The main effect of estrogen is to reduce the rate of bone remodeling activation and so to reduce the whole body rates of resorption, formation and the rate of bone loss. There is both clinical and (in vivo and in vitro) evidence for an additional effect of estrogen to increase the recruitment and function of osteoblasts. Such an effect could increase the completeness with which resorption cavities are refilled, despite a reduction in whole body bone formation rate. We will test the efficacy of estrogen replacement therapy in correcting the age-related worsening of focal remodeling imbalance between resorption and formation in iliac cancellous bone, manifested principally as a decline in wall thickness. The subjects will be recruited from among 200 expected to participate in a companion proposal to test the efficacy of estrogen replacement therapy in reducing the rate of bone loss from the upper femur. All subjects will already have undergone prospective measurement of the rate of bone loss for two years prior to randomization into active and placebo- treated groups. We hope to recruit subjects in each arm who will have had bone biopsy 2-24 months before randomization and are willing to have a second bone biopsy on the opposite side after completion of the two-year intervention trial period. We will compare all methods that have been proposed, both by other investigators and ourselves, for measuring wall thickness and erosion depth and select the most appropriate methods after validation. We will also apply established stereologic methods for counting the number of cells in three-dimensional tissue volume, and express formation and resorption rates per osteoblast or osteoclast nuclei, and per aggregate osteoblast or osteoclast volume. A panel of putative indirect mediators of estrogen effect on bone, including parathyroid hormone, basal and calcium stimulated calcitonin, calcitriol, growth hormone, insulin-like growth factor I and its binding proteins, will be measured in each subject before and after the conclusion of the intervention trial. If we confirm a beneficial effect of estrogen replacement therapy on osteoblast recruitment or function, this will have important therapeutic implications, since estrogen replacement therapy will no longer need to be restricted to patients within the first few years after menopause, or with high bone turnover, but could be useful in preventing bone loss and fractures in older women, regardless of how long ago they underwent menopause, and whatever their level of bone turnover.
