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01-05-2014 | Original Research

1,25(OH)₂D₃ Induces a Mineralization Defect and Loss of Bone Mineral Density in Genetic Hypercalciuric Stone-Forming Rats

Authors: Adeline H. Ng, Kevin K. Frick, Nancy S. Krieger, John R. Asplin, Madison Cohen-McFarlane, Christopher D. Culbertson, Kelly Kyker-Snowman, Marc D. Grynpas, David A. Bushinsky

Published in: Calcified Tissue International | Issue 5/2014

Abstract

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague–Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)₂D₃ (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats. To examine the effect of the increased VDR on the osseous response to 1,25D, we fed GHS and SD rats an ample Ca diet and injected either 1,25D [low dose (LD) 12.5 or high dose (HD) 25 ng/100 g body weight/day] or vehicle (veh) daily for 16 days. Femoral areal bone mineral density (aBMD, by DEXA) was decreased in GHS+LD and GHS+HD relative to GHS+veh, while there was no effect on SD. Vertebral aBMD was lower in GHS compared to SD and further decreased in GHS+HD. Both femoral and L6 vertebral volumetric BMD (by μCT) were lower in GHS and further reduced by HD. Histomorphometry indicated a decreased osteoclast number in GHS+HD compared to GHS+veh or SD+HD. In tibiae, GHS+HD trabecular thickness and number increased, with a 12-fold increase in osteoid volume but only a threefold increase in bone volume. Bone formation rate was decreased in GHS+HD relative to GHS+veh, confirming the mineralization defect. The loss of BMD and the mineralization defect in GHS rats contribute to increased hypercalciuria; if these effects persist, they would result in decreased bone strength, making these bones more fracture-prone. The enhanced effect of 1,25D in GHS rats indicates that the increased VDRs are biologically active.

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Title: 1,25(OH)2D3 Induces a Mineralization Defect and Loss of Bone Mineral Density in Genetic Hypercalciuric Stone-Forming Rats
Authors: Adeline H. Ng
Kevin K. Frick
Nancy S. Krieger
John R. Asplin
Madison Cohen-McFarlane
Christopher D. Culbertson
Kelly Kyker-Snowman
Marc D. Grynpas
David A. Bushinsky
Publication date: 01-05-2014
Publisher: Springer US
Published in: Calcified Tissue International / Issue 5/2014
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-014-9838-7

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