Quantitative analysis of the efficacy and associated factors of intra-articular hyaluronic acid with respect to osteoarthritis symptoms: a systematic review of randomized trials and model-based meta-analysis.

OBJECTIVE The literature on the efficacy of hyaluronic acid (HA) to treat osteoarthritis (OA) remains controversial, and the applicable subpopulation is unclear. Our study aimed to quantitatively evaluate HA efficacy and identify potential responders who would benefit most from HA. METHOD Embase, MEDLINE (PubMed), and the Cochrane Library Central Register of Controlled Trials were searched from inception to March 13, 2023. A pharmacodynamic Bateman function model was used to quantitatively evaluate the efficacy characteristics of HA treatments as well as placebo, while a covariate model was employed to identify factors that significantly affected efficacy. RESULTS In total, 24 101 participants with symptomatic or radiographic OA from 168 studies with aggregate data were included. Simulation analysis from the pharmacodynamic time-effect model showed that HA treatment effects plateaued at approximately 2 months. The final model analysis indicated that intra-articular injection of HA combined with corticosteroids (the Western Ontario and McMaster Universities Arthritis Index [WOMAC] pain effect size [ES] = 4.4 [95% CI: 3.0 to 5.7]) or platelet-rich plasma (PRP) (WOMAC pain ES = 4.0 [95% CI: 2.7 to 5.3]) achieved the best efficacy compared with other groups (contrast between meta-analyses: WOMAC pain ES = 1.9 [95% CI: 1.2 to 5.2]). Subgroups analysis showed that younger (age < 65), overweight (BMI ≥ 25) knee OA patients, with more severe baseline symptoms and a lower Kellgren-Lawrence (KL) grade (≤ 2), could benefit more. CONCLUSION The quantitative model suggested that HA interventions were statistically more effective than placebo, with participants receiving HA+ corticosteroids (CS) or platelet-rich plasma (PRP) experiencing the best efficacy. Patients with lower age, higher weight, higher severity of baseline symptoms, and lower KL grade appeared to benefit more from HA treatment. DATA AND MATERIALS AVAILABILITY All data are available in the main text or the supplementary materials.