PATHOPHYSIOLOGY OF INVOLUTIONAL OSTEOPOROSIS

退化性骨质疏松症的病理生理学

• 批准号: 6267226
• 负责人: B L RIGGS
• 金额: $ 26.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267226
• 关键词: 1,25 dihydroxycholecalciferol; aging; bone metabolism; calcium metabolism; circadian rhythms; cytokine; dietary calcium; dietary supplements; estrogens; female; gastrointestinal nutrient absorption; hormone regulation /control mechanism; hormone therapy; human genetic material tag; human subject; nutrition related tag; osteoporosis; parathyroid hormones; pathologic bone resorption; photon absorptiometry; postmenopause; receptor; receptor expression; renal tubular transport; urinalysis

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.

骨质疏松症是一种多因素疾病。 我们的总体目标是 对病因学和病理生理学有更连贯的理解 与年龄相关的骨质流失导致骨质疏松症。 我们将追求 使用两种策略来实现这一目标。 首先，我们将研究正常女性 更好地了解退化性骨质流失的两个最重要原因 - - 雌激素缺乏和与年龄相关的过程。 这些研究将允许 我们旨在阐明普通人群骨质流失的机制 骨质疏松发生前的潜伏期。 其次，我们要学习 已经绝经的女性的一种丧失机制 骨质疏松症。 这些研究将使我们能够确定是否有机制 骨质疏松女性的骨质流失与普通女性的骨质流失有很大不同 与没有骨质疏松症的女性相当。 这些问题将通过 执行 8 个实验方案，涵盖 3 个具体目标。 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 a) 阐明正常绝经后妇女的平衡和骨质流失 减少肠道 Ca 吸收的机制（方案 1），b) 阐明增加肾脏 Ca 排泄的机制（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（方案 3）。 具体目标#2 是 进一步定义正常人与年龄相关的骨质流失的因果机制 老年妇女 y a) 确定她们是否有肠道抵抗力 维生素 D 作用（方案 4），b) 确定先前观察到的情况是否 夜间血清甲状旁腺激素随衰老而增加与 钙缺乏（方案 5），以及 c) 确定雌激素是否缺乏 继续促进晚年骨转换的增加（协议 5) 和 c) 确定雌激素缺乏是否继续导致 晚年骨转换增加（方案 6）。 学习正常后 个人在研究中解决前两个具体目标 具体目标#3，我们将寻找潜在的独特异常 患有绝经后骨质疏松症的女性可能会 通过 a) 寻找缺陷来增加骨转换率和骨丢失率 甲状旁腺激素介导的肾钙转运可能解释 先前观察到这些女性肾钙保存异常 （方案 7）和 b）定义了我们寻求的骨质流失机制 需要发现并制定更合理的预防策略 和骨质疏松症的治疗。