PATHOPHYSIOLOGY OF OSTEOPOROSIS

我们的中心假设是，雌激素(E)缺乏通过各种组织特异性机制起作用，导致了老年女性和老年男性的大部分骨质流失。特异性目的1将定义E对甲状旁腺激素（PTH）分泌可能的直接或间接影响，通过评估实验改变了E状态的老年妇女的PTH分泌动态，从而更好地了解老年妇女继发性甲状旁腺功能亢进的发病机制。方案2将确定骨蛋白素（OPG），一种新发现的有效骨吸收抑制剂及其认知配体（OPGL），通过测量经绝经前后接受和不接受E治疗的妇女的骨髓血浆水平，是E对骨作用的主要旁分泌介质。具体目标2将通过测量未治疗的骨质疏松症和非骨质疏松症绝经后妇女的骨髓血浆水平，确定OPG受损或OPGL分泌过多是否使一些（而非其他）E缺乏妇女易患骨质疏松症（方案3）。特异性目标3将确定睾酮e (T)和甲状旁腺激素在调节老年男性骨转换中的比较作用。方案4将直接测试与年龄相关的男性血清甲状旁腺激素水平升高在调节骨吸收增加中的因果作用。方案5将比较E、T + E在预防老年男性GnRH激动剂急性性腺功能减退引起的骨吸收增加方面的作用，方案6将评估老年男性用安慰剂或雷洛昔芬（对骨骼有E激动剂作用，但不会使女性化）治疗6个月对骨转换生化标志物的影响。这些最新的研究将阐明E缺乏在绝经后和老年妇女骨质流失和骨质疏松症的病理生理学中的作用，以及它对老年男性骨质流失的贡献，并可能导致创新类型的治疗。

Our central hypothesis is that estrogen (E) deficiency acts through various tissue-specific mechanisms to account for most of the bone loss in aging women and for a substantial part of it in aging men. Specific Aim 1 will define possible direct versus indirect effects of E on parathyroid hormone (PTH) secretion, leading to a better understanding of the pathogenesis of the secondary hyperparathryoidism of elderly women by assessing PTH secretory dynamics in elderly women in whom E status has been experimentally altered. Protocol 2 will determine id osteoprotegrin (OPG), a newly discovered potent inhibitor of bone resorption and its cognitive ligand, (OPGL), are major paracrine mediators of E action on bone by measuring their bone marrow plasma levels in women followed transmenopausally with and without E therapy. Specific Aim 2 will determine if impaired OPG or excessive OPGL secretion predisposes some, but not other E deficient women to develop osteoporosis by measuring marrow plasma levels in untreated osteoporotic and non-osteoporotic postmenopausal women (Protocol 3). Specific Aim 3 will define the comparative roles for E. testosterone (T), and PTH in regulation bone turnover in elderly men. Protocol 4 will test directly for a causal role for the age-related increase in serum PTH levels in men in mediating increases in bone resorption. Protocol 5 will compare thje effects of E, T + E in preventing increased bone resorption induced by acute induction of hypogonadism with GnRH agonist administration in elderly men, and Protocol 6 will assess the effects of 6 month treatment of elderly men with placebo or raloxifene (which has an E agonist effect on bone but is not feminizing) on biochemical markers of bone turnover. These state-of-the-art studies will elucidate the role of E deficiency on the pathophysiology of bone loss and osteoporosis in postmenopausal and aging women and its contribution to bone loss in aging men and may lead to innovative types of therapy.