Does intra-articular hyaluronate decrease symptoms of osteoarthritis of the knee? - Patient-Oriented Evidence that Matters - Brief Article

Journal of Family Practice, May, 2002 by Keith Cubbage

Petrella R, DiSilvestro M, Hildebrand C. Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee. A randomized double-blind, placebo-controlled clinical trial. Arch Intern Med 2002; 162:292-8.

* BACKGROUND Current therapies for osteoarthritis (OA) include long-term NSAIDs and joint replacement surgeries, but these are not without significant morbidity and mortality. HA is a joint component that acts as a shock absorber and lubricant, and its concentration declines with advancing age. "Viscosupplementation" is an intriguing idea as an alternative to exclusive treatment with NSAIDs. This study evaluated the effectiveness of hyaluronate injections to decrease symptoms associated with OA and improve functioning.

* POPULATION STUDIED The investigators of this study recruited 120 subjects from an outpatient referral center. Included patients displayed radiographic evidence of medial compartment unilateral knee OA grades 1 - 3. Allocation concealment was not mentioned, meaning that the investigators could have chosen patients on the basis of what therapy they were about to receive in the study.

* STUDY DESIGN AND VALIDITY This study was a randomized, controlled, double-blind comparison of (1) HA, (2) an NSAID, (3) both, or (4) neither. Physicians, patients, and analysis staff were all blinded. Each patient received both 3 weekly intra-articular knee injections of either placebo or hyaluronate sodium and 12 weeks of twice daily placebo or diclofenac 75 mg plus misoprostol 200 [micro]g. The follow-up period lasted 12 weeks, with a 99.2% follow-up rate and 9.2% dropout rate. Pain, stiffness, and disability were evaluated at baseline and weeks 4 and 12 using the Western Ontario McMaster Universities (WOMAC) Index, a visual analog scale for pain and performance. Analysis was by intention-to-treat.

Overall, this study was poorly performed and does not support the author's positive conclusions. Despite randomizing patients, baseline pain scores were markedly different among the 4 groups. This discrepancy could be caused by chance, but also could be caused by the lack of concealed allocation, which allowed the investigators to stack the deck at the time of enrollment. In addition, the statistical analysis was rudimentary, incorrect, and misleading to the casual reader. At 12 weeks, NSAID-treated patients reported lower pain scores, but not the HA or placebo only patients. In all 4 groups, pain improved at rest.

* OUTCOMES MEASURED The primary outcomes were patient-reported measures of pain, stiffness, and disability at baseline and weeks 4 and 12. Other outcomes were pain at rest and following walking and stepping activities.

* RESULTS The authors declared HA effective on the basis of changes within each group from baseline to the end of therapy. However, the accompanying editorial performed a more appropriate statistical analysis that evaluated the effect across all 4 groups and found no evidence to suggest that hyaluronate sodium in this trial is more effective than placebo. (1)

RECOMMENDATIONS FOR CLINICAL PRACTICE

Contrary to the assertions of the authors, careful evaluation of the results of this study reveal that hyaluronic acid (HA) injection is no better than placebo in the treatment of osteoarthritis (OA) of the knee. Do not let yourself be fooled when shown this study -- the analysis was not carried out across all 4 groups. When this was carried out, no benefit could be found. (1) Previous studies have also failed to find a benefit of HA versus placebo. This is another good idea that does not work. For now, stick with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).

REFERENCE

(1.) Felson D, Anderson J. Hyaluronate sodium injections for osteoarthritis. Hope, hype, and hard truths. Arch Intern Med 2002; 162:245-7.

Keith Cubbage, MD
University of Virginia Health System
Department of Family Medicine
Charlottesville
E-mail: bkc7x@hscmail.mcc.virginia.edu