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骨皮质区室化的方式尚不清楚。甲状旁腺激素过多和不足的两种疾病，原发性甲状旁腺功能亢进症（PHPT）和甲状旁腺功能减退症（HypoPT），分别提供了丰富的数据库，表明甲状旁腺激素不仅与循环生化和矿物质代谢的密度指标有关，而且可能更重要的是与骨小梁和皮质骨的基本组织形态和结构特性有关。本研究计划的目标是应用跨学科的方法来确定PTH如何影响PHPT或HypoPT患者在纠正异常PTH状态前后的区隔化和骨微结构，通过甲状旁腺切除术（PHPT）或PTH管理（HypoPT）使PTH水平正常化。我们期望在基线和纠正这些异常PTH状态后看到的变化将使我们能够以一种以前未显示的方式归因于PTH最终控制下的骨骼的特定特征。此外，我将研究PTH对皮质骨和骨小梁的双重作用是否可以通过使用核因子κ B配体受体激活剂（RANKL）特异性阻断剂denosumab阻断其分解代谢信号通路而转变为单峰的骨合成代谢作用。本研究项目将使用的定量工具包括骨转换的生化标志物；通过双能x线吸收仪（DXA）和高分辨率外围定量计算机断层扫描（HRpQCT）测量骨密度；有限元分析；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. PUBLIC HEALTH RELEVANCE: Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism, yet the mechanisms by which PTH regulates compartmentalization and microarchitecture of bone remain unknown. The knowledge obtained in this study should help to better characterize the specific features of the skeleton that are under the ultimate control of PTH. This understanding may lead to the development of new therapeutic interventions.