A MECHANISTIC STUDY OF SKELETAL ACTIONS OF 1-34hPTH

1-34hPTH骨骼动作机制研究

• 批准号: 7643369
• 负责人: ROBERT LINDSAY
• 金额: $ 63.41万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643369
• 关键词: Address; Alendronate; Anabolic Agents; Biochemical; Biochemical Markers; Biopsy; Bone Density; Bone Surface; Bone remodeling; Clinical; Data; Development; Fracture; Individual; Label; Methods; Nature; Osteogenesis; Osteoporosis; Phase; Postmenopausal Osteoporosis; Rest; Skeleton; Stimulus; Subcutaneous Injections; Surrogate Markers; System; Teriparatide; Tetracyclines; Time; Woman; bisphosphonate; bone; high risk; indexing; novel; response; skeletal; subcutaneous; tool

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- 34 rhPTH（特立帕肽）作为骨质疏松症的治疗是一项重大进展。目前，1- 34 rhPTH的使用仅限于每天皮下注射2年。PTH刺激骨形成，其次是骨重建，其作用约2年消失。关于PTH产生其作用的细胞机制知之甚少。本申请旨在评价松质骨和皮质骨以及髂嵴骨内（皮质内）和外（骨膜）表面对PTH的早期（7周）和晚期（7.5个月）反应。我们将使用我们独特的四重四环素标记系统，使我们能够仅使用一次活检就获得有关2个时间点骨形成动态指数的信息。通过在开始PTH治疗前给予1对四环素标记物，在开始PTH治疗后1个月给予第二对四环素标记物，我们可以使用每例受试者作为其自身对照，从而在分析重复活检时显著降低受试者之间和受试者内的众所周知的变异性。我们将在7周时检查骨骼对PTH的早期形成反应，此时几乎没有再吸收刺激，后来在7.5个月时，这一时间点与生化标志物评估的最大重塑刺激一致。我们还将寻求确定是否周期性地（3个月/3个月）输送PTH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，在7周和7.5个月时进行活检，我们假设在关闭阶段会有更少的重塑，并且我们将在7.5个月时检测到第二次促进形成。最后，我们将解决一个重要的临床问题，通过检查骨骼对PTH的反应（每日和周期性）24个月后，无论是初治或阿仑膦酸钠至少1年，谁是在一个新的稳定状态。这些数据应提供重要的信息，在细胞水平上的PTH的作用机制，允许更好地理解的抗反应剂和合成代谢剂的相互作用，并描绘一个更有效的方法，PTH的临床使用。

项目成果

Three dimensional cancellous bone structure in hypoparathyroidism.

• DOI: 10.1016/j.bone.2009.09.020
• 发表时间: 2010-01
• 期刊: BONE
• 影响因子: 4.1
• 作者: Rubin, Mishaela R.;Dempster, David W.;Kohler, Thomas;Stauber, Martin;Zhou, Hua;Shane, Elizabeth;Nickolas, Thomas;Stein, Emily;Sliney, James, Jr.;Silverberg, Shonni J.;Bilezikian, John P.;Mueller, Ralph
• 通讯作者: Mueller, Ralph