Although age-related bone loss is a universal problem, the bone loss that is associated with ovarian hormone deficiency at menopause is by far the commonest cause of osteoporosis and in 25% to 30% of aging women the bone loss results in major orthopedic problems. Beyond the consensus that postmenopausal osteoporosis is related to ovarian hormone deficiency, there is a lack of agreement on its pathogenesis. However, the different theories of postmenopausal bone loss that have been proposed share in common a linkage of an imbalance in the calcium regulating hormones to an imbalance in bone remodeling that favors bone resorption as a result of ovarian hormone deficiency. Therefore, a rational therapy for the disease is a regimen that promotes net bone formation and thereby reverses the remodeling defect caused by lack of ovarian hormones. It is the applications' longterm goal to advance our basic understanding of the pathogenesis of ovarian hormone deficiency bone loss, and contribute in enlarging the pool of therapeutic alternatives available for combating the disease. The hypothesis to be tested in this proposal is that age-related bone loss due to ovarian hormone deficiency can be reduced or prevented by stimulating net bone formation and intestinal calcium absorption. To test the hypothesis, we will determine the efficacy of the following treatment regimens in reducing or preventing ovarian hormone deficiency bone loss: 1) Parathyroid hormone; 2) Combination treatment with parathyroid hormone and calcitonin; 3) Combination treatment with parathyroid hormone and 1,25(OH)2 vitamin D; 4) Somatomedin C and 5) Determine the mechanism by which the treatment regimens of Specific Aims 1 to 4 act to reduce or prevent ovarian hormone deficiency bone loss. A newly characterized rat model of ovarian hormone deficiency will be used in these studies and the analyses to be carried out to fulfill the above objectives are grouped under the following headings: (i) Physical measurements of bone; (ii) Bone chemistry; (iii) Bone histomorphometry and bone cell dynamics; (iv) Intestinal calcium absorption; (v) Intestinal receptors for 1,25(OH)2 vitamin D; (vi) Renal function and kidney excretion of calcium, phosphorus and hydroxyproline; (vii) Serum calcium, phosphorus, alkaline phosphatase, total proteins, albumin and globulin, (viii) Serum calcium regulating hormones and sex hormones (parathyroid hormone, calcitonin, 25(OH) vitamin D, 1,25(OH)2 vitamin D, estradiol and progesterone).
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