We have shown that patients with osteoarthritis are at increased risk of fracture after total knee replacement (TKR). We conducted a population-based cohort study to assess the effect of bisphosphonate use on their post-surgery fracture risk. Cox regression adjusted by propensity score suggested a 50-55% reduction in risk of fracture post-surgery. Introduction: Patients with osteoarthritis have a higher bone mass but similar or higher risk of fracture. We recently demonstrated that patients have an elevated fracture risk after TKR, but it is unknown if bisphosphonate therapy in this patient group would reduce fracture risk. We aimed to assess the effect of bisphosphonate prescription to patients undergoing a TKR, on their risk of fracture after surgery. Methods: From the General Practice Research Database, all patients≥40 years old, who received a TKR from 1986 to 2006 for knee osteoarthritis were eligible. We identified bisphosphonate use (BPU) as the main exposure. Propensity scores (equivalent to the estimated conditional probability of being treated given the individual's covariates) were calculated using logistic regression and used to reduce observed confounding. We fitted Cox models to study the effect of BPU on post-surgery fracture occurrence. Analyses were stratified by history of previous fracture: no fracture, osteoporotic fracture (hip, wrist, humerus, spine), and other fractures. Results: The hazard ratio (HR) associated with BPU in non-previously fractured patients was 0.50 (95% confidence interval, 0.37-0.68; propensity-adjusted model), and 0.48 (0.35-0.65; matched analysis). In subjects with osteoporotic and with other previous fracture, BPU was associated with a propensity-adjusted HR of 0.46 (0.30 to 0.71) and 0.47 (0.26-0.85), respectively, and with a propensity-matched HR of 0.45 (0.29 to 0.70) and 0.45 (0.25-0.82). Conclusion: Our results suggest that BPU in primary prevention could reduce post-operative risk of fracture by 50% and by 55% in secondary prevention. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation.