© 2001 American Heart Association, Inc.
Vascular Biology |
Bisphosphonates Alendronate and Ibandronate Inhibit Artery Calcification at Doses Comparable to Those That Inhibit Bone Resorption
Presented at the 22nd Annual Meeting of the American Society for Bone and Mineral Research, Toronto, Canada, September 22–26, 2000.
From the Department of Biology, University of California, San Diego, La Jolla.
Correspondence to Dr Paul A. Price, Department of Biology, 0368, University of California, San Diego, La Jolla, CA 92093-0368. E-mail pprice{at}ucsd.edu
Abstract—The
present experiments were carried out to test the hypothesis that
artery calcification is linked to bone resorption by determining
whether the selective inhibition of bone resorption with the
bisphosphonates alendronate and ibandronate will inhibit artery
calcification. Artery calcification was first induced by treatment of
42-day-old male rats with warfarin, a procedure that inhibits the
-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 treatment. A 10-fold lower
dose of alendronate reduced artery calcification by 50%
(P<0.005). These
bisphosphonate doses are comparable to those that inhibit bone
resorption in rats of this age. More rapid artery calcification was
induced by treatment with warfarin together with high doses of vitamin
D, a procedure that causes extensive artery calcification by 84 hours.
Alendronate and ibandronate again completely inhibited calcification of
all arteries and heart valves examined. The subcutaneous doses of
alendronate and ibandronate 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 artery calcification at 20 µg
alendronate · kg-1 · d-1
and at 1 µg
ibandronate · kg-1 · d-1.
Bisphosphonate treatment did not affect serum calcium and phosphate,
and so the inhibition of artery calcification cannot be due to a simple
lowering of the serum calcium phosphate ion product. We conclude
that bisphosphonates inhibit the calcification of arteries and heart
valves at doses comparable to the doses that inhibit bone resorption.
These results support the hypothesis that artery calcification is
linked to bone resorption. The mechanism of this linkage remains to be
established, however, and an alternative explanation for the
present results is also considered.
Key Words: artery calcification • bisphosphonates • bone resorption • alendronate • ibandronate
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