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（由申请方提供）：由于病态肥胖和2型糖尿病的患病率不断上升，接受Roux-en-Y胃旁路（RYGB）手术减肥的患者数量从2002年的75，000例增加到2012年的近300，000例。尽管其流行和成功，RYGB与骨吸收增加的状态相关，这最终会降低骨量。这被认为主要是由于肠道钙和维生素D吸收受损导致继发性甲状旁腺功能亢进。改善这种再吸收的临床努力集中在增加钙和维生素D的补充上，很少有研究来了解负责任的机制并预防它们。在2010年NIH K 08奖的资助下，我们的小组建立了一种饮食诱导的肥胖（DIO）RYGB雄性大鼠模型，该模型模仿人类RYGB程序，具有相似的术后体重减轻和脂肪吸收不良。我们对该雄性RYGB模型中骨标志物和质量的初步研究表明，与年龄匹配的假手术对照组相比，RYGB后肥胖大鼠的骨小梁体积显著减少，皮质骨减少，骨吸收标志物升高（由血清CTX水平升高证明）。此外，我们的RYGB动物有较低水平的P1 NP，骨形成的生物标志物，比假对照组-在继发性甲状旁腺功能亢进的设置一个意想不到的发现。高PTH水平应刺激形成和再吸收，因为这两个过程在体内是偶联的。我们假设，在我们的模型中的骨转换RYGB的肠道和生殖激素活性的改变，除了已知的继发性甲状旁腺功能亢进和体重减轻的骨骼效应的负面影响。这些异常可能代表了接受RYGB的人类骨丢失预防策略的目标。迄今为止，关于RYGB对骨和矿物质代谢影响的实验室研究仅依赖于雄性啮齿动物模型。尽管80%的人类RYGB手术是在女性中完成的。本申请的目的是确定RYGB手术的女性模型中这种高吸收和低形成状态的原因，术后补充维生素D。托马斯卡彭特博士（耶鲁大学），安妮谢弗博士（加州大学旧金山分校），西尔维娅Christakos博士（UMDNJ），临床和基础科学专家在骨和矿物质代谢，和本杰明卡纳莱斯博士，泌尿外科医生与RYGB效应的兴趣，设计了一项干预性研究，以实现这一目标。DIO 18周后，将雌性大鼠分配到三组中的一组：假对照-维生素D充足饮食（1000 IU/kg）; RYGB -维生素D充足饮食（1000 IU/kg）;和RYGB -维生素D补充剂（5000 IU/kg）。专注于女性特有的骨和矿物质代谢和维生素D的结果，我们希望我们的工作模型将克服人类营养和骨骼研究的许多局限性，如放射设备重量限制，髂嵴骨活检的侵入性和成本，患者的可靠性或失访，以及患者对标准化饮食或补充剂的依从性。这项工作将成为未来RYGB研究的基础，这些研究将评估更详细的组织形态计量学，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。