OBJECTIVES: Cost-effectiveness of denosumab versus oral bisphosphonates in PMO from a US third party payer perspective was evaluated.  METHODS: A lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporotic fracture, post hip fracture, post vertebral fracture, and dead. During each cycle, a patient could fracture, remain healthy, remain in a post fracture state or die. Relative fracture risk reduction, background fracture risks, mortality rates, utilities, medical and drug costs were derived using published sources. Expected costs and quality-adjusted life years (QALYs) were estimated for denosumab, risedronate, ibandronate, and generic alendronate in the overall PMO population and high risk subgroups: 1) 2 of the 3 risks i.e., >70years-old, bone mineral density T-score≤-3.0 and prevalent vertebral fracture, and 2) ≥75 years-old. Costs and QALYs were discounted at 3% annually. Extensive sensitivity analyses were conducted. RESULTS: In the overall PMO population, total lifetime costs for alendronate, risedronate, denosumab, and ibandronate were $55,500, $58,200, $58,800 and $59,800, respectively.  Total QALYs were 8.33, 8.33, 8.37 and 8.32, respectively. The incremental cost-effectiveness ratio (ICER) for denosumab versus generic alendronate was $103,000/QALY. Risedronate was dominated by alendronate and ibandronate was dominated by denosumab.  In high risk subgroup (a), total costs for alendronate, denosumab, risedronate and ibandronate were $60,900, $62,200, $64,100 and $66,600, respectively.  Total QALYs were 7.27, 7.32, 7.27 and 7.26, respectively. Denosumab had an ICER of $28,200/QALY versus generic alendronate and dominated all other strategies. Denosumab dominated all strategies in women ≥75 years. Results between denosumab and generic alendronate were most sensitive to the relative risk of hip fracture for denosumab and the cost of denosumab.    CONCLUSIONS: In each PMO population examined, denosumab represented good value for money compared to branded bisphosphonates.  Furthermore, denosumab was either cost-effective or dominant compared to generic alendronate in the high-risk subgroups.