Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials.
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.


METHODS
Therapeutic study, Level II-3b (systematic review; nonhomogeneous Level-I studies). See Instructions to Authors for a complete description of levels of evidence.
Wang
Chen-Ti
CT
Department of Orthopedics, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan. shengmou@ha.mc.ntu.edu.tw
Lin
Jinn
J
Chang
Chee-Jen
CJ
Lin
Yu-Tsan
YT
Hou
Sheng-Mou
SM
D000203:Activities of Daily Living; D015982:Bias; D004311:Double-Blind Method; D004342:Drug Hypersensitivity / Q000209:etiology; D004487:Edema / Q000139:chemically induced; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D020370:Osteoarthritis, Knee / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010146:Pain / Q000175:diagnosis / Q000209:etiology; D010147:Pain Measurement; D011643:Publishing / Q000592:standards; D016032:Randomized Controlled Trials as Topic / Q000592:standards; D016059:Range of Motion, Articular; D012044:Regression Analysis; D012107:Research Design / Q000592:standards; D012449:Safety; D012720:Severity of Illness Index; D016037:Single-Blind Method; D016896:Treatment Outcome; D014657:Vasculitis / Q000139:chemically induced
D006820:Hyaluronic Acid