MECHANISM OF ANABOLIC ACTION OF PTH IN VIVO

骨量是骨折风险的强烈决定因素，最近的证据表明 这表明骨转换也可能与骨折风险有关。当前 FDA批准的治疗骨质疏松的方法包括雌激素、降钙素、 双膦酸类和雷洛昔芬。所有这些都会降低骨骼的转换，并导致 骨量的适度增加，被认为主要是由于减少 在重塑空间中。在许多患有骨质疏松症的人中，这些绅士会 没有增加足够的骨量来消除骨折，表明 需要对骨骼具有合成代谢作用的制剂。在过去，资金 期间，e表明hPTH增加骨量，特别是在脊椎。 绝经后雌激素化的女性，可能与雌激素减少有关 脊椎骨折的风险。从机械上讲，PTH在一个 抗吸收药，在第一次增加骨形成标志物 治疗几周后，吸收标记物增加，之后 两者都处于类似的高位。我们目前的建议旨在评估 甲状旁腺素对人体骨生理的作用机制。我们建议定义 甲状旁腺素引起的早期骨骼反应 使用组织形态计量学方法，进行组织生化和骨量的测定。我们会 评估抗吸收药物在确定 最初的骨骼反应和可能修改特定部位的骨骼 对甲状旁腺素的反应。最后，我们将确定骨骼对 终止PTH并随后再次挑战以确定是否有第二个 合成代谢反应可以由骨骼安装。这些研究应该 允许更好地定义PTH使用的适当临床方案，如 以及定义短期和长期的 甲状旁腺素在人体内的合成代谢作用。

Bone mass is a strong determinant of fracture risk, and recent evidence suggests that bone turnover may also be related to fracture risk. Current FDA approved approaches to osteoporosis consist of estrogens, calcitonin, bisphosphonates, and raloxifene. All reduce bone turnover and result in modest increases in bone mass, presumed to be due primarily to reduction in remodeling space. In many individuals with osteoporosis, these gents do not increase bone mass sufficiently to eliminate fractures, indicating a need for agents that are anabolic to the skeleton. In the past funding period, e showed that hPTH increases bone mass especially in the spine in postmenopausal estrogenized women and may be associated with a reduction in vertebral fracture risk. Mechanistically, PTH, in the presence of an anti-resorptive agent, increases bone formation markers within the first weeks of treatment, while resorption markers increase later, after which both are similarly elevated. Our current proposal seeks to evaluate the mechanism of PTH action on human bone physiology. We propose to define the early skeletal response to PTH which underlies the rapid increase in formation biochemistry and bone mass, using histomorphometry. We will evaluate the importance of the anti-resorptive agent in determining the initial bone response and possibly modifying site specific skeletal responses to PTH. Finally, we will determine the skeletal responses to discontinuation of PTH and subsequent rechallenge to determine if a second anabolic response can be mounted by the skeleton. These studies should allow better definition of appropriate clinical protocols for PTH use, as well as defining the mechanisms underlying the short-term and long-term anabolic actions of PTH in the human.