MECHANISM OF ANABOLIC ACTION OF PTH IN VIVO

骨量是骨折风险的一个强有力的决定因素， 提示骨转换也可能与骨折风险有关。电流 FDA批准的治疗骨质疏松症的方法包括雌激素，降钙素， 双膦酸盐和雷洛昔芬。所有这些都会降低骨转换， 骨量适度增加，推测主要是由于减少 重塑空间。在许多患有骨质疏松症的个体中， 没有增加足够的骨量来消除骨折，这表明 对骨骼合成代谢剂的需求。在过去的融资 研究表明，hPTH增加骨量，特别是在脊柱中， 绝经后雌激素化妇女，可能与减少 脊椎骨折风险。机械地，PTH，在存在 抗吸收剂，增加骨形成标志物内的第一 周的治疗，而吸收标志物增加后， 两者都同样升高。我们目前的建议旨在评估 PTH对人体骨生理作用的机制。我们建议将 早期骨骼对PTH的反应，这是快速增加的基础， 形成生化和骨量，使用组织形态计量学。我们将 评价抗吸收剂在确定 初始骨反应和可能改变的部位特异性骨骼 对PTH的反应最后，我们将确定骨骼对 停止PTH和随后的再激发，以确定第二次 合成代谢反应可以通过骨骼来安装。这些研究应 允许更好地定义PTH使用的适当临床方案， 以及确定短期和长期的机制， PTH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.