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

描述(申请人提供)：由于病态肥胖症和2型糖尿病的发病率不断上升，接受Roux-en-Y胃分流术(RYGB)减肥的患者数量已从2002年的75,000人增加到2012年的近300,000人。尽管RYGB很受欢迎并取得了成功，但它与骨吸收增加的状态有关，这种状态最终会减少骨量。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。临床上改善这种吸收的努力主要集中在增加钙和维生素D的补充上，几乎没有研究来了解其相关机制并加以预防。在2010年NIH K08奖项的资助下，我们团队建立了饮食诱导肥胖(DIO)雄性RYGB大鼠模型，该模型模仿人类RYGB手术，术后体重减轻和脂肪吸收不良相似。我们对这一雄性RYGB模型的骨标志物和质量的初步研究表明，与年龄匹配的假对照组相比，RYGB治疗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(血清CTX水平升高)明显增加。此外，我们的RYGB动物的P1NP水平低于假对照组-这在继发性甲状旁腺功能亢进症的背景下是一个意想不到的发现。高水平的甲状旁腺激素应该会刺激形成和吸收，因为这两个过程在体内是耦合的。我们假设，在我们的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还会对骨转换产生负面影响。这些异常可能代表了接受RYGB的人类骨丢失预防策略的靶点。到目前为止，关于RYGB对骨骼和矿物质代谢影响的实验室研究完全依赖于雄性啮齿动物模型。尽管80%的人类RYGB手术是在女性身上进行的，但这一点仍然存在。这项应用的目的是在术后富含维生素D的女性RYGB手术模型中确定这种高吸收和低形成状态的原因。托马斯·卡彭特博士(耶鲁大学)、Anne Schafer博士(加州大学旧金山分校)、Sylvia Christakos博士(UMDNJ)，骨和矿物质代谢的临床和基础科学专家，以及对RYGB效应感兴趣的泌尿外科医生Benjamin Canales博士为实现这一目标设计了一项干预性研究。DIO 18周后，雌性大鼠分为三组：假手术对照组-维生素D充足日粮(1000IU/kg)；RYGB-维生素D充足日粮(1000IU/kg)；RYGB-维生素D补充组(5000IU/kg)。我们的工作模型专注于女性特有的骨骼和矿物质代谢以及维生素D的结果，我们预计我们的工作模型将克服人类营养和骨骼研究的许多限制，例如放射设备重量限制、髂骨活组织检查的侵袭性和成本、患者的可靠性或损失，以及患者对标准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。

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.