OBJECTIVES: Denosumab represents a new therapeutic opportunity for the treatment of osteoporosis, that received a positive opinion from the European Committee for Medical Products for Human Use in December 2009. This study aims to evaluate the cost-effectiveness of denosumab compared with the most relevant alternative (i.e. generic alendronate) in the treatment of postmenopausal osteoporotic women. METHODS: The cost-effectiveness of treatment for 3-years with denosumab was compared with generic alendronate using an updated version of a previously validated Markov microsimulation model (Value Health 2009:12:687-96). The model was populated with relevant cost, adherence and epidemiological data for Belgium from a health-care perspective and the results were presented in cost (€2009) per quality-adjusted life-year (QALY) gained. Analyses were performed in populations (over 60 years) where osteoporosis medications are currently reimbursed in many European countries, i.e. bone mineral density T-score is below or equal to -2.5 or presence of prevalent vertebral fracture. Univariate and probabilistic sensitivity analyses were conducted to assess the robustness of the results. RESULTS: The cost-effectiveness of denosumab compared with generic alendronate was estimated at €38,875, €20,690 and €26,153 per QALY for women with T-score ≤-2.5 aged 60, 70 and 80 years, respectively. The equivalent values were €37,856, €18,764 and €17,309 per QALY for women with prevalent vertebral fractures. Discount rates, fracture risk and patient’s adherence to generic alendronate were found to be particularly sensitive when varied within the model. At 70 years of age, probabilistic sensitivity analyses showed that the probability of the ICERs remaining below €40,000 is 84% in women with prevalent vertebral fracture and 74% in those with T-score ≤-2.5, confirming the cost-effectiveness of denosumab. CONCLUSIONS: This study suggests that denosumab is a cost-effective strategy (cost per QALY gained ≤€40,000) compared with generic alendronate for the treatment of postmenopausal Belgian osteoporotic women, aged 60 years and above.