The Amino Bisphosphonate Ibandronate Prevents Vitamin D Toxicity and Inhibits Vitamin D-Induced Calcification of Arteries, Cartilage, Lungs and Kidneys in Rats

Abstract

Experiments were carried out to determine whether the doses of the amino bisphosphonate ibandronate that inhibit bone resorption inhibit soft tissue calcification and death in rats treated with a toxic dose of vitamin D. These studies were prompted by the recent discovery that ibandronate doses that 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 x kg(-1)) died by d 6 after the first vitamin D injection (median survival: 4.5 d), whereas the 12 rats treated with vitamin D plus ibandronate (0.25 mg x kg(-1) x d(-1)) were 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 the aorta, the carotid, hepatic, mesenteric, renal and femoral arteries, kidneys 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 and 10. Ibandronate treatment also inhibited the dramatic increase in the levels of calcium and phosphate seen in the abdominal aorta, kidneys, lungs and trachea of the vitamin D-treated rats (P < 0.001). Serum calcium levels were, however, not different in rats treated with vitamin D alone (3.4 +/- 0.2 mmol x L(-1)) and in rats treated with vitamin D plus ibandronate (3.5 +/- 0.2 mmol x L(-1)). Treatment with vitamin D alone increased levels of matrix Gla protein, an inhibitor of soft tissue calcification, in the arteries, kidneys, lungs and trachea by 10- to 100-fold, and ibandronate treatment prevented this increase. The importance of these studies in the rat model is that 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 inhibits 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 exposed to toxic levels of vitamin D.

Reducing the Burden of Cardiovascular Calcification in Patients with Chronic Kidney Disease

“…Unfortunately, vitamin D may predispose to vascular calcification. Rats that were treated with high-dose vitamin D developed calcification in the aorta, carotid, hepatic, mesenteric, renal, and femoral arteries (26). Clinical studies have also reported an association between vascular calcification and use of vitamin D therapy in hyperphosphatemic patients with renal failure (27,28).…”

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

“…(15) Agents that enhance bone quality also reduce cardiovascular calcification. (16)(17)(18)(19)(20)(21)(22)(23) Additionally, soft-tissue calcification including vascular calcification is a common feature of genetic mouse and rat models harboring defects associated with bone mineralization. (24)(25)(26) Clinical improvements in bone health, regardless of the initial bone defect, ameliorate progression of cardiovascular disease.…”

Effect of Crystallization Inhibitors on Vascular Calcifications Induced by Vitamin D A Pilot Study in Sprague-Dawley Rats

“…In general, crystallization inhibitors bind to the crystal nucleus or to the crystal face and hence prevent or disturb crystal development without any cellular signaling capacity. Pyrophosphate, 28 bisphosphonates (such as etidronate, alendronate and ibandronate) [29][30][31] and phytate (myoinositol hexakisphosphate) 32 have been shown to inhibit crystallization in the form of vascular calcification. Etidronate is used to treat osteoporosis, 33 and phytate is a naturally occurring compound that can either be ingested 34,35 or absorbed topically.…”