OBJECTIVES: To compare effectiveness, medical costs and cost-effectiveness of zoledronic acid, one single yearly infusion, versus usual care in post-menopausal osteoporosis in France, taking into account compliance profiles. METHODS: Twelve simulation based models were built to investigate 3 types of fractures: vertebral (VF), non-vertebral (NVF) and hip (HF), comparing 2 groups: zoledronic acid and usual care. Two effectiveness assumptions have been tested to handle the issue of clinical trial population heterogeneity: (1) specific agent effectiveness values, and 2) same standard effectiveness range of values for all active agents. Direct medical costs include drug costs, medical visits, monitoring and fracture medical management. Compliance has been integrated into the model with the assumption that non-compliant patients have the placebo effectiveness range of values. Conservative compliance range of rates for active agents has been expressed in accordance with the literature and expert opinion, from 40% to 60% for oral drugs and from 50% to 100% for Zoledronic acid single yearly infusion. A full probabilistic sensitivity analysis has been carried out to generate costs, effectiveness and cost-effectiveness over 3 years, with confidence intervals. Statistical tests were performed to calculate potential significant differences. RESULTS: Using the second assumption (2), the zoledronic acid strategy leads to less vertebral, non-vertebral and hip fractures than usual care: (88.0% vs. 85.7%, 89.4% vs. 88.2% and 97.2% vs. 95.4%) respectively, (p<0.001).Zoledronic acid generates lower total medical costs versus usual care in all types of fracture (p<0.001): 944€ vs. 995€ (VF), 1164€ vs. 1245€ (NVF) and 1156€ vs. 1261€ (HF). CONCLUSION: Zoledronic acid is the dominant strategy, regardless of fracture type or effectiveness assumptions. A simulation modeling approach seems appropriate to investigate various effectiveness values from heterogeneous clinical trials. Isolating the compliance effect allows us to confirm the added value of a once yearly infusion of zoledronic acid 5 mg.