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Original Investigation
June 13, 2011

Proton Pump Inhibitor Use and the Antifracture Efficacy of Alendronate

Author Affiliations

Author Affiliations: Odense Patient Data Exploratory Network (OPEN), Institute of Clinical Research, University of Southern Denmark, Odense, and Department of Medicine and Endocrinology F, Copenhagen University Hospital Gentofte, Hellerup, Denmark (Dr Abrahamsen); Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, Denmark (Dr Eiken); and Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, England (Dr Eastell).

Arch Intern Med. 2011;171(11):998-1004. doi:10.1001/archinternmed.2011.20

Proton pump inhibitors (PPIs) are very widely used among the elderly population with a considerable overlap with the population that receives antiosteoporotic treatment with bisphosphonates. Thus, as shown herein, 26% of alendronate sodium users in Denmark take PPIs during the first 3 years of alendronate use. A recent editorial in the Archives1 warned that more than half of all PPI prescriptions are for inappropriate indications. Proton pump inhibitors have the potential to interact with the absorption of calcium, vitamin B12, and oral bisphosphonates themselves,2-4 as well as affecting the osteoclast proton pump. Observational studies have shown that patients receiving PPI treatment make up a high-risk group for osteoporotic fractures.5-8 Recently, data from the Women's Health Initiative revealed no significant effect of PPI exposure on the risk of hip fracture (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.18-1.82), but a significant increase in clinical spine, forearm, and total fractures.9 Several studies suggest a causal relationship6-8 between PPI use and fractures, while other studies do not10,11 or have found the effect to be small.12 Using national health data for Denmark, we therefore undertook a comprehensive analysis that included both the degree of refill compliance for alendronate and the cumulative exposure to PPIs during alendronate therapy for osteoporosis. We hypothesized that PPIs would blunt the antifracture efficacy of alendronate and that this phenomenon would not be reproduced by exposure to histamine H2 receptor blockers or glucocorticoids, the former identifying a patient group with increased gastrointestinal (GI) tract morbidity and the latter a patient group with strongly increased fracture risk.