PATHOPHYSIOLOGY OF INVOLUTIONAL OSTEOPOROSIS

骨质疏松症是一种多因素的疾病。我们的总体目标是 对病因学和病理生理学有更一致的理解 导致骨质疏松症的与年龄相关的骨质流失。我们将继续追查 这一目标使用了两种策略。首先，我们将研究正常女性 更好地理解退化性骨丢失的两个最重要的原因- -雌激素缺乏和与年龄有关的过程。这些研究将允许 美国将阐明普通人群骨丢失的机制 骨质疏松发生前的潜伏期。第二，我们将研究 绝经后妇女一次丢失的发生机制 骨质疏松。这些研究将使我们能够确定 骨质疏松症女性的骨丢失与女性明显不同 未患骨质疏松症的可比女性。这些问题将通过以下方式解决 执行包含3个具体目标的8个实验方案。 具体目标#1是更完整地定义病理生理学 雌激素缺乏导致钙负值的机制(S) 通过a)阐明正常绝经后妇女的平衡和骨丢失 肠道钙吸收减少的机制(S)(方案1)，b 阐明肾脏钙排泄增加的机制(S)(方案2)，以及 C)评估雌激素缺乏、骨转换和 骨吸收细胞因子的产生(第3号议定书)。具体目标2是 进一步明确正常人增龄性骨丢失的致病机制(S) 老年妇女a)确定她们是否对 维生素D作用(议定书4)，b)确定先前观察到的 夜间血清甲状旁腺激素随增龄增加与 钙缺乏(第5号议定书)，以及c)确定雌激素缺乏 继续促进晚年骨周转增加(议定书 5)，以及c)确定雌激素缺乏是否继续导致 晚年骨转换增加(方案6)。在学习了正常之后 个人应解决前两个具体目标，在研究中涉及 具体目标#3，我们将搜索潜在的独特异常 患有绝经后骨质疏松症的女性 通过a)搜索缺陷来增加骨转换和骨丢失的速率 在甲状旁腺激素介导的肾钙转运中 先前在这些妇女中观察到的肾脏钙保存异常 (议定书7)和b)界定我们寻求的骨丢失的机制 需要发现，以制定更合理的预防策略 以及骨质疏松症的治疗。

Osteoporosis is a multifactorial disorder. Our overall objective is to develop a more coherent understanding of the etiology and pathophysiology of the age-related bone loss that leads to osteoporosis. We will pursue this objective using two strategies. First, we will study normal women to understand better the two most important causes of involutional bone loss - - estrogen deficiency and age-related processes. These studies will allow us to elucidate mechanisms of bone loss in the general population during the latent period before osteoporosis has occurred. Second, we will study mechanisms of one loss in a women who have already developed postmenopausal osteoporosis. These studies will allow us to determine if mechanisms of bone loss in osteoporotic women differ substantially from those in comparable women without osteoporosis. These issues will be addressed by carrying out 8 experimental protocols encompassed in 3 specific aims. Specific Aim #1 is to define more completely the pathophysiologic mechanism(s) by which estrogen deficiency causes negative calcium (Ca) balance and bone loss in normal postmenopausal women by a) elucidating mechanism(s) for decreased intestinal Ca absorption (Protocol 1), b) elucidating mechanism(s) for increased renal Ca excretion (Protocol 2), and c) assessing the relationship among estrogen deficiency, bone turnover, and production of bone-resorbing cytokines (Protocol 3). Specific Aim #2 is to define further the causal mechanism(s) for age-related bone loss in normal elderly women y a) determining if they have intestinal resistance to vitamin D action (Protocol 4), b) determining if the previously observed nocturnal increases in serum parathyroid hormone with aging are related to Ca deficiency (Protocol 5), and c) determining if estrogen deficiency continues to contribute to increased bone turnover late in life (Protocol 5), and c) determining if estrogen deficiency continues to contribute to increased bone turnover late in life (Protocol 6). After studying normal individuals to address the first two specific aims, in studies addressing Specific Aim #3, we will search for potentially unique abnormalities in women with postmenopausal osteoporosis that could account for their increased rate of bone turnover and bone loss by a) searching for a defect in parathyroid hormone-mediated renal Ca transport that might explain previously observed abnormalities in renal Ca conservation in these women (Protocol 7) and b) defining the mechanisms of bone loss that we seek to uncover is needed to develop more rational strategies for the prevention and treatment of osteoporosis.