title: Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis.
abstract: BACKGROUND
  Intra-articular hyaluronic acid is a US Food and Drug Administration-approved treatment for knee osteoarthritis (OA); however, its efficacy is controversial.
  
  
  OBJECTIVE
  To evaluate whether intra-articular hyaluronic acid is efficacious in treating knee OA.
  
  
  METHODS
  We searched for human clinical trials in MEDLINE (1966 through February 2003) and the Cochrane Controlled Trials Register, using the search terms (osteoarthritis, osteoarthrosis, or degenerative arthritis) and (hyaluronic acid, Hyalgan, Synvisc, Artzal, Suplasyn, BioHy, or Orthovisc). We also hand searched manuscript bibliographies that met inclusion criteria, selected rheumatic disease journals, and abstracts from scientific meetings.
  
  
  METHODS
  Included were published or unpublished, English and non-English, single- or double-blinded, randomized controlled trials comparing intra-articular hyaluronic acid with intra-articular placebo injection for the treatment of knee OA. Trials also were required to have extractable data on pain reported by 1 of the outcome measures recommended by the Osteoarthritis Research Society.
  
  
  METHODS
  Two reviewers independently performed data extraction using standardized data forms. For each trial, we calculated an effect size (small-effect sizes, 0.2-0.5; large-effect sizes, 1.0-1.8, equivalent to a total knee replacement). We used a random-effects model to pool study results, the Cochrane Q test to evaluate heterogeneity, and a funnel plot and the Egger test to evaluate publication bias.
  
  
  RESULTS
  The overall dropout rate in the 22 selected trials was 12.4%. The pooled effect size for hyaluronic acid was 0.32 (95% confidence interval [CI], 0.17-0.47). There was significant heterogeneity among studies (P<.001). Two outlier trials, both evaluating the highest-molecular-weight hyaluronic acid, had effect sizes in excess of 1.5. However, the third trial of the same compound showed a nearly null effect. When the 3 trials of this compound were removed, heterogeneity was no longer significant (P =.58), and the pooled effect size for intra-articular hyaluronic acid decreased to 0.19 (95% CI, 0.10-0.27). There was evidence of publication bias with an asymmetric funnel plot, a positive Egger test, and identification of 2 unpublished trials whose pooled effect size was 0.07 (95% CI, - 0.15 to 0.28).
  
  
  CONCLUSIONS
  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. Compared with lower-molecular-weight hyaluronic acid, the highest-molecular-weight hyaluronic acid may be more efficacious in treating knee OA, but heterogeneity of these studies limits definitive conclusions.
authors.affiliation: The Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Mass, USA. grace.lo@bmc.org
authors.forename: Grace H
authors.initials: GH
authors.lastname: Lo
authors.forename: Michael
authors.initials: M
authors.lastname: LaValley
authors.forename: Timothy
authors.initials: T
authors.lastname: McAlindon
authors.forename: David T
authors.initials: DT
authors.lastname: Felson
mesh_terms: D002986:Clinical Trials as Topic; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D020370:Osteoarthritis, Knee / Q000188:drug therapy*
chemical_list: D006820:Hyaluronic Acid