Background: Proton pump inhibitors (PPIs) are widely used in elderly patients and are frequently coadministered in users of oral bisphosphonates. Biologically, PPIs could affect the absorption of calcium, vitamin B12, and bisphosphonates and could affect the osteoclast proton pump, thus interacting with bisphosphonate antifracture efficacy. Moreover, PPIs themselves have been linked to osteoporotic fractures. Methods: Population-based, national register-based, open cohort study of 38 088 new alendronate sodium users with a mean duration of follow-up of 3.5 years. We related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate. Results: For hip fractures, there was statistically significant interaction with alendronate for PPI use (P<.05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52-0.71; P<.001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64-1.01;P =.06). The attenuation of the risk reduction was dose and age dependent. In contrast, there was no significant impact of concurrent use of histamine H2 receptor blockers. Conclusions: Concurrent PPI use was associated with a dose-dependent loss of protection against hip fracture with alendronate in elderly patients. This is an observational study, so a formal proof of causality cannot be made, but the dose-response relationship and the lack of impact of prior PPI use provides reasonable grounds for discouraging the use of PPIs to control upper gastrointestinal tract complaints in patients treated with oral bisphosphonates.