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 导致骨质疏松症的年龄相关性骨质流失。 我们将奉行 这一目标使用两种策略。 首先，我们将研究正常女性， 更好地了解更年期骨质流失的两个最重要的原因- - 雌激素缺乏和年龄相关的过程。 这些研究将使 我们要阐明的机制，骨丢失在一般人群中， 骨质疏松症发生前的潜伏期。 第二，我们将研究 已经绝经的女性中一种损失的机制 骨质疏松 这些研究将使我们能够确定 骨质疏松症妇女的骨丢失与 没有骨质疏松症的女性。 这些问题将通过以下方式解决： 开展了3个具体目标的8项实验方案。 具体目标#1是更完整地定义病理生理学 雌激素缺乏导致负钙（Ca）的机制 正常绝经后妇女的平衡和骨丢失， 降低肠钙吸收的机制（方案1），B） 阐明肾钙排泄增加的机制（方案2），和 c）评估雌激素缺乏、骨转换之间的关系，和 产生骨吸收细胞因子（方案3）。 具体目标#2是 进一步定义正常人年龄相关性骨丢失的因果机制 老年妇女y a）确定她们是否对以下肠抵抗力 维生素D的作用（方案4），B）确定先前观察到的 夜间血清甲状旁腺激素增加与年龄有关， Ca缺乏（方案5），和c）确定雌激素缺乏是否 持续促进生命后期骨转换的增加（方案 c）确定雌激素缺乏是否继续有助于 增加晚年的骨转换（方案6）。 正常学习后 个人解决前两个具体目标，在研究解决 具体目标#3，我们将寻找潜在的独特异常， 绝经后骨质疏松症的女性， 通过a）寻找缺损，提高骨转换率和骨丢失率 在甲状旁腺炎介导的肾脏钙转运中， 先前观察到的这些女性肾钙保存异常 （方案7）和B）定义我们寻求的骨丢失机制， 需要发现，以制定更合理的预防策略， 和骨质疏松症的治疗。

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.