Effects of Gastric Bypass Surgery on Calcium Metabolism and the Skeleton

描述(由申请人提供)： 这是退伍军人事务部医学中心(SFVAMC)的内分泌学家和临床研究员Anne Schafer博士的退伍军人职业发展奖(CDA-2)申请。Schafer博士在面向患者的临床研究中确立了自己作为年轻研究员的地位，该研究涉及肥胖、外科减肥和骨代谢等跨学科领域。肥胖是一种慢性疾病，其规模之大令人震惊。由于通过饮食和锻炼减肥很难实现和保持，因此人们对外科减肥手术的兴趣与日俱增，包括Roux-en-Y胃分流术。胃分流术在普通人群和我们的退伍军人患者中显著和持久地减轻了体重，并改善了并发症。然而，越来越多的证据表明，胃旁路手术会对骨骼产生负面影响，增加骨转换，降低骨密度(BMD)。鉴于骨质疏松症和骨折对男性和女性的巨大影响，这是一个令人严重关切的问题。肥胖和术后吸收不良导致的维生素D缺乏可能是胃旁路手术后骨量下降的部分原因。其他因素也可能涉及，如非维生素D介导的钙吸收不良，与骨骼负荷减少有关的信号，以及脂肪分泌激素或雌激素的变化(由于脂肪质量和身体成分的变化)。谢弗博士将在60名男性和女性的队列中研究胃旁路手术对钙代谢和骨骼的影响，这些男性和女性的血清25-羟基维生素D水平被补充并维持在E30毫微克/毫升。首先，她将验证胃旁路手术后肠道钙吸收受损的假设，即使在维生素D充足的情况下也是如此。她将通过使用双稳定同位素示踪剂测量手术前和手术后6个月的钙吸收分数来做到这一点(目标1)。然后，她将检验胃旁路手术导致骨密度降低和骨骼力量受损相关的结构变化的假设。她将通过术前、术后6个月和12个月进行双能X线吸收测量(DXA)、定量计算机断层扫描(QCT)和高分辨率外周QCT(HR-pQCT)来实现这一点(目标2)。QCT和HR-pQCT是先进的成像技术，与标准方法相比具有明显的优势，但尚未在这一人群中应用。最后，她将通过人体测量、DXA和QCT来评估身体成分的变化，以及脂肪分泌激素的变化，她将评估骨骼参数的变化与身体成分和激素变化之间的关系(目标3)。这项研究预计将通过帮助形成关于术后营养、骨密度筛查和潜在治疗的建议，来影响胃旁路手术患者的临床护理-无论是退伍军人还是非退伍军人。这项拟议的研究将为Schafer博士提供初步数据，以便对胃旁路手术的骨骼影响进行更大规模和更长期的前瞻性研究，她将在CDA-2周期结束前提交一份Merit Review应用程序。CDA-2还将为谢弗博士未来作为退伍军人管理局调查员的职业生涯提供必要的关键培训。具体地说，她将接受以下方面的培训：(1)设计和执行前瞻性队列研究；(2)代谢研究的翻译工具(例如，稳定同位素方法)；(3)先进骨骼成像模式的使用和解释；以及(4)身体成分评估。为了实现她的培训目标，谢弗博士组建了一个由内分泌学、研究设计、外科和放射学专家组成的导师团队。她的培训将包括与她的导师和科学顾问的个人教程、实践经验和正式课程相结合。她将在加州大学旧金山分校(UCSF)完成临床研究硕士学位，并将利用SFVAMC和UCSF丰富的科学环境。谢弗博士致力于通过临床研究改善退伍军人的医疗保健，CDA-2对实现她的职业目标至关重要。

DESCRIPTION (provided by applicant): This is a VA Career Development Award-2 (CDA-2) application for Dr. Anne Schafer, an endocrinologist and Clinical Research Fellow at the San Francisco Veterans Affairs Medical Center (SFVAMC). Dr. Schafer is establishing herself as a young investigator in patient-oriented clinical research involving the cross-disciplinary fields of obesity, surgical weight loss, and bone metabolism. Obesity is a chronic disease of staggering proportions. Because weight loss through diet and exercise is difficult to attain and maintain, there is escalating interest in surgical weight loss procedures, including Roux-en-Y gastric bypass. Gastric bypass results in marked and durable weight loss and improvement in comorbidities in the general population and in our veteran patients. However, growing evidence indicates that gastric bypass can have negative effects on the skeleton, increasing bone turnover and decreasing bone mineral density (BMD). This is of critical concern given the tremendous impact of osteoporosis and fracture in both men and women. Vitamin D deficiency due to obesity and post-surgical malabsorption may partially explain the decline in bone mass observed after gastric bypass. Other factors are likely involved as well, such as non-vitamin D-mediated calcium malabsorption, signals related to decreased skeletal loading, and changes in fat-secreted hormones or estrogen (due to changes in fat mass and body composition). Dr. Schafer will characterize the effects of gastric bypass on calcium metabolism and the skeleton in a cohort of 60 men and women whose serum 25- hydroxyvitamin D levels are supplemented and maintained at e30 ng/mL. First, she will test the hypothesis that intestinal calcium absorption is impaired following gastric bypass, even in the setting of vitamin D sufficiency. She will do this by measuring fractional calcium absorption pre-operatively and 6 months post- operatively using dual stable isotopic tracers (Aim 1). Then, she will test the hypothesis that gastric bypass results in decreased BMD and in structural changes associated with impaired skeletal strength. She will do this by performing dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) pre-operatively and 6 and 12 months post-operatively (Aim 2). QCT and HR-pQCT are advanced imaging techniques that have distinct advantages over standard methods but have not yet been applied to this population. Finally, she will assess body composition changes by anthropometry, DXA, and QCT, and changes in fat-secreted hormones, and she will evaluate the relationship between changes in skeletal parameters and changes in body composition and hormones (Aim 3). This research is expected to impact the clinical care of gastric bypass patients-veterans and non-veterans alike- by helping to shape recommendations about post-operative nutrition, BMD screening, and potential therapy. The proposed research will provide Dr. Schafer with preliminary data for a larger and longer-term prospective study of the skeletal effects of gastric bypass, which she will propose in a Merit Review application before the end of the CDA-2 period. The CDA-2 will also provide Dr. Schafer with crucial training required for her future career as a VA investigator. Specifically, she will acquire training in (1) design and execution of a prospective cohort study; (2) translational tools of metabolic research (e.g., stable isotope methods); (3) use and interpretation of advanced skeletal imaging modalities; and (4) body composition assessment. To achieve her training goals, Dr. Schafer has assembled a mentorship team comprised of experts in endocrinology, study design, surgery, and radiology. Her training will involve a combination of individual tutorials with her mentors and scientific advisors, hands-on experience, and formal coursework. She will complete a Masters Degree in Clinical Research at the University of California, San Francisco (UCSF) and will take advantage of the rich scientific environment at the SFVAMC and UCSF. Dr. Schafer is committed to improving the health care of veterans through clinical research, and the CDA-2 is critical for the attainment of her career objectives.