Intra-articular hyaluronic acid is a US Food and Drug Administration–approved
treatment for knee osteoarthritis (OA); however, its efficacy is controversial.
To evaluate whether intra-articular hyaluronic acid is efficacious in
treating knee OA.
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.
Included were published or unpublished, English and non-English, single-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.
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
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asymmetric funnel plot, a positive Egger test, and identification of 2 unpublished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).
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