Abstract
BACKGROUND: Females have a higher risk of incident knee osteoarthritis (KOA) than males, particularly in the lateral compartment; however, the underlying mechanisms remain unclear. We investigated whether knee flexor and extensor strength mediate the association between sex and lateral radiographic and symptomatic KOA risk. METHODS: This cohort study utilized data from the Osteoarthritis Initiative, a longitudinal prospective study of participants aged 45–79 years. We included knees without radiographic or symptomatic KOA at baseline. Knee extensor and flexor strength were measured isometrically using a validated device (Good Strength Chair) and normalized to body mass index. Mediation analyses were performed using marginal structural models to assess the contribution of knee flexor and extensor strength to the relationship between sex and the risk of lateral radiographic and symptomatic KOA, adjusting for age, race, knee injury history, physical activity, knee alignment, cartilage volume, and hormone therapy. RESULTS: A total of 5,126 eligible knees from 3,056 participants without radiographic KOA and 6,773 from 3,720 participants without symptomatic KOA were identified at baseline. Among 5,126 knees without radiographic KOA, the 8-year risks of lateral radiographic KOA were 5.9% in females and 3.4% in males, with an odds ratio (OR) of 1.72 (95% confidence interval [CI]: 1.28 to 2.31). The indirect effects of female sex on lateral radiographic KOA via flexors and extensor strength were OR = 1.14 (95% CI: 1.04 to 1.26) and 1.16 (95% CI: 1.05 to 1.27), respectively. The direct effects (not mediated through flexor/extensor strength) were OR = 1.48 (95% CI: 1.01 to 1.95) and 1.46 (95% CI: 1.01 to 1.92). Knee flexor and extensor strength mediated 31.1% and 33.9% of the total effect of sex on lateral radiographic KOA risk, respectively. Similar results were also observed for incident lateral symptomatic KOA. CONCLUSION: The lateral radiographic and symptomatic KOA risk is higher in females than males, partly mediated by lower flexor and extensor strength. These findings suggest that enhancing knee flexor and extensor strength in females may help reduce their risk of developing lateral radiographic and symptomatic KOA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-026-03745-6.