commentary & Prospective

Commentary & Perspective on
"Therapeutic Effects of Hyaluronic Acid on Osteoarthritis of the Knee: A Meta-Analysis of Randomized Controlled Trials"
by Chen-Ti Wang, MD, et al.

Commentary & Perspective by
Michael D. Ries, MD*,
Department of Orthopaedic Surgery, University of California-San Francisco, San Francisco, California

Hyaluronic acid is an effective lubricant that is present in normal synovial fluid. Since the concentration of hyaluronic acid is decreased in osteoarthritis, intra-articular injections of synthetic forms of hyaluronic acid may be beneficial. Many clinical studies have been conducted in an effort to determine the relative safety and efficacy of the use of hyaluronic acid injections for the management of osteoarthritis, and these studies have yielded varying results. Wang et al. have addressed this controversial issue by performing a meta-analysis of randomized controlled studies of hyaluronic acid treatment for osteoarthritis of the knee. Of 665 studies on this topic, only twenty met the rigid criteria for inclusion in the meta-analysis (single or double-blind randomized controlled trials that compared hyaluronic acid injection with placebo injection and had adequate outcome measures for pain or function and quantitative data on therapeutic effects), for a total of 818 knees treated with hyaluronic acid and 829 treated with placebo.

The authors did find that pain and function were improved with hyaluronic acid treatment and that there were few side effects. These findings support the use of hyaluronic acid injections as an alternative to or in addition to other conservative measures, such as activity restrictions, nonsteroidal anti-inflammatory or analgesic medications, glucocorticoid injections, exercise, and bracing for the treatment of osteoarthritis of the knee. Importantly, the treatment was less effective in patients who were more than sixty-five years of age and for the most advanced radiographic stage of osteoarthritis. Younger patients, particularly those in the early to moderate stages of osteoarthritis, seem to be the best candidates for this treatment that is used in an effort to delay the need for total knee arthroplasty.

It should be noted that some patients, including those with relative contraindications, may specifically request this treatment, which may partially reflect their access to various sources of medical information on the Internet1. The lack of adverse side effects would indicate that hyaluronic acid injections are a reasonable treatment, even in older patients or those with more advanced disease, provided that they understand that the efficacy of treatment would be expected to be low. For patients with medical disorders that would increase the risk associated with surgery, hyaluronic acid injections would appear to be appropriate in an effort to avoid surgical complications.

The authors also found that the results were quite variable between studies. Many of the studies were industry funded. Industry-funded studies have been associated with a more positive outcome than non-industry-funded studies and report a lower rate of adverse effects2-4. However, in this meta-analysis the authors used very strict inclusion criteria and a quantitative pain and function scoring system that should have overcome any potential bias. The authors have conducted a well-designed analysis of the available literature on hyaluronic acid treatment for osteoarthritis of the knee and found a beneficial effect with a low complication rate. Patients should also be aware of the variable response to treatment and the risk of adverse side effects.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive 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 author is affiliated or associated.


1. Murray E, Lo B, Pollack L, Donelan K, Catania J, Lee K, Zapert K, Turner R. The impact of health information on the Internet on health care and the physician-patient relationship: national U.S. survey among 1.050 U.S. physicians. J Med Internet Res. 2003;5:e17.
2. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003;326:1167-70.
3. Puttick MP, Wade JP, Chalmers A, Connell DG, Rangno KK. Acute local reactions after intraarticular hylan for osteoarthritis of the knee. J Rheumatol. 1995;22:1311-4.
4. Leopold SS, Warme WJ, Fritz Braunlich E, Shott S. Association between funding source and study outcome in orthopaedic research. Clin Orthop. 2003;415:293-301.