Loss of bone mineral after ovariectomy was studied in mice exposed to dietary cadmium at 0.25, 5, or 50 ppm. Results show that dietary cadmium at 50 ppm increased bone mineral loss to a significantly greater extent in ovariectomized mice than in sham-operated controls. These results were obtained from two studies, one in which skeletal calcium content was determined 6 months after ovariectomy and a second in which 45Ca release from 'Ca-prelabeled bones was measured immediately after the start of dietary cadmium exposure. Furthermore, experiments with 4sCa-prelabeled fetal rat limb bones in culture demonstrated that Cd at 10 nM in the medium, a concentration estimated to be in the plasma of mice exposed to 50 ppm dietary Cd, strikingly increased bone resorption, from 27 ± 2% (mean ± SEM) "Ca release in cultures with no added cadmium to 68 ± 6% release in cultures containing cadmium (n -4). These in vitro results indicate that cadmium may enhance bone mineral loss by a direct action on bone. Results of the in vivo studies are consistent with a significant role of cadmium in the etiology of Itai-Itai disease among postmenopausal women in Japan and may in part explain the increased risk of postmenopausal osteoporosis among women who smoke.Osteoporosis affects [15][16][17][18][19][20] million people in the United States and is a major cause ofbone fractures in older persons, particularly postmenopausal women (1). One striking form of postmenopausal bone disease has occurred among women in Toyama prefecture, Japan, in the form of Itai-Itai (OuchOuch) disease, which is characterized by severe osteoporosis/osteomalacia and renal tubular dysfunction (2-5). Elevated levels of cadmium were present in both the diet and drinking water of women with Itai-Itai disease. The Japanese Ministry of Health in May 1968 declared cadmium to be one of the causative factors in the etiology of this bone disease on the basis of epidemiologic data relating disease incidence to cadmium exposure and the finding of high cadmium levels in tissues taken at autopsy from women with the disease (4, 6).The studies reported here were designed on the basis of the unusual finding that 95% of the cases of Itai-Itai disease occurred in postmenopausal women, not in younger women, men, or children (4). Although many studies of cadmiuminduced bone loss had been conducted in male animals or in females with intact ovaries, none had addressed the question of whether the combination of cadmium exposure and ovariectomy (to simulate conditions of postmenopausal hormone depletion) might accelerate the loss of bone calcium that normally occurs after removal of the ovaries. Such results might explain why Itai-Itai disease did not appear until after menopause.Results of our studies show that loss of bone mineral after ovariectomy in female mice was strikingly increased by dietary cadmium exposure. In addition, when cadmium was added at low concentrations (10 nM) to bone cultures, bone resorption was stimulated to an extent similar to that observed after treat...

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Renal medullary cells contain high levels of (glycine) betaine, glycerophosphorylcholine (GPC), myo-inositol, and sorbitol. Two functions of these have been proposed: 1) that they are compatible osmolytes which regulate cell volume (against high external NaCl) without inhibiting proteins and 2) that methylamines (GPC and betaine) are counteracting osmolytes which stabilize proteins against perturbation from high renal urea. As a test of the latter, osmolyte contents in kidney medullas were measured in rats subjected to three types of dietary manipulation: 1) diets with protein and NaCl contents varied oppositely, 2) diets with a constant low NaCl and varied protein content, and 3) a low-calorie diet. With low-protein and low-calorie diets, only renal contents of urea, GPC, and inositol decreased; betaine and sorbitol contents increased such that contents of total nonurea organic osmolytes remained constant. With high-protein diets, only renal contents of sodium, urea, and GPC increased, with the latter giving total organic osmolytes a consistent correlation to sodium. Across all diets, the only consistent (linear) correlations were 1) between urea and GPC contents, supporting previous suggestions that GPC is the major counteractant to urea, and 2) between total organic osmolytes and sodium (but not urea) contents, as predicted by the compatible osmolytes hypothesis.

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