There is evidence that both aging and menopause contribute to bone loss from the proximal femur. The menopause component is more clearly defined, it causes about 20% of the lifetime loss in the femoral neck, and that component occurs in about 7 years. The cause of femoral neck loss prior to menopause is not understood at all, but it represents 30% of lifetime loss. The other 50% of femoral neck loss occurs between age 60 and 90 years. Our hypothesis is that malabsorption of calcium, which starts in the mid sixties, together with secondary hyperparathyroidism plays a pathogenic role. The objectives of these studies are to identify the causes of malabsorption of calcium in a random subset of 100 women before starting the clinical trial. We will measure calcium absorption, vitamin D metabolites and duodenal samples for 1,25 dihydroxy vitamin D receptor concentration. An initial classification of 'aging gut' versus 'kidney' could be made by finding low receptor concentration but normal serum 1,25(OH)2D in the former and the opposite in the latter. However, in the 'kidney' group, there is a possibility of a primary or secondary decrease in 1,25(OH)2D production. To separate primary from secondary, subjects will undergo dynamic stimulation with PTH, presumably the aging kidney (primary) will produce less 1,25(OH)2D than the secondary group. After a year on therapy, the subset (25 from each group) will have all tests repeated and the effect of estrogen or 1alphahydroxyvitamin D2 on receptors, vitamin D levels and absorption followed. Because secondary hyperparathyroidism increases bone turnover, serum osteocalcin, urine hydroxyproline and Pyridinium cross links will be used to follow turnover. Correlations between absorption and bone turnover in the placebo group of 125 subjects will be examined, as well as the effect of improved calcium absorption (after 1alpha-OH-D2 therapy) on bone turnover. Estrogen may have an independent action on bone resorption irrespective of changes in absorption. These studies could identify subsets of elderly subjects who would benefit selectively from estrogen or vitamin D analogues and provide a rational basis for the treatment of bone loss.
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