OBJECTIVES The objective of this study was to estimate the cost effectiveness of oral bisphosphonates administered on extended dosing intervals (i.e., monthly or weekly instead of daily regimens) in the U.S. Military Health System. METHODS Claims data were analyzed for all female patients over age 18 prescribed oral bisphosphonates in the Military Health System. Patients were identified as persistent or non-persistent [defined as patients whose proportion of days covered (PDC) was less than 80% during a 1-year period] in a regression model that adjusted for comorbidities, duration of illness, and demographics. Two hypothetical cohorts (weekly alendronate vs monthly ibandronate) were evaluated in the second stage of the model. Total health care costs for the hypothetical 10,000-patient cohorts were estimated based on fracture rates (persistent group = 8.9%, non-persistent group = 11%) and treatment costs (average $3,053/fracture) obtained from the clinical literature and mean days of therapy and drug acquisition costs obtained from claims data. RESULTS The regression model predicted persistence probabilities of 45.92% and 41.76%, respectively, for patients receiving oral bisphosphonate products dosed monthly versus weekly. This improved adherence was projected to result in an additional 9 fractures avoided over a one-year treatment period with monthly vs. weekly dosing. Treatment given monthly was estimated to increase 1-year total healthcare costs by $212 per patient compared to weekly treatment. Taking into account pricing of recently available generics for alendronate, the incremental cost effectiveness ratio (ICER) analysis resulted in an incremental cost of $235,605 per fracture avoided. CONCLUSIONS The analysis and model suggest that monthly-dosed bisphosphonate products likely result in increased persistence and more fractures avoided when compared to weekly bisphosphonate treatment, but at a significant cost per fracture avoided.