Skeletal Regulation of Cortical and Trabecular Bone by Parathyroid Hormone

描述(申请人提供)：甲状旁腺激素(PTH)是骨骼和矿物质代谢的主要调节剂。然而，甲状旁腺激素调节骨小梁和皮质骨的区域化的方式仍不清楚。甲状旁腺激素过多和不足的两种疾病，分别是原发性甲状旁腺机能亢进症(PHPT)和甲状旁腺功能减退症(HypoPT)，提供了丰富的数据，表明甲状旁腺激素不仅在循环生化和矿物质代谢密度学指标方面发挥作用，而且可能更重要的是，对骨小梁和皮质骨的基本组织形态和结构特性起作用。本研究的目的是应用一种跨学科的方法，通过甲状旁腺切除术(PHPT)或甲状旁腺激素(HypoPT)治疗使甲状旁腺激素水平正常化，来确定甲状旁腺激素在纠正异常甲状旁腺激素状态前后，对甲状旁腺功能亢进或甲状旁腺功能低下受试者的骨分区和微结构的影响。在这些异常的甲状旁腺激素状态校正后，我们期望在基线上看到的变化将使我们能够以一种以前没有显示的方式将骨骼THA的特定特征归因于甲状旁腺素的最终控制。此外，我将研究甲状旁腺素对皮质和松质骨的双重作用是否可以通过核因子kappa B受体激活剂配体受体激活剂(RANKL)的特异性阻断剂denosumab阻断其分解代谢信号通路而转变为单峰、骨合成代谢的作用。本研究项目中将使用的定量工具包括骨转换的生化标记物；双能X射线骨密度仪(DXA)和高分辨率外周定量计算机断层扫描(HRpQCT)的骨密度；有限元分析(FEA)；以及个体小梁分割(ITS)分析。

DESCRIPTION (provided by applicant): Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism. However, the manner by which PTH regulates the compartmentalization of trabecular and cortical bone remains unknown. Two diseases of PTH excess and deficiency, primary hyperparathyroidism (PHPT) and hypoparathyroidism (HypoPT), respectively, offer a rich repository of data that suggest roles for PTH not only with regard to circulating biochemical and densitometric indices of mineral metabolism, but perhaps more importantly, for fundamental histomorphometric and structural properties of trabecular and cortical bone. The goal of this research proposal is to apply an interdisciplinary approach to determine how PTH affects compartmentalization and microarchitecture of bone in subjects with PHPT or HypoPT before and after correction of the abnormal PTH state, either by normalization of PTH levels by parathyroidectomy (PHPT) or by administration of PTH (HypoPT). The changes that we expect to see at baseline and after correction of these abnormal PTH states will allow us to attribute, in a manner not previously shown, specific features of the skeleton tha are under the ultimate control of PTH. In addition, I will investigate whether the dual actions of PTH on cortical and trabecular bone can be shifted to a unimodal, osteoanabolic one by blocking its catabolic signaling pathway by denosumab, a specific blocker of receptor activator of nuclear factor kappa B ligand (RANKL). The quantitative tools that will be used in this research project include biochemical markers of bone turnover; bone mineral density by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT); Finite Element Analysis (FEA); and Individual Trabeculae Segmentation (ITS) analysis.