Osteoporosis is a syndrome of excessive skeletal fragility resulting from estrogen deficiency and aging. Estrogen loss leads to a reduction in trabecular bone mass and an irreversible alteration of the trabecular bone structure. The decline of trabecular bone structure secondary to estrogen deficiency is suppressed by treatment with anti-resorptive agents (estrogen, bisphosphonates, calcitonin and SERMs). These agents work by reducing the activation of new bone remodeling units (BMUs) while still allowing normal bone formation to continue in already activated BMUs. This results in a more complete secondary mineralization of basic structural units (BSUs) due to reduced turnover and an increased degree of bone mineralization (DMB). These agents have been associated with preservation of trabecular microarchitecture and with reduction in new fractures in clinical studies. However, the mechanism of action of antiresorptive agents is not fully understood. While BMD increases in sites rich in trabecular bone, in alendronate treated patients, no increase in bone mass (BV/TV) has been observed from lilac crest biopsies. These data suggest that factors other than bone mass explain changes in BMD and fracture reduction. Based on these observations, we hypothesize that long-term reduction of bone turnover with anti-resorptive agents in the estrogen deficient older rats will increase the degree of trabecular bone mineralization and improve bone strength. In addition, we further hypothesize that the change in the degree of trabecular bone mineralization induced by anti-resorptJve agents will contribute independently to bone strength. To test these hypotheses we propose the following Specific Aims. To determine if the prevention and treatment of bone loss in the estrogen deficient state with anti-resorptive agents in old rats is associated with an increase in degree of bone mineralization relative to ovariectomized and intact rats; 2: To determine if treatment of estrogen deficient bone loss with anti-resorptive agents in old rats is associated with an increase in bone strength, 3:To determine if there is an association between the reduction in biochemical markers of bone turnover, and the degree of bone mineralization, in the long-term prevention and treatment of old estrogen deficient rats with anti-resorptive agents.To accomplish these Specific Aims we will perform two experiments using 12 month old ovariectomized rats, taking serial XTM scans of the proximal tibia metaphysis before and at specified timepoints during anti-resorptive agent treatment. Conventional histomorphometry, microCT, biochemical markers of bone turnover, and biomechanical tests will be done at times corresponding to the XTM scans and at sacrifice.
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