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

描述（申请人提供）：由于病态肥胖和2型糖尿病的患病率上升，接受Roux-en-Y胃旁路手术（RYGB）减肥的患者数量从2002年的7.5万增加到2012年的近30万。尽管RYGB广受欢迎并取得了成功，但它与骨吸收增加的状态有关，这最终会减少骨量。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。改善这种吸收的临床努力主要集中在增加钙和维生素D的补充，很少有研究来了解负责的机制和预防它们。在2010年NIH K08奖的资助下，我们的研究小组建立了一种饮食性肥胖（DIO）雄性大鼠RYGB模型，该模型模仿人类RYGB过程，具有类似的术后体重减轻和脂肪吸收不良。我们对雄性RYGB模型的骨标记物和质量的初步调查表明，RYGB后肥胖大鼠的骨小梁体积明显减少，皮质骨较少，骨吸收标记物较高（血清CTX水平较高），与年龄匹配的假对照组相比。此外，我们的RYGB动物的P1NP水平较低，P1NP是骨形成的生物标志物，比假对照组低，这是继发性甲状旁腺功能亢进的一个意想不到的发现。高甲状旁腺激素水平应刺激形成和吸收，因为这两个过程在体内是耦合的。我们假设，在RYGB模型中，除了已知的继发性甲状旁腺功能亢进和体重减轻对骨骼的影响外，肠道和生殖激素活性的改变也会对骨转换产生负面影响。这些异常可能代表了RYGB患者骨质流失预防策略的目标。迄今为止，关于RYGB对骨骼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。尽管事实上80%的人类RYGB手术都是在女性身上进行的。本应用程序的目的是在一个女性模型的RYGB手术中确定这种高吸收和低形成状态的原因，术后补充维生素d。Thomas Carpenter博士（耶鲁），Anne Schafer博士（UCSF）， Sylvia Christakos博士（UMDNJ），骨骼和矿物质代谢的临床和基础科学专家，以及Benjamin Canales博士，泌尿外科医生对RYGB的影响感兴趣，设计了一项介入研究来实现这一目标。DIO 18周后，雌性大鼠将被分为三组之一：假对照组-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（5000 IU/kg）。专注于女性在骨骼和矿物质代谢和维生素D方面的独特结果，我们期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，例如放射设备重量限制，髂脊骨活检的侵入性和成本，患者可靠性或随访损失，以及患者对标准化饮食或补充剂的依从性。这项工作将为未来的RYGB研究奠定基础，这些研究将评估更详细的组织形态学、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。

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.