Enhancing adaptation to loading with PTH in osteoporosis

增强骨质疏松症患者对 PTH 负荷的适应

• 批准号: 9299008
• 负责人: Marjolein C van der Meulen
• 金额: $ 20.99万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299008
• 关键词: Aging; Anatomy; Animals; Architecture; Cells; Clinical; Clinical Treatment; Data; Effectiveness; Estrogen Receptor alpha; Estrogens; Evaluation; FDA approved; Female; Fracture; Future; Genetic; Goals; Hormonal; Hormones; Human; Immunohistochemistry; Individual; Knowledge; Mechanics; Metabolic; Metaphysis; Modeling; Mus; Neck; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Outcome Measure; PTH gene; Physiological; Postmenopausal Osteoporosis; Postmenopause; Pre-Clinical Model; Proteins; Role; Site; Skeletal bone; Stimulus; Testing; Tissues; Torsion; Treatment Protocols; Variant; Weight-Bearing state; Woman; age related; base; bisphosphonate; bone; bone cell; bone loss; bone mass; bone strength; cortical bone; experience; experimental study; fracture risk; fragility fracture; human data; improved; in vivo; in vivo Model; mechanical behavior; mechanical load; mechanotransduction; microCT; mouse model; novel; pre-clinical; prevent; response; skeletal; substantia spongiosa; synergism; tibia

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.

项目摘要 由于激素和代谢的影响， 随着年龄的增长而变化，导致皮质松质骨部位骨折。间歇性甲状旁腺 iPTH是FDA批准的唯一一种改善骨量的合成代谢治疗方法， 架构机械负荷协同放大PTH的有益作用，但 机制不被理解。我们的初步数据表明，PTH在负荷下更有效 承受张力的部位比承受压力的部位更易受损伤。 在这个探索性的建议中，我们的目标是了解机械载荷和 骨质疏松症期间的PTH治疗，目的是增强PTH的合成代谢作用 在实验和临床上。使用绝经后骨质疏松症的模型，我们将 确定负荷模式在间歇性PTH（iPTH）治疗反应中的作用， 皮质骨和PTH对骨形成的激活对骨形成的协同作用 松质骨中iPTH和机械负荷的影响。在具体目标1中，我们将确定 拉伸和压缩负荷对协同合成代谢的不同影响 绝经后妇女临床前模型对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预处理是否能增强 iPTH和体内机械负荷在松质骨中协同合成代谢作用 健康和骨质减少小鼠。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治疗和受控胫骨负荷。成果将 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。机械性能也将在 目标二。 这些实验将进一步加深我们对之间关系的机械理解 PTH和体内骨骼机械负荷的基础上，我们的新假设， PTH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的机制， 制定策略以抑制年龄相关的和绝经后的骨质流失， 骨折我们的目标是为未来的临床治疗方案提供信息和指导， 最大限度地提高PTH的临床疗效。