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发挥作用，以解释老年女性的大部分骨质流失和老年男性的大部分骨质流失。 具体目标1将定义可能的直接与间接影响的E对甲状旁腺激素（PTH）分泌，从而更好地了解老年妇女继发性甲状旁腺功能亢进症的发病机制，通过评估PTH分泌动力学的老年妇女中，E状态已被实验改变。 方案2将确定id骨保护素（OPG），一种新发现的有效的骨吸收抑制剂和其认知配体（OPGL），是通过测量绝经后妇女的骨髓血浆水平来确定E对骨作用的主要旁分泌介质。 具体目标2将通过测量未经治疗的绝经后妇女和非绝经后妇女的骨髓血浆水平，确定OPG受损或OPGL分泌过量是否使某些（而非其他）E缺乏妇女易患骨质疏松症（方案3）。具体目标3将定义E的比较角色。睾酮（T）和甲状旁腺素（PTH）调节老年男性骨转换。 方案4将直接测试男性血清PTH水平的年龄相关性增加在介导骨吸收增加中的因果作用。 方案5将比较E、T + E在预防老年男性中GnRH激动剂给药急性诱导性腺功能减退引起的骨吸收增加方面的作用，方案6将评估老年男性接受安慰剂或雷洛昔芬（对骨具有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作用。 这些最先进的研究将阐明E缺乏对绝经后和老年女性骨丢失和骨质疏松症的病理生理学的作用，以及其对老年男性骨丢失的贡献，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.