Non-vitamin D related mechanisms of bone loss after gastric bypass

胃绕道术后骨丢失的非维生素 D 相关机制

• 批准号: 8624117
• 负责人: Benjamin K Canales
• 金额: $ 7.99万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624117
• 关键词: Age; Animal Model; Animals; Award; Bariatrics; Basic Science; Biochemical Markers; Biological Markers; Biomechanics; Biopsy; Body Weight decreased; Bone Density; Bone Resorption; Budgets; Calcium; Caring; Cholecalciferol; Clinical; Clinical Sciences; Coupled; Cyclophosphamide; Diabetes Mellitus; Diet; Equipment; Estradiol; Fatty acid glycerol esters; Female; Femur; Fracture; Funding; Future; Gastric Bypass; Goals; Grant; Health; Hormones; Human; Hypertension; Intervention Studies; Investigation; Laboratory Research; Malabsorption Syndromes; Measures; Mechanics; Mediating; Medical; Medical Economics; Metabolism; Minerals; Modeling; Morbid Obesity; Morbidity - disease rate; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Operative Surgical Procedures; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Patients; Peptide YY; Population; Positioning Attribute; Postoperative Period; Prevalence; Prevention; Prevention strategy; Procedures; Process; Rattus; Reporting; Research; Research Personnel; Risk; Rodent; Rodent Model; Secondary Hyperparathyroidism; Serum; Structure; Supplementation; Testing; Time; United States National Institutes of Health; Urologic Surgeon; Vitamin D; Vitamin D Deficiency; Weight; Woman; Work; absorption; bariatric surgery; base; bone; bone health; bone loss; bone mass; bone strength; bone turnover; calcium absorption; cohort; compliance behavior; cost; design; economic impact; follow-up; improved; in vivo; insight; interest; male; micronutrient deficiency; mortality; prevent; public health relevance; reproductive axis; reproductive hormone; research study; senescence; sham surgery; skeletal; substantia spongiosa; success

DESCRIPTION (provided by applicant): Due to the rising prevalence of morbid obesity and type 2 diabetes mellitus, the number of patients undergoing Roux-en-Y gastric bypass (RYGB) surgery for weight loss has increased from 75,000 in 2002 to almost 300,000 patients in 2012. Despite its popularity and successes, RYGB is associated with a state of increased bone resorption which can ultimately decrease bone mass. This is thought to be due primarily to compromised gut calcium and vitamin D absorption leading to secondary hyperparathyroidism. Clinical efforts to improve this resorption have focused on increased calcium and vitamin D supplementation with little research to understand the responsible mechanisms and prevent them. With funding from an NIH K08 award in 2010, our group established a diet-induced obese (DIO) male rat model of RYGB that mimics the human RYGB procedure, with similar post-operative weight loss and fat malabsorption. Our preliminary investigations of bone markers and mass in this male RYGB model have demonstrated that obese rats after RYGB have markedly reduced trabecular bone volume, less cortical bone, and higher markers of bone resorption (evidenced by higher serum CTX levels) than age-matched sham controls. In addition, our RYGB animals have lower levels of P1NP, a biomarker of bone formation, than sham controls-an unexpected finding in the setting of secondary hyperparathyroidism. High PTH levels should stimulate both formation and resorption, since the two processes are coupled in vivo. We hypothesize that bone turnover in our model of RYGB is negatively influenced by altered gut and reproductive hormone activity in addition to the known skeletal effects of secondary hyperparathyroidism and weight loss. These abnormalities may represent targets for bone loss prevention strategies in humans undergoing RYGB. Laboratory research into the effects of RYGB on bone and mineral metabolism, to date, has relied solely on male rodent models. This is despite the fact that 80% of human RYGB procedures are done in women. The objective of this application is to identify the cause of this high resorptive and low formative state in a femae model of RYGB surgery replete post- operatively with vitamin D. Dr. Thomas Carpenter (Yale), Dr. Anne Schafer (UCSF), Dr. Sylvia Christakos (UMDNJ), clinical and basic science experts in bone and mineral metabolism, and Dr. Benjamin Canales, urologic surgeon with an interest in RYGB effects, have designed an interventional study to accomplish this goal. After 18 weeks of DIO, female rats will be assigned into one of three groups: sham controls - vitamin D sufficient diet (1000 IU/kg); RYGB - vitamin D sufficient diet (1000 IU/kg); and RYGB - vitamin D supplementation (5000 IU/kg). Focusing uniquely on female-specific outcomes in bone and mineral metabolism and vitamin D, we expect our working model will overcome many of the limitations of human nutritional and skeletal research studies, such as radiological equipment weight limitations, invasiveness and cost of iliac crest bone biopsies, patient reliability or lossof follow up, and patient compliance with standardized diets or supplements. This work will form the basis for future RYGB studies that will evaluate more detailed histomorphometry, gut calcium absorption studies, and the impact of senescence and female reproductive axis function on bone health.

