A MECHANISTIC STUDY OF SKELETAL ACTIONS OF 1-34hPTH

1-34hPTH骨骼动作机制研究

• 批准号: 7280679
• 负责人: ROBERT LINDSAY
• 金额: $ 6.09万
• 依托单位: HELEN HAYES HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280679
• 关键词: alendronate; biopsy; clinical research; drug administration rate /duration; female; hormone therapy; human subject; human therapy evaluation; osteogenesis; osteoporosis; parathyroid hormones; patient oriented research; postmenopause; skeletal disorder chemotherapy; skeletal pharmacology

DESCRIPTION (provided by applicant): The introduction of 1-34rhPTH (teriparatide) as a treatment for osteoporosis has been a major advance. Currently, the use of 1-34rhPTH is limited to 2 years of daily subcutaneous injections. PTH stimulates bone formation and secondarily bone remodeling, effects which dissipate by about 2 years. Little is known about the cellular mechanisms by which PTH produces its effects. This application seeks to evaluate the early (7 week) and later (7.5 month) responses to PTH in cancellous, and cortical bone, as well as on the inner (endocortex) and outer (periosteal) surfaces of bone from the iliac crest. We will use our unique quadruple tetracycline labeling system that allows us to obtain information about dynamic indices of bone formation at 2 time points using only a single biopsy. By giving 1 pair of tetracycline labels before initiating PTH and the second pair 1 month after starting PTH, we can use each subject as her own control, thereby markedly reducing the well known variability across subjects and within subjects when analyzing duplicate biopsies. We will examine the early formation response of the skeleton to PTH at 7 weeks when there is little stimulation of resorption, and later at 7.5 months, a time point that coincides with maximal stimulation of remodeling as assessed by biochemical markers. We will also seek to determine if delivering PTH cyclically (3 months on/3 months off) can separate the early formation response from the remodeling response, and provide repetitive stimuli to new bone formation. Using the quadruple labeling system with biopsies at 7 weeks and 7.5 months in women receiving cyclic PTH, we hypothesize that there will be less remodeling during the off phase and a second boost to formation that we will detect at 7.5 months. Finally, we will address an important clinical question, by examining the skeletal response to PTH (daily and cyclic) after 24 months in subjects either naive to treatment or on alendronate for at least 1 year, and who are in a new steady state. These data should provide important information on the mechanism of action of PTH at the cellular level, allow for a better understanding of the interaction of an antiresoptive agent and an anabolic agent, and delineate a more efficient approach to the clinical use of PTH.

描述（由申请人提供）：引入 1-34rhPTH（特立帕肽）作为骨质疏松症的治疗方法是一项重大进步。目前，1-34rhPTH 的使用仅限于 2 年每日皮下注射。 PTH 刺激骨形成，继而刺激骨重塑，效果会在大约 2 年内消失。对于 PTH 产生作用的细胞机制知之甚少。该应用旨在评估松质骨和皮质骨以及髂嵴骨的内（皮质内）和外（骨膜）表面对 PTH 的早期（7 周）和后期（7.5 个月）反应。我们将使用我们独特的四环素标记系统，该系统使我们能够仅使用一次活检就获得有关两个时间点骨形成动态指数的信息。通过在开始 PTH 之前给予一对四环素标签，并在开始 PTH 后 1 个月给予第二对四环素标签，我们可以使用每个受试者作为自己的对照，从而在分析重复活检时显着减少受试者之间和受试者内部众所周知的变异性。我们将在 7 周时检查骨骼对 PTH 的早期形成反应，当时几乎没有再吸收刺激，随后在 7.5 个月时检查骨骼对 PTH 的早期形成反应，该时间点与生化标记物评估的重塑最大刺激一致。我们还将寻求确定周期性提供 PTH（3 个月/3 个月停）是否可以将早期形成反应与重塑反应分开，并为新骨形成提供重复刺激。使用四重标记系统在接受周期性 PTH 的女性中进行 7 周和 7.5 个月的活检，我们假设在休止期重塑会减少，并且我们将在 7.5 个月时检测到第二次形成促进。最后，我们将解决一个重要的临床问题，通过检查 24 个月后受试者对 PTH（每日和周期）的骨骼反应，这些受试者无论是初次接受治疗还是服用阿仑膦酸钠至少 1 年，并且处于新的稳定状态。这些数据应提供有关 PTH 在细胞水平的作用机制的重要信息，以便更好地了解抗反应剂和合成代谢剂的相互作用，并描绘出更有效的 PTH 临床使用方法。