Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D

The present experiments were carried out to test the hypothesis that arteri al calcification is linked to bone resorption by determining whether the se lective inhibition of bone resorption with osteoprotegerin will inhibit art erial calcification. In the first test, arterial calcification was induced by treating 22-day-old male rats with warfarin, a procedure that inhibits t he gamma -carboxylation of matrix Gla protein and causes extensive calcific ation of the arterial media. Compared with rats treated for 1 week with war farin alone, rats treated with warfurin plus osteoprotegerin at a dose of 1 mg/kg per day had dramatically reduced alizarin red staining for calcifica tion in the aorta and in the carotid, hepatic, mesenteric, renal, and femor al arteries, and they had 90% lower levels of calcium and phosphate in the abdominal aorta (P<0.001) and in tracheal ring cartilage (P<0.01). More rap id arterial calcification was induced by treating 49-day-old male rats with toxic doses of vitamin D. Treatment for 96 hours with vitamin D caused wid espread alizarin red staining for calcification in the aorta and the femora l, mesenteric, hepatic, renal, and carotid arteries, and osteoprotegerin co mpletely prevented calcification in each of these arteries and reduced the levels of calcium and phosphate in the abdominal aorta to control levels (P <0.001). Treatment with vitamin D also caused extensive calcification in th e lungs, trachea, kidneys, stomach, and small intestine, and treatment with osteoprotegerin reduced or prevented calcification in each of these sites. Measurement of serum levels of cross-linked N-teleopeptides showed that os teoprotegerin dramatically reduced bone resorption activity in each of thes e experiments (P<0.001). Therefore, we conclude that doses of osteoproteger in that inhibit bone resorption are able to potently inhibit the calcificat ion of arteries that is induced by warfarin treatment and by vitamin D trea tment. These results support the hypothesis that arterial calcification is linked to bone resorption.