Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption

The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the sele ctive inhibition of bone resorption with the bisphosphonates dendronate and ibandronate will inhibit artery calcification. Artery calcification was fi rst induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma -carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg . kg(-1) . d(-1)) and alendronate (0.1 mg . kg(-1) . d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin tre atment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inh ibit bone resorption in rats of this age. More rapid artery calcification w as induced by treatment with warfarin together with high doses of vitamin D , a procedure that causes extensive artery calcification by 84 hours. Alend ronate and ibandronate again completely inhibited calcification of all arte ries and heart valves examined. The subcutaneous doses of alendronate and i bandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of art ery calcification at 20 <mu>g alendronate . kg(-1) . d(-1) and at 1 mug iba ndronate . kg(-1) . d(-1). Bisphosphonate treatment did not affect serum ca lcium and phosphate, and so the inhibition of artery calcification cannot b e due to a simple lowering of the serum calcium phosphate ion product. We c onclude that bisphosphonates inhibit the calcification of arteries and hear t valves at doses comparable to the doses that inhibit bone resorption. The se results support the hypothesis that artery calcification is linked to bo ne resorption. The mechanism of this linkage remains to be established, how ever, and an alternative explanation for the present results is also consid ered.