Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet.

Abstract

Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients.

• Authors: Kevin K Frick, John R Asplin, Christopher D Culbertson, Ignacio Granja, Nancy S Krieger, David A Bushinsky
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 306 Issue 9 Pg. F1081-7 (May 01 2014) ISSN: 1522-1466 [Electronic] United States
• PMID: 24573387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Bone Density Conservation Agents
• Calcium, Dietary
• Calcitriol
• Alendronate

Topics

• Alendronate (pharmacology)
• Animals
• Bone Density (drug effects)
• Bone Density Conservation Agents (pharmacology)
• Bone Resorption (chemically induced, genetics, prevention & control, urine)
• Calcitriol
• Calcium, Dietary (administration & dosage, urine)
• Disease Models, Animal
• Genotype
• Hypercalