Osteoporosis is a major health problem in the elderly population. Affected subjects suffer fractures of the vertebrae, distal forearm and hip. While the frequency with which osteoporosis occurs in the aged has made research into its pathogenesis and treatment of high priority, routine, efficacious therapy for improvement of the underlying skeletal abnormalities of osteoporosis (both bone fragility and volume deficit) remains unrealized. The present application outlines research aimed at generating information on the pathogenesis of osteoporosis, an understanding of which must be obtained if the means for abatement or cure of the debilitating symptoms is to be found. The primary objective is to characterize and compare the endocrine control of bone and mineral metabolism in aging and osteoporosis. Since a thorough knowledge of the changes in calcium homeostasis which accompany normal aging is necessary to recognize any changes which occur uniquely in osteoporosis, initially, the effects of age and dietary calcium on the metabolism of vitamin D and the secretion of parathyroid hormone (PTH) and calcitonin (CT) in the Fisher F-344 rat model of human aging will be studied utilizing a longitudinal design. This approach will eliminate much of the variation that has plagued earlier experiments of cross-sectional design and may integrate apparently conflicting previous data obtained from animals in which the level of dietary calcium was not considered as a cofactor. Circulating concentrations of 25(OH)D, 24,25(OH)2D and 1,25(OH)2D, the vitamin D binding protein (as an index of free 1,25(OH)2D), immunoreactive CT and PTH will be serially determined and bioactive PTH-like activity (using a cytochemical bioassay technique domestically available only in our laboratory) will be measured. Further, gastrointestinal calcium absorption, metabolic clearance of 1,25(OH)2D, and 250HD-1- and 24-hydroxylase activities (using an in vitro assay) will be assessed at each age and dietary calcium level. These experiments will be supplemented with human studies in which the same metabolites are measured in plasmas of osteoporotics and age-matched controls. In addition, the association of any alterations in the hormonal milieu in individual affected subjects with the nature of the bone histomorphological abnormalities that are manifest will be explored. These studies will yield significant new insight into: 1) age-related changes in the control of bone and mineral metabolism in human and rats; 2) the adequacy of the F-344 rat as a model of human aging; and 3) whether unique abnormalities of vitamin D metabolism and/or PTH or CT secretion exist in osteoporotics.
