Efficacy of Ultra-high and High Molecular Weight Cross-Linked Hyaluronic Acids Compared with Saline in Knee Osteoarthritis: A Randomized Controlled Trial.

Introduction: Intra-articular hyaluronic acid (HA) injections are widely used for knee osteoarthritis (OA) to reduce pain and improve function. The efficacy of cross-linked HA over placebo remains debated. This study aimed to compare the efficacy of 2 single-injection, ultra-high, and high molecular weight (HMW) cross-linked HAs against a saline placebo for symptomatic knee OA. Methods: We conducted a single-center, double-blind, randomized, placebo-controlled trial with 24-week follow-up. A total of 276 patients with primary knee OA were randomized into 3 groups: ultra-high MW HA (Hyruan ONE), HMW HA (hylan G-F 20), and saline. All participants received a single intra-articular injection. Primary outcomes were visual analog scale (VAS) pain scores at rest and during motion at weeks 1 to 24 and the change from baseline over the 24-week period. Secondary outcomes included the modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short Form-36 (SF-36), Lequesne index, Time Up and Go (TUG) test, and active knee flexion at weeks 2, 4, 12, and 24. Patients who did not improve could receive a rescue corticosteroid injection, after which they were excluded from further analysis. Results: No significant differences in pain reduction were observed between the HA and saline groups at rest (p = 0.92) and during motion (p = 0.99). All groups showed significant improvement in VAS scores over 24 weeks (p < 0.0001). Modified WOMAC scores were also similar among the 3 groups (p > 0.05). All groups had comparable outcomes for the SF-36 (p = 0.91), Lequesne index (p = 0.93), TUG test (p = 0.48), and knee flexion (p = 0.90). The rates of rescued corticosteroid injections rates were similar across the 3 groups (17% vs. 21% vs. 25%, p = 0.98). Conclusions: Ultra-high and HMW cross-linked HA injections did not provide superior pain or functional outcomes compared with saline for knee OA. These findings provided high-level evidence challenging the clinical benefit of cross-linked HAs. Consequently, the cost-effectiveness is uncertain and warrants formal economic evaluation. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.