A MECHANISTIC STUDY OF SKELETAL ACTIONS OF 1-34hPTH

描述（由申请人提供）：引进1-34rhPTH（特立帕肽）治疗骨质疏松症是一项重大进展。目前，1-34rhPTH的使用仅限于每日皮下注射2年。甲状旁腺激素刺激骨形成和继发性骨重塑，其影响约2年消退。人们对甲状旁腺激素产生作用的细胞机制知之甚少。本应用旨在评估早期（7周）和后期（7.5个月）松质骨、皮质骨以及髂骨内（内皮质）和外（骨膜）表面对甲状旁腺激素的反应。我们将使用我们独特的四环素标记系统，该系统允许我们仅使用一次活检就能在2个时间点获得有关骨形成动态指标的信息。通过在PTH开始前给予1对四环素标签，在PTH开始后1个月给予第二对四环素标签，我们可以将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了受试者之间和受试者内部众所周知的可变性。我们将检查骨骼对甲状旁腺激素的早期形成反应，在7周时，吸收刺激很少，后来在7.5个月时，一个时间点与生化标志物评估的重塑刺激最大一致。我们还将试图确定是否周期性（3个月开/3个月停）给予甲状旁腺激素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7周和7.5个月时对接受周期性甲状旁腺激素的妇女进行活检，我们假设在退行期会有更少的重塑，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24个月后骨骼对甲状旁腺激素（每日和周期性）的反应，这些受试者要么是首次接受治疗，要么是服用阿仑膦酸钠至少1年，并且处于新的稳定状态。这些数据将为PTH在细胞水平上的作用机制提供重要信息，有助于更好地理解抗反应药物和合成代谢药物的相互作用，并为PTH的临床应用提供更有效的方法。

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.