OBJECTIVES: To estimate the differences in fracture-related treatment costs (FTC) between osteoporosis patients with and without proton pump inhibitor (PPI) use. METHODS: Data from the 2001-2008 Medical Expenditure Panel Surveys was used to identify osteoporosis patients >50 years old through an ICD-9-CM code of 733 or clinical classification code of 206. Patients were categorized into two groups based on PPI use. Considered medications included osteoporosis agents (bisphosphonates, hormone therapy, and raloxifene) and corticosteroids (excluding topicals). Fractures were identified based on ICD-9-CM codes 804-829. Mean of treatment costs were calculated with bootstrap confidence interval due to skewed costs. FTC were estimated using generalized linear model with log link function and gamma distribution. First, FTC for patients treated with PPI were predicted using the estimated coefficients from patients without PPIs using a generalized linear model with adjustments for patient characteristics, medication use, and comorbidities.  Second, attributable costs to the use of PPI were estimated by the difference between predicted and observed costs for PPI users.  Treatment costs for one year were calculated and converted to 2009 U.S. dollar using appropriate price indices. RESULTS: We identified 4,979 patients with osteoporosis. PPI use was found in 970 patients and in 4,009 it was not. Unadjusted cost differences showed patients with PPI use had similar osteoporosis-related costs (excluding fracture costs) to patients without ($883 vs. $798). However, patients treated with PPI had higher FTC by $335 than patients without PPI use ($709 vs. $374). After adjusting for the study variables, PPI use was associated with an increase in FTC by 63% when compared to patients not taking PPIs. CONCLUSIONS: Use of PPIs increases the economic burden of osteoporosis patients primarily due to fracture-related costs.  Additional studies are warranted to further explore the cost attributable to fracture due to use of PPIs in osteoporosis patients.