A bone of contention in drug-induced osteomalacia

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Public release date: 11-May-2006

http://www.eurekalert.org/pub_releases/2006-05/joci-abo050306.php

Contact: Grindlinger

press_releases@...

Journal of Clinical Investigation

A bone of contention in drug-induced osteomalacia

Long-term therapy with some antiepileptic drugs and antibiotics can

cause osteomalacia, a condition marked by softening of the bones that is

usually the result of vitamin D and calcium deficiency. However, the

molecular mechanism of drug-induced osteomalacia remains unclear. In a

study appearing online on May 11 in advance of print publication in the

June issue of the Journal of Clinical Investigation, Thummel and

colleagues from the University of Washington report that the adverse

effect on bone mineral density of these drugs occurs through their

activation of the steroid and xenobiotic receptor (SXR), which induces

expression of the enzyme CYP3A4 that breaks down vitamin D, diminishing

its beneficial effects on bone, and resulting in osteomalacia.

The biologically active forms of vitamin D are broken down to

biologically inactive products by the enzyme CYP24, which itself is

regulated by the vitamin D receptor (VDR). A 2005 study by another

research group that also appeared in the JCI reported that activation of

SXR induced CYP24 expression in mice, which would explain an increase in

vitamin D breakdown and the resulting osteomalacia observed in

individuals taking some SXR-activating antiepileptic drugs or

antibiotics. In contrast, the current study by Thummel et al. found that

SXR does not induce CYP24 expression in mice to any appreciable extent.

Instead, SXR inhibited VDR-mediated CYP24 activity. They also found that

treatment of humans with the SXR-activating antibiotic rifampicin had no

effect on CYP24 expression, but did increase expression of another

enzyme that breaks down vitamin D – CYP3A4. The authors conclude that

while SXR negatively regulates CYP24 expression and subsequent vitamin D

breakdown, it can also enhance vitamin D hydroxylation and breakdown by

inducing the expression of CYP3A4. This explains how SXR activators can

cause osteomalacia. The study establishes SXR as a potential therapeutic

target for clinical treatment or prevention of osteomalacia.

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TITLE: Steroid and xenobiotic receptor and vitamin D receptor crosstalk

mediates CYP24 expression and drug-induced osteomalacia

AUTHOR CONTACT: E. Thummel

University of Washington, Seattle, Washington, USA.

Phone: ; Fax: ; E-mail:

thummel@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=27793

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