A MECHANISTIC STUDY OF SKELETAL ACTIONS OF 1-34hPTH

描述(由申请人提供)：1-34rhPTH(Teriparatide)作为治疗骨质疏松症的药物的引入是一项重大进展。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，这种作用大约2年后消失。关于甲状旁腺素产生作用的细胞机制，人们知之甚少。这项应用旨在评估早期(7周)和后期(7.5个月)对松质骨和皮质骨以及髂骨骨的内(内皮质)和外(骨膜)表面的甲状旁腺素的反应。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组织检查就可以获得两个时间点的骨形成动态指标的信息。通过在开始PTH前给出1对四环素标记，在开始PTH后1个月给出第二对四环素标记，我们可以用每个受试者作为她自己的对照，从而显著减少分析重复活检时受试者之间和受试者内的众所周知的变异性。我们将在7周时检测骨骼对甲状旁腺素的早期形成反应，当时几乎没有吸收的刺激，然后在7.5个月时，这一时间点与生化标记物评估的最大重塑刺激相吻合。我们还将寻求确定周期性地给予甲状旁腺素(3个月开/停3个月)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。在接受周期性甲状旁腺激素治疗的妇女中，使用四重标记系统在7周和7.5个月时进行活检，我们假设在非周期甲状旁腺激素治疗期间重塑较少，并在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，通过检测24个月后甲状旁腺素(每日和周期)的骨骼反应，无论是未接受治疗的受试者，还是服用阿伦磷酸钠至少一年的受试者，以及处于新的稳定状态的受试者。这些数据将为甲状旁腺激素在细胞水平的作用机制提供重要信息，有助于更好地了解抗肿瘤药物和合成代谢药物之间的相互作用，并为甲状旁腺激素的临床应用提供更有效的途径。

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.