We have demonstrated that cadmium at 50 ppm in the diet strikingly increases the loss of bone mineral in mice after ovariectomy. We propose to determine (1) whether the enhanced effect of cadmium in ovariectomized mice can be elicited without the one-year preexposure to cadmium used in our first study, (2) whether the effect is specific to cadmium (and not lead), (3) whether early changes in calcium metabolism can be identified in ovariectomized mice exposed to 50 ppm dietary cadmium, and (4) whether an enhanced effect of cadmium occurs in ovariectomized dogs. We will also test the hypotheses that the combination of cadmium exposure and ovariectomy causes (1) changes in plasma concentrations of the major bone-active hormones (parathyroid hormone, calcitonin, 1,25(OH)2 vitamin D), (2) altered biochemical responses to these hormones, or (3) altered secretion of bone-active hormones in response to specific stimuli. We have demonstrated in vitro that addition of cadmium a 2- to 3-fold increase in bone resorption in cultured fetal rat limb bones. We propose to use the in vitro bone culture system to determine whether cadmium causes the same changes as does parathyroid hormone, whether cadmium enhances the action of known stimulators of bone resorption, whether addition of estrogen or progestogens inhibits the bone-resorbing action of cadmium, whether plasma from ovariectomized or sham-operated mice influence the bone resorbing action of cadmium, and in which bone cell-types cadmium is localized. Results of our studies on cadmium-induced bone resorption in ovariectomized animals and in bones in culture may provide mechanistic insights into the development of postmenopausal osteoporosis in women in general and of Itai-Itai disease among Japanese women. Our studies suggest that women exposed to cadmium in industry may be at increased risk of developing postmenopausal osteoporosis. They may also explain, in part, the increased risk of postmenopausal osteoporosis among women who smoke.
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