Estrogen plays a critical role in the pathogenesis of osteoporosis, a common disease of skeletal fragility. Reduction of estrogen at menopause or following ovariectomy leads to increased skeletal turnover and bone loss in humans and most other mammals. However, our preliminary studies indicate that the common marmoset, a primate which naturally undergoes prolonged periods of hypoestrogenemia due to social suppression of reproduction, does not appear to experience estrogen- depletion bone loss following ovariectomy. If this preliminary finding is correct, elucidation of the mechanisms by which estrogen deficiency fails to cause bone loss in marmosets could have important preventative and therapeutic consequences. Therefore, the specific aims of the proposed research are to confirm that ovariectomy in adult female common marmosets results in estrogen deficiency, and to determine whether this estrogen deficiency is associated with bone loss and increased skeletal turnover. Subjects will be 24 adult female common marmosets, each of which will be pair-housed with a vasectomized male and will initially be undergoing regular ovulatory cycles. Twelve animals will undergo ovariectomy at 4-6 years of age, and the remaining twelve will serve as intact controls. Two weeks before surgery, and one, three, five, and seven months following surgery, data will be collected on markers of estrogen status (uterine size, plasma estradiol, estrone); bone mineral density, as determined by dual energy x-ray absorptiometry (DXA) of the total body and lumbar [L5-L6] spine; biochemical measures of skeletal turnover (plasma osteocalcin, urinary N-telopeptide of Type I collagen cross-links (NTx]), and physiological parameters of skeletal relevance (serum calcium, creatinine, phosphorus, alkaline phosphatase; plasma parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, cortisol). If our hypotheses are correct, the data will confirm that ovariectomy causes estrogen deficiency in marmosets and will demonstrate that this does not result in bone loss. We would thus have defined a unique animal model, i.e. a non-human primate with regular ovarian cycles which does not sustain estrogen-depletion bone loss. This would offer novel insights into the dynamics of hormonal regulation of skeletal turnover. Subsequent elucidation of the mechanism(s) by which estrogen-depletion bone loss is averted in these animals would be anticipated to contribute significantly to the development of new therapies for the prevention and treatment of osteoporosis.
