Enhancing adaptation to loading with PTH in osteoporosis

项目摘要 由于荷尔蒙和代谢作用，骨骼骨量和承重能力下降。 随着年龄的增长而变化，导致皮质松质细胞部位的骨折。间歇性甲状旁腺 激素(IPTH)是FDA批准的唯一一种可以改善骨量和 建筑。机械负荷协同放大甲状旁腺素的有益作用，但 机制还不清楚。我们的初步数据显示，甲状旁腺素在负荷时更有效 经历紧张的站点比那些以压缩方式加载的站点更紧张。 在这个探索性的提案中，我们的目标是了解机械加载和 骨质疏松症时甲状旁腺素的治疗，目的是增强甲状旁腺素的合成代谢作用 在实验和临床上都能看到。使用绝经后骨质疏松症模型，我们将 确定负荷模式在间歇性甲状旁腺激素(IPTH)治疗反应中的作用 皮质骨与甲状旁腺激素激活骨形成的协同作用 IPTH对松质骨力学负荷的影响。在具体目标1中，我们将确定 拉伸和压缩载荷对协同合成代谢的不同影响 绝经后临床前模型对iPTH和机械负荷的反应 骨质疏松。在具体目标2中，我们将确定iPTH预治疗是否增强了 IPTH与体内机械负荷对大鼠松质骨合成代谢的协同作用 健康和骨量减少的小鼠。这两个目标都将使用绝经后的雌性小鼠模型 骨质疏松症联合iPTH治疗和控制胫骨负荷。结果将会 包括组织结构、骨细胞活性和通过MicroCT进行蛋白质定位， 组织形态计量学和免疫组织化学方法。力学行为也将在 目标2. 这些实验将进一步加深我们对两者之间关系的机械理解 甲状旁腺素和活体骨骼机械负荷基于我们关于 甲状旁腺素在绝经后骨质疏松症中的作用机制。这些实验对于 了解松质骨适应负荷和压力的机制 制定策略以抑制与年龄相关的和绝经后的骨丢失以及由此产生的 骨折。我们的目标是告知和指导未来的临床治疗方案，并使 临床应最大限度地发挥甲状旁腺激素的疗效。

Project Summary Skeletal bone mass and load-bearing capacity diminish as a result of hormonal and metabolic changes with aging, resulting in fractures at corticocancellous sites. Intermittent parathyroid hormone (iPTH) is the only FDA-approved anabolic treatment that improves bone mass and architecture. Mechanical loading synergistically amplifies the beneficial effects of PTH but the mechanism is not understood. Our preliminary data show that PTH is more effective at loaded sites that experience tension than those that are loaded in compression. In this exploratory proposal we aim to understand the interaction of mechanical loading and PTH treatment during osteoporosis, with the goal of enhancing the anabolic effects of PTH seen experimentally and clinically. Using a model of postmenopausal osteoporosis we will determine the role of loading mode in the response to intermittent PTH (iPTH) treatment in cortical bone and the contribution of activation of bone formation by PTH to the synergistic effect of iPTH and mechanical loading in cancellous bone. In Specific Aim 1 we will determine the differential effects of tensile and compressive loading on the synergistic anabolic response to iPTH and mechanical loading in a preclinical model of postmenopausal osteoporosis. In Specific Aim 2 we will establish if iPTH pre-treatment enhances the synergistic anabolic effects of iPTH and in vivo mechanical loading in cancellous bone of healthy and osteopenic mice. Both aims will use a female mouse model of postmenopausal osteoporosis combined with iPTH treatment and controlled tibial loading. Outcomes will include tissue architecture, bone cell activity, and protein localization by microCT, histomorphometry and immunohistochemistry. Mechanical behavior will also be assessed in Aim 2. These experiments will further our mechanistic understanding of the relationship between PTH and in vivo skeletal mechanical loading based on our novel hypothesis regarding the mechanisms of PTH action in postmenopausal osteoporosis. These experiments are critical to understanding the mechanisms underlying cancellous bone adaptation to loading and to developing strategies to inhibit age-related and postmenopausal bone loss and the resulting fractures. Our goal is to inform and direct future clinical treatment regimens and enable the effectiveness of PTH to be maximized clinically.