Effect of Chronic Proton Pump Inhibitor Therapy on Bone Mineral Density and Bone

描述(由首席研究人员提供)：质子泵抑制剂(PPI)是使用最广泛的药物之一。对于患者来说，长期和持续服用这些有效的抑酸剂来治疗腐蚀性食管炎、巴雷特食道和预防非类固醇抗炎药物相关胃病正变得越来越普遍。PPI治疗导致血清胃泌素水平升高，并可能损害钙和食物结合维生素B12的吸收。PPI诱导的高胃泌素血症对甲状旁腺有直接的营养作用，导致甲状旁腺增生、甲状旁腺激素分泌增加和骨质丢失。此外，钙吸收不良和维生素B12缺乏都与骨密度降低和骨质疏松性骨折风险增加有关。与这些数据一致的是，最近的研究显示，PPI治疗与骨质疏松性骨折的风险呈正相关。外周定量计算机断层扫描(PQCT)可以提供骨小梁和皮质体积骨密度(VBMD)及其维度的三维结构分析。这些数据对于有效评估慢性PPI治疗对骨强度的影响是必不可少的。我们假设PPI治疗导致皮质和骨小梁vBMD、皮质尺寸和骨强度降低。我们的主要目标是：1)。比较长期服用和不服用PPI者的皮质和骨小梁vBMD、皮质尺寸和骨强度估计值随时间的变化；2)。在PPI使用者中，确定PPI的平均日剂量和PPI依附程度是否预测骨vBMD、尺寸和强度的更大损失；3)。比较长期PPI使用者和非使用者甲状旁腺激素水平随时间的变化。这项拟议的研究将纵向测量宾夕法尼亚大学卫生系统招募的两组55岁至75岁的受试者的桡骨、胫骨小梁和皮质vBMD和维度：1)。对新诊断的糜烂性食管炎或Barrett‘s食管炎开始长期持续PPI治疗的患者；PPI-非PPI用户在种族、年龄、性别和体重指数上与PPI用户的频率匹配。PQCT测量将在基线时获得，然后在接下来的3年内每年获得。将使用广义估计方程或准最小二乘模型进行纵向回归分析，以比较两组骨强度的pQCT测量的变化。这项研究解决了一个新的和重要的临床问题，该问题对庞大的老年PPI使用者的骨骼健康有直接影响。目前的研究结果将有助于确定在这一人群中监测骨密度的必要性、强度以及适当的方式选择，并指导制定有效的战略来预防和/或逆转抑酸疗法的这种不利影响。 公共卫生相关性：质子泵抑制剂(PPI)是使用最广泛的药物之一。这些有效的胃酸抑制剂可能会降低骨密度，增加骨质疏松性骨折的风险。这项研究将使用一种名为外周定量计算机断层扫描的有效放射学工具来评估PPI疗法对骨强度的影响。这个项目解决了一个新的和重要的临床问题，对数百万PPI用户的骨骼健康有直接影响。当前项目产生的数据将有助于确定慢性PPI使用者监测骨密度和骨结构的需求、强度以及适当的方式选择，并指导制定有效的策略来预防和/或逆转抑酸疗法的这种不利影响。

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-na¿ve 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.