OBJECTIVES: Denosumab has recently been approved in the United States for the treatment of postmenopausal women with ostepoporosis. Denosumab, a twice yearly 60mg injection, provides an opportunity to model the effect of improved treatment persistence on outcomes when compared to the daily dosing required of patients on 60mg raloxifene, also a second line osteoporotic therapy. METHODS: A previously developed Markov model was used to simulate outcomes for post-menopausal women aged 65 with a bone mineral density (BMD) of less than -2.5. We assumed a 20-year time horizon and a managed care perspective. Modeled health states included vertebral, hip, and wrist fractures. Disease progression parameters were derived from phase III clinical trials. Costs were obtained using large epidemiologic studies. Quality-adjusted life-years (QALYS) were used to assess outcomes, and utility weights were derived from recent systematic reviews detailing utility values associated with various osteoporotic fracture states. RESULTS: Denosumab is dominated by raloxifene, as indicated by higher costs and poorer outcomes. Persistence rates associated with both treatments had the greatest impact on resulting incremental cost-effectiveness ratios. Estimated 20-year aggregated costs and QALYs per person using denosumab are $26,123 and 12.63, respectively compared to $23,670 per person and 13.05 per person for raloxifene. The ICER was most sensitive to changes in persistence rates. Raloxifene was universally dominant under all one-way sensitivity analysis scenarios. CONCLUSIONS: Denosumab is not cost-effective compared to raloxifene. Further research should assess whether the costs associated with improved denosumab persistence are offset by reduced fracture rates and costs of fracture treatment.