OBJECTIVES: Poor compliance and failure to persist with osteoporosis medications are common, but the clinical and economic consequences have not been well described. This study aims to estimate the clinical and economic burden of nonadherence with oral bisphosphonates in osteoporotic patients and to examine the scope for adherence-enhancing interventions. METHODS: A validated Markov microsimulation model estimated costs and outcomes (i.e. the number of fractures and the quality-adjusted life-year (QALY)) for three adherence scenarios: no treatment, real-world adherence and full adherence over three years. Simulated patients matched the populations where osteoporosis medications are reimbursed. The real-world adherence scenario employed adherence data from a published Belgian observational study and adherence was divided into persistence and compliance. The incremental cost per QALY gained was estimated comparing the three adherence scenarios. We also examined the clinical and economic implications of adherence-enhancing interventions assuming that adherence failure would be reduced by 10%, 20% or 30%. RESULTS: The estimated number of fractures prevented and the lifetime QALY gained in the real-world adherence scenario represents only 42.0% and 41.9% to that obtained under full adherence scenario, respectively. The cost per QALY gained of real-world adherence versus no treatment was estimated at €11,175, and full adherence was found to be cost-saving compared to real-world adherence. An intervention that decreases adherence failure by 20% was associated with a 28% increase in the number of fractures prevented and the costs per QALY gained compared to real-world adherence were respectively €29,350 and €46,275 if the intervention costs €100 and €150 per year. CONCLUSIONS: This study suggests that more than half of the potential benefits from oral bisphosphonates in patients with osteoporosis are lost due to poor compliance and failure to persist. Depending on its cost, interventions that improve adherence to therapy have the potential to be an attractive use of resources.