The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats

Experiments were carried out to determine whether the doses of the amino bi sphosphonate iban-dronate that inhibit bone resorption inhibit soft tissue calcification and death in rats treated with a toxic dose of vitamin D. The se studies were prompted by the recent discovery that ibandronate doses tha t inhibit bone resorption potently inhibit artery calcification induced by treatment with the vitamin K antagonist warfarin. All 16 rats treated with the toxic dose of vitamin D (12.5 mg cholecalciferol . kg(-1)) died by d 6 after the first vitamin D injection (median survival: 4.5 d), whereas the 1 2 rats treated with vitamin D plus ibandronate (0.25 mg . kg(-1) . d(-1)) w ere alive and in good health at d 10. Rats treated with vitamin D alone and examined at d 4 had extensive Alizarin red staining for calcification in t he aorta, the carotid, hepatic, mesenteric, renal and femoral arteries, kid neys and lungs, whereas rats treated with vitamin D plus ibandronate had no evidence for calcification at any of these tissues when examined at d 7 an d 10. lbandronate treatment also inhibited the dramatic increase in the lev els of calcium and phosphate seen in the abdominal aorta, kidneys, lungs an d trachea of the vitamin D-treated rats (P < 0.001). Serum calcium levels w ere, however, not different in rats treated with vitamin D alone (3.4 +/- 0 .2 mmol . L-1) and in rats treated with vitamin D plus ibandronate (3.5 +/- 0.2 mmol . L-1). Treatment with vitamin D alone increased levels of matrix Gla protein, an inhibitor of soft tissue calcification, in the arteries, k idneys, lungs and trachea by 10- to 100-fold, and ibandronate treatment pre vented this increase. The importance of these studies in the rat model is t hat they identify a class of drugs in current clinical use that can be used to treat patients with vitamin D toxicity and that they identify the dose of the drug that is predicted to be effective, namely the dose that inhibit s bone resorption. Because there is no other known treatment for vitamin D toxicity, there would seem to be good reason to try bisphosphonates such as ibandronate in future studies aimed at treating patients who have been exp osed to toxic levels of vitamin D.