Interaction of Mechanical Loading and Teriparatide on Bone Mass and Performance

退伍军人骨骼脆弱和骨折的风险很高。特别是，限制 移动性--从而降低骨骼的生理负荷-- 增加骨折风险。已知近交系小鼠品系对 实验施加载荷、骨密度和长骨骨干几何形状。 已知甲状旁腺激素的作用可增强负荷诱导的建模 (Pth)。然而，这种效应在遗传背景中的一致性还没有被研究过。 而重组人甲状旁腺素1-34(Teriparatide，TPT)则导致脊椎显著增加 骨小梁体积分数和骨密度(BMD)，这可能是以牺牲 在卸载部位，皮质孔隙率增加，骨小梁体积分数减少。 最后，对机械负荷和甲状旁腺激素相互作用的动物研究已成为重点。 完全依赖于建模反应，并在很大程度上忽略了增加 皮质孔隙度。因此，缺乏关于PTH和PtH相互作用的数据 不同遗传背景下破骨细胞活动的机械负荷。目标是 这项建议的目的是比较TPT、机械加载以及它们之间的相互作用在 C57BL/6J(B6)和A/J(A)雄性小鼠。这个项目的中心假设是基因 背景不仅影响对机械负荷的反应，而且影响对TPT和TPT的反应 加载和TPT之间的相互作用，无论是在实验加载的现场还是在 远程站点。我们将让雄性A和B6小鼠承受右侧胫骨的间歇性循环载荷 在3周的时间里，用TPT治疗每个品系的一半小鼠。利用这些老鼠，我们将 承担以下具体目标：1)测量小鼠对TPT的品系特异性反应 和机械负荷对皮质模型的影响，2)确定负荷和TPT对大脑皮质模型的影响 卸载部位的皮质骨，3)确定负荷和TPT治疗对 松质骨。我们将使用胫骨压缩时的定义载荷作为实验 实现具体目标的方法。在建议的研究完成后，我们会 已经确定了TPT和机械载荷在A组皮质骨模型中的相互作用 和B6小鼠。我们将确定机械负荷和TPT对皮质的影响 以及A和B6小鼠未受实验载荷的部位的骨小梁。这些 数据将提供对TPT、机械加载和 它们的相互作用在一对小鼠品系中用来构建协作性杂交。他们会 让我们做好准备开发一项旨在优化骨骼组合的研究计划 应用合成代谢药物和物理疗法预防低位创伤性骨折。 我们期望这一系列调查将带来更好的药物治疗和锻炼。 低创伤骨折风险患者的处方，特别是那些活动受限的患者。

Veterans are at high risk for skeletal fragility and fracture. In particular, conditions that limit mobility-and consequently decrease physiologic loading of the skeleton-concomitantly increase fracture risk. Inbred mouse strains are known to differ in their responsiveness to experimentally imposed loading, bone mineral density, and long bone diaphyseal geometry. Loading-induced modeling is known to be enhanced by the action of parathyroid hormone (PTH). However, the uniformity of this effect across genetic backgrounds has not been studied. While recombinant human PTH 1-34 (teriparatide, TPT) leads to dramatic increases in vertebral trabecular bone volume fraction and bone mineral density (BMD), this may occur at the expense of increased cortical porosity and reduced trabecular bone volume fraction at unloaded sites. Finally, animal studies of the interaction of mechanical loading and PTH have focused exclusively on the modeling response, and have largely ignored the potential for increased cortical porosity. There is therefore a lack of data addressing the interaction of PTH and mechanical loading on osteoclastic activity across diverse genetic backgrounds. The objective of this proposal is to compare the effects of TPT, mechanical loading, and their interaction in C57BL/6J (B6) and A/J (A) male mice. The central hypothesis of this project is that genetic background affects not only the response to mechanical loading, but the response to TPT and the interaction between loading and TPT as well, at both experimentally loaded sites and at remote sites. We will subject male A and B6 mice to intermittent cyclic loading of the right tibia over a 3-week period, treating half the mice of each strain with TPT. Using these mice, we will undertake the following specific aims: 1) Measure the mouse strain-specific response to TPT and mechanical loading on cortical modeling, 2) Determine the impact of loading and TPT on cortical bone at unloaded sites, 3) Determine the impact of loading and TPT treatment on trabecular bone. We will use defined loading of the tibia in compression as the experimental approach to accomplish the specific aims. At the conclusion of the proposed studies, we will have determined the interaction of TPT and mechanical loading on cortical bone modeling in A and B6 mice. We will have determined the effects of mechanical loading and TPT on cortical and trabecular bone at sites not subjected to experimental loading in A and B6 mice. These data will provide a comprehensive comparison of the response to TPT, mechanical loading, and their interaction in a pair of mouse strains used in constructing the collaborative cross. They will leave us poised to develop a research program aimed at optimizing the combination of bone anabolic drugs and physical therapy in immobilized patients to prevent low trauma fractures. We expect that this line of investigation will lead to better-informed medication and exercise prescriptions for patients at risk for low trauma fracture, particularly those with limited mobility.