PATHOPHYSIOLOGY OF INVOLUTIONAL OSTEOPOROSIS

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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.