Aluminum intoxication in vitamin D-deficient rats: Studies of bone aluminum localization and histomorphometry before and after vitamin D repletion
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AbstractAluminum accumulation by both dialysis patients and nonuremic patients, requiring chronic total parenteral nutrition, may be an etiological factor in the development of severe osteomalacia. To study the role of aluminum toxicity in bone, further experiments have been conducted in the nonuremic, vitamin D-deficient rat. Weanling rats were raised on vitamin D-deficient diets, and half received parenteral aluminum (5 mg/wk), for 30 days. In the first experiment low doses of 25-OH cholecalciferol (500 ng/week) were given subcutaneously for a further 30 days. Control rats were maintained on a similar protocol, but were supplemented with cholecalciferol (5 μg/week) from the outset until sacrifice at 60 days. In the second experiment a single bolus of cholecalciferol (5 μ/g) was given to study short-term changes in serum biochemistry and bone histology at 96 hr. Quantitative bone histomorphometric analyses of the proximal tibial metaphysis were made in all experimental groups. In the experimental vitamin D-deficient group, with the highest bone aluminum content (as assessed by extraction of whole bone aluminum), X-ray microanalysis was performed to determine the distribution of aluminum in bone tissue and bone cell organelles. The results showed that control rats treated with prolonged aluminum therapy (30 mg over 60 days) had evidence of both reduced osteoid matrix synthesis and mineralization. However, in vitamin D-deficient rats, there was no evidence that aluminum exacerbated the osteomalacic lesion, even though there was histochemical evidence of aluminum deposition at the bone-osteoid interface. X-ray microanalysis confirmed the presence of aluminum at this site, but did not reveal significant peaks of aluminum either in mineralized bone or within osteoblasts. In both experiments, vitamin D-induced osteomalacia was rapidly reversed by both low-dose 25-OH cholecalciferol and bolus cholecalciferol, suggesting that aluminum accumulation alone does not lead to impaired mineralization if other conditions favoring bone metabolism are present. In these experiments, secondary hyperparathyroidism may have been one such factor in explaining the failure of bone aluminum accumulation to impair bone mineralization in vitamin D-deficient rats when compared to vitamin D-replete controls. Although several animal models of aluminum toxicity have been explored, clearly the experimental conditions, dose, and duration of aluminum administration, and the degree of secondary hyperparathyroidism, are critical factors in determining whether aluminum accumulation in bone results in significant pathology.
