Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews.
The prevalence of knee osteoarthritis (OA)/degenerative joint disease (DJD) is increasing in the USA. Systematic reviews of treatment efficacy and adverse events (AEs) of hyaluronic acid (HA) injections report conflicting evidence about the balance of benefits and harms. We review evidence on efficacy and AEs of intraarticular viscosupplementation with HA in older individuals with knee osteoarthritis and account for differences in these conclusions from another systematic review.



We searched PubMed and eight other databases and gray literature sources from 1990 to December 12, 2014. Double-blind placebo-controlled randomized controlled trials (RCTs) reporting functional outcomes or quality-of-life; RCTs and observational studies on delay/avoidance of arthroplasty; RCTs, case reports, and large cohort studies and case series assessing safety; and systematic reviews reporting on knee pain were considered for inclusion. A standardized, pre-defined protocol was applied by two independent reviewers to screen titles and abstracts, review full text, and extract details on study design, interventions, outcomes, and quality. We compared our results with those of a prior systematic review and found them to be discrepant; our analysis of why this discrepancy occurred is the focus of this manuscript.



Eighteen RCTs reported functional outcomes: pooled analysis of ten placebo-controlled, blinded trials showed a standardized mean difference of -0.23 (95 % confidence interval (CI) -0.45 to -0.01) favoring HA at 6 months. Studies reported few serious adverse events (SAEs) and no significant differences in non-serious adverse events (NSAEs) (relative risk (RR) [95 % CI] 1.03 [0.93-1.15] or SAEs (RR [95 % CI] 1.39 [0.78-2.47]). A recent prior systematic review reported similar functional outcomes, but significant SAE risk. Differences in SAE inclusion and synthesis accounted for the disparate conclusions.



Trials show a small but significant effect of HA on function on which recent systematic reviews agree, but lack of AE synthesis standardization leads to opposite conclusions about the balance of benefits and harms. A limitation of the re-analysis of the prior systematic review is that it required imputation of missing data.
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA. cohanlon@rand.org.|Pardee RAND Graduate School, 1776 Main St., Santa Monica, CA, 90407, USA. cohanlon@rand.org.
Claire E
CE
O'Hanlon
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.
Sydne J
SJ
Newberry
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.
Marika
M
Booth
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.
Sean
S
Grant
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.
Aneesa
A
Motala
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.
Margaret A
MA
Maglione
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.|Division of Rheumatology, Department of Internal Medicine, UCLA, 1000 Veteran Avenue, Los Angeles, CA, 90095, USA.
John D
JD
FitzGerald
RAND Corporation, 1776 Main St., Santa Monica, CA, 90407, USA.|Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA, 90073, USA.
Paul G
PG
Shekelle
D006801:Humans; D006820:Hyaluronic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D007719:Knee Joint; D020370:Osteoarthritis, Knee / Q000188:drug therapy*; D012196:Review Literature as Topic
D006820:Hyaluronic Acid
Adverse events; Hyaluronic acid; Osteoarthritis, knee; Viscosupplementation