OBJECTIVES: To evaluate the cost-effectiveness of denosumab (Prolia®, 60 mg every 6 month) compared to generic zoledronic acid (5 mg once yearly) in the treatment of postmenopausal osteoporosis in the U.S. societal perspective. METHODS: Comprehensive literature and online search was employed to obtain data on the clinical effectiveness of drugs, health-related quality of life (HRQoL) of disease states and costs. Databases searched were PubMed and Google Scholar engine. A Markov cohort model was constructed within the framework of incremental cost effectiveness ratios (ICERs) and net monetary benefit analyses. Given that generic zoledronic acid dominates denosumab in the base-case scenario, only one-way sensitivity analyses were performed to evaluate the sensitivity of results to model parameters. Finally, threshold analyses were used to determine the price at which denosumab would be as cost-effective as generic zoledronic acid. RESULTS: In the base-case scenario, generic zoledronic acid increased 0.003 QALYs and decreased $227 costs incrementally compared to denosumab. Assuming a willingness-to-pay threshold of $150,000 per QALY, the NMB value of generic zoledronic acid compared to denosumab was $679. In the one-way sensitivity analyses, generic zoledronic acid dominated denosumab in all scenarios when model parameters were varied within a range of 10% -15%. The threshold analyses indicated that even at a zero price, denosumab would not be cost effective relative to generic zoledronic acid. CONCLUSIONS: Based on a U.S. societal perspective, generic zoledronic acid is more cost-effective than denosumab in the treatment of high-risk patients with postmenopausal osteoporosis.