描述（由申请人提供）：由于病态肥胖症和2型糖尿病的患病率上升，接受Roux-en-Y-Y胃搭桥手术（RYGB）体重减轻手术的患者数量已从2002年的75,000人增加到2012年的近300,000名患者，尽管它的受欢迎程度和成功率是Rygb的群体。这被认为主要是由于肠道钙和维生素D吸收造成的损害，导致继发性甲状旁腺功能亢进。改善这种吸收的临床努力集中在增加钙和维生素D的补充上，很少研究以了解负责任的机制并预防它们。在2010年获得NIH K08奖的资助下，我们的小组建立了饮食引起的肥胖（DIO）男性大鼠RYGB模型，该模型模仿了人类RYGB程序，并具有相似的术后体重减轻和脂肪吸收症。我们对这个雄性RYGB模型中骨标记和质量的初步研究表明，与年龄匹配的假手术对照相比，RYGB后的肥胖大鼠显着降低了小梁骨体积，较少的骨吸收骨骼骨体积，较少的皮质骨和更高的骨吸收标记（由更高的血清CTX水平证明）。此外，与假控制在继发性甲状旁腺功能亢进症的情况下，我们的RYGB动物具有较低的P1NP（骨形成的生物标志物），这是骨形成的生物标志物。高PTH水平应刺激形成和吸收，因为两个过程在体内耦合。我们假设我们的RYGB模型中的骨转换还受到肠道改变和生殖激素活性的影响，此外还有继发性甲状旁腺功能亢进和体重减轻的已知骨骼效应。这些异常可能代表了经历RYGB的人类预防骨质损失策略的目标。迄今为止，RYGB对骨和矿物质代谢的影响的实验室研究仅依赖于男性啮齿动物模型。尽管事实是，在女性中，有80％的人类RYGB手术。该应用的目的是确定Rygb手术模型中这种高吸收性和低形成状态的原因，该模型与维生素D手术。对RYGB效应的兴趣已经设计了一项介入研究以实现这一目标。经过18周的DIO，将雌性大鼠分为三组之一：假对照 - 维生素D足够的饮食（1000 IU/kg）； RYGB-维生素D足够的饮食（1000 IU/kg）；和RYGB-维生素D补充（5000 IU/kg）。我们希望我们的工作模型独特地专注于骨骼和矿物质代谢和维生素D的特定成果，将克服许多人类营养和骨骼研究研究的局限性，例如放射设备的体重限制，侵入性限制和ILIAC CREST骨骼活检的成本，患者可靠性，患者可靠性，患者的可靠性或损失随访，并伴随着患者的依从性，并提供标准饮食或补充剂或补充剂。这项工作将构成未来RYGB研究的基础，该研究将评估更详细的组织形态法，肠道钙吸收研究以及衰老和女性生殖轴功能对骨骼健康的影响。