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; 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（Teriparatide）作为骨质疏松症的治疗方法已成为重大进展。目前，1-34RHPTH的使用限制为每天2年的皮下注射。 PTH刺激骨骼形成，其次是骨骼重塑，其作用消失了大约2年。关于PTH产生其作用的细胞机制知之甚少。该应用程序旨在评估iLiac Crest的骨骼和内（内皮层）和内（内皮层）和外部（内皮层）和外部（骨膜）表面的早期（7周）和更晚（7.5个月）对PTH的反应。我们将使用独特的四环四环素标记系统，该系统使我们能够仅使用一次活检在2个时间点获得有关骨形成动态指数的信息。通过在开始PTH 1个月后启动PTH之前给出1对四环素标签，我们可以将每个受试者用作自己的控制，从而在分析重复的活检时显着降低了跨受试者和受试者的众所周知的可变性。我们将在7周的吸收刺激时检查骨架对PTH的早期形成反应，然后在7.5个月时，这与生物化学标记所评估的最大刺激相吻合。我们还将寻求确定周期性传递PTH（休假3个月）是否可以将早期的形成反应与重塑响应分开，并为新骨形成提供重复的刺激。在接受环状PTH的女性中，使用具有活检的四倍标记系统，我们假设在关闭阶段的重塑将较少，而第二次提升了地层，我们将在7.5个月中检测到。最后，我们将通过检查对PTH（每日和周期性）的骨骼反应在对治疗天真的受试者或Alendronate中至少1年后的骨骼反应，并处于新的稳态状态，来解决一个重要的临床问题。这些数据应提供有关PTH在细胞水平上作用机理的重要信息，从而更好地了解抗凋亡剂和合成代谢剂的相互作用，并描述一种更有效的PTH临床使用方法。