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OBJECTIVE: To investigate the effectiveness of intervention strategies for primary and secondary prevention of knee osteoarthritis (OA). DESIGN: Intervention systematic review of randomized controlled trials (RCTs). DATA SOURCES: The Medline, EMBASE, CINAHL, PEDro, and The Cochrane Library databases were searched from inception to June 10, 2025. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs evaluating interventions for primary/secondary knee OA prevention. Eligible trials targeted populations at-risk of developing knee OA or population with knee OA, and the outcome of interest must not have been present at study entry. Primary outcomes were self-reported knee pain and associated disability. Secondary outcomes included imaging features of knee joint structure and the incidence of knee arthroplasty. Data were synthesized narratively and reported as relative risks (RRs) with 95% Confidence Intervals (CIs). RESULTS: Five published reports from three RCTs (1481 participants) were included. We found evidence that a self-management lifestyle program for community-based women with BMI ≥ 25 kg/m 2 may reduce the risk of developing pain associated with knee OA at 12-months, when compared to a single education session (RR: 0.27, 95%CI: 0.16-0.46). There was uncertain evidence from four reports to draw conclusions about the effects of diet & exercise, glucosamine supplements, diet & exercise plus glucosamine supplements, and intra-articular sprifermin interventions for preventing or reducing Knee OA progression or arthroplasty. CONCLUSION: A self-management lifestyle program may be effective for reducing the risk of developing pain associated with knee OA in women with a BMI ≥ 25 kg/m 2 . Evidence for other preventive interventions remains uncertain.