DESCRIPTION (provided by principal investigator): Proton pump inhibitors (PPIs) are among the most widely used medications. It is becoming increasingly common for patients to take these potent acid suppressants on a long-term and continuous basis for erosive esophagitis, Barrett's esophagus and protection against nonsteroidal anti-inflammatory drug-related gastropathy. PPI therapy leads to elevated serum gastrin levels and may impair the absorption of calcium and food-bound vitamin B12. PPI-induced hypergastrinemia has a direct trophic effect on the parathyroid glands, leading to parathyroid hyperplasia, increased parathyroid hormone secretion and bone loss. Furthermore, both calcium malabsorption and vitamin B12 deficiency are associated with reduced bone mineral density (BMD) and increased osteoporotic fracture risk. Consistent with these data, recent studies revealed a positive association between PPI therapy and the risk of osteoporotic fractures. Peripheral quantitative computed tomography (pQCT) can provide a three-dimensional structural analysis of trabecular and cortical volumetric BMD (vBMD) and dimensions. These data are imperative for a valid assessment of the effect of chronic PPI therapy on bone strength. We hypothesize that PPI therapy leads to decreased cortical and trabecular vBMD, cortical dimensions and bone strength. Our primary aims are: 1). To compare the changes over time in cortical and trabecular vBMD, cortical dimensions and estimates of bone strength between long-term PPI users and non-users; 2). Among PPI users, to determine whether average PPI daily dose and extent of PPI adherence are predictors of greater loss in bone vBMD, dimensions and strength; 3). To compare the changes over time in PTH levels between long-term PPI users and non-users. The proposed study will longitudinally measure radial and tibial trabecular and cortical vBMD and dimensions in two groups of subjects between 55 to 75 years of age recruited at the University of Pennsylvania Health System:1). PPI-nave patients who are starting long-term continuous PPI therapy for newly diagnosed erosive esophagitis or Barrett's esophagus; 2). PPI-non users frequency matched with the PPI users on race, age, sex and body mass index. The pQCT measurements will be obtained at baseline and then yearly over the next 3 years. Longitudinal regression analyses will be conducted using generalized estimating equations or quasi-least squares modeling to compare the changes in pQCT measures of bone strength between the two groups. This study addresses a novel and important clinical question that has a direct impact on the bone health of the enormous population of elderly PPI users. The results of the current study will help determine the need, the intensity, as well the appropriate choice of modality for monitoring BMD in this population and guide the development of effective strategies to prevent and/or reverse this adverse effect of acid suppressive therapy. PUBLIC HEALTH RELEVANCE: Proton pump inhibitors (PPIs) are among the most widely used medications. These potent stomach acid suppressants may reduce bone density and increase the risk of osteoporotic fractures. This study will assess the effect of PPI therapy on bone strength using a valid radiographic tool called peripheral quantitative computed tomography. This project addresses a novel and important clinical question that has a direct impact on the bone health of the millions of PPI users. The data generated by the current project will help determine the need, the intensity, as well the appropriate choice of modality for monitoring bone mineral density and bone structure among chronic PPI users and guide the development of effective strategies to prevent and/or reverse this adverse effect of acid suppressive therapy.