The present experiments were carried out to further test the hypothesis that arterial calcification is linked to
bone resorption by determining whether the selective inhibition of
bone resorption with
SB 242784, a specific inhibitor of the osteoclastic V-
H+-ATPase, will inhibit arterial calcification. Treatment for 96 hours with toxic doses of
vitamin D caused widespread calcification in the aorta and in the femoral, mesenteric, hepatic, renal, and carotid arteries, and treatment with
SB 242784 completely prevented the
vitamin D-induced calcification of each of these arteries at a dose of 40 mg/kg per day and significantly reduced calcification at a dose of 10 mg/kg per day. Treatment with
vitamin D also caused extensive calcification in the lungs, tracheal cartilage, and kidneys, and treatment with
SB 242784 prevented or reduced calcification at each of these sites. Measurement of serum levels of cross-linked N-telopeptides, a specific measure of
bone resorption activity, showed that treatment with
vitamin D alone produced the expected 2.4-fold increase in
bone resorption activity and that concurrent treatment with the 40-mg dose of
SB 242784 reduced
bone resorption activity to below control levels. With the inclusion of the present results, there are now three types of
bone resorption inhibitors (each with an entirely different mode of action on the osteoclast) that share the ability to potently inhibit arterial calcification in the rat, the V-
H+-ATPase inhibitor
SB 242784, the
cytokine osteoprotegerin, and the amino
bisphosphonates alendronate and
ibandronate.