Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure

Koba A. Lomashvili, Marie Claude Monier-Faugere, Xiaonan Wang, Hartmut H. Malluche, W. Charles O'Neill

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Although it is known that bisphosphonates prevent medial vascular calcification in vivo, their mechanism of action remains unknown and, in particular, whether they act directly on the blood vessels or indirectly through inhibition of bone resorption. To determine this, we studied the effects of two bisphosphonates on calcification of rat aortas in vitro and on in vivo aortic calcification and bone metabolism in rats with renal failure. We produced vascular calcification in rats with adenine-induced renal failure fed a high-phosphate diet. Daily treatment with either etidronate or pamidronate prevented aortic calcification, with the latter being 100-fold more potent. Both aortic calcification and bone formation were reduced in parallel; however, bone resorption was not significantly affected. In all uremic rats, aortic calcium content correlated with bone formation but not with bone resorption. Bisphosphonates also inhibited calcification of rat aortas in culture and arrested further calcification of precalcified vessels but did not reverse their calcification. Expression of osteogenic factors or calcification inhibitors was not altered by etidronate in vitro. Hence, these studies show that bisphosphonates can directly inhibit uremic vascular calcification independent of bone resorption. The correlation between inhibition of aortic calcification and bone mineralization is consistent with a common mechanism such as the prevention of hydroxyapatite formation and suggests that bisphosphonates may not be able to prevent vascular calcification without inhibiting bone formation in uremic rats.

Original languageEnglish
Pages (from-to)617-625
Number of pages9
JournalKidney International
Volume75
Issue number6
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
This work was supported by Grant DK069681 from the National Institutes of Health and a grant from the Genzyme Renal Innovations Program (to Dr O’Neill), and Nephrology Fellowship and Junior Faculty Grants from Amgen (to Dr Lomashvili). Portions of this work have previously been presented in abstract form at the American Society of Nephrology Annual Meeting 2006 and 2008.

Keywords

  • Bone formation
  • Bone histomorphometry
  • Bone resorption
  • Pyrophosphate
  • Rat aorta
  • Uremic osteodystrophy

ASJC Scopus subject areas

  • Nephrology

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