Effect of cadmium on bone calcium and 45Ca in nonpregnant mice on a calcium-deficient diet: evidence of direct effect of cadmium on bone.

To clarify the mechanism of the effect of Cd on bone, virgin female mice with 45Ca prelabeled skeletons (15 microCi/mouse) were exposed to a Ca-deficient diet (0.002%) containing 0, 5, or 25 ppm Cd or 25 ppm Pb for 32 days. During the first 72 hr, the 0 ppm controls showed a 2.5-fold decrease in fecal 45Ca excretion (decreased bone resorption), a 12-fold decrease in total fecal stable Ca, a 5-fold decrease in endogenous fecal Ca excretion, and a significant elevation in both serum 45Ca (108%) and specific activity (92%) due to the Ca-deficient diet. In contrast, Cd immediately and significantly increased fecal 45Ca excretion (55%), total fecal stable Ca (13%), endogenous fecal Ca excretion (32%), as well as serum 45Ca (15%) and specific activity (17%) (25 ppm Cd vs 0 ppm), supporting the hypothesis of an early, direct effect of Cd on bone. Overall, during 32 days, Cd at 25 ppm induced a 60% increase in fecal 45Ca excretion compared to 0 ppm controls, providing a sensitive measure of the Cd-induced increase in bone resorption. In contrast, the effect of Cd was too small to cause a statistically significant 45Ca loss from the right femur and lumbar vertebrae, but a significant 45Ca loss (up to -13%) was seen for the remaining skeleton (25 ppm vs 0 ppm group). In addition, Cd at 25 ppm induced small but statistically significant decreases in ash weight (-12%), ash weight to dry weight (-5%), Ca/dry (-7%), and Ca/ash (-2%) in the right femur and significant decreases in ash/dry (-7%) and Ca/dry (-12%) in the lumbar vertebrae compared with the controls. Our present study supports the hypothesis that Cd at 25 ppm had a significant direct effect on bone, with no effect at 5 ppm Cd or 25 ppm Pb, and no appearance of the extreme demineralization characteristic of Itai-Itai disease, although mice were exposed to a Ca-deficient diet for 32 days. Our results from this and earlier studies support the view that chronic Cd exposure along with nutritional deficiency contributed to the pathogenesis of Itai-Itai disease among multiparous, postmenopausal women in Japan.