Beyond Molecular Weight: Formulation Characteristics and Structural Disease Severity as Modifiers of Response to Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Component Network Meta-analysis

Background Intra-articular hyaluronic acid (IAHA) is widely used for symptomatic knee osteoarthritis (KOA), yet most evidence classifies products primarily according to molecular weight despite important differences in cross-linking, concentration, cumulative dose, injection schedule, and biological origin. Whether these formulation characteristics independently influence clinical outcomes remains uncertain. Purpose To determine whether formulation characteristics beyond molecular weight are associated with clinical response to IAHA in KOA and to explore, as a secondary hypothesis-generating analysis, whether radiographic disease severity may modify treatment effects Methods A systematic review and component network meta-analysis of randomized controlled trials was conducted in accordance with PRISMA 2020 recommendations. Adults with symptomatic primary KOA treated with IAHA were eligible. Formulation characteristics evaluated included molecular weight, cross-linking, concentration, cumulative dose, injection schedule, injected volume, and biological origin. Pain was the primary outcome. Conventional network meta-analysis, exploratory component modeling, sensitivity analyses, and certainty assessment were performed. Results Sixty-six randomized controlled trials including 9,822 participants were analyzed. Ultra-high- and high-molecular-weight formulations demonstrated the most favorable directional estimates for intermediate-term pain reduction, although confidence intervals remained wide and did not establish definitive superiority. Exploratory component network meta-analysis identified an association between higher molecular weight and greater pain reduction (β = −0.78, 95% CI −1.48 to −0.07; P=.030); however, substantial collinearity among formulation characteristics and incomplete support for the additivity assumption precluded interpretation of this estimate as an independent causal component effect. The treatment-level NMA was therefore considered the preferred model. No statistically significant component associations were identified for cross-linking, concentration, cumulative dose, or injection schedule. Exploratory analyses suggested that less advanced radiographic disease may be associated with greater symptomatic improvement, although no statistically reliable interaction according to structural severity was identified. Overall certainty of evidence was moderate-to-low for pain outcomes and very low for independent component effects. Conclusion Treatment-level NMA suggested directional differences among IAHA formulation categories, with higher-molecular-weight formulations showing the most favorable intermediate-term estimates, although definitive superiority was not established. Component-level findings, including the statistically significant association observed for molecular weight, should be considered exploratory and hypothesis-generating because substantial collinearity and incomplete support for additivity prevented reliable isolation of independent component effects. Personalized formulation selection according to structural disease severity requires validation through individual-participant-data meta-analyses and prospectively stratified randomized trials. Level of Evidence Level I, systematic review and component network meta-analysis of randomized controlled trials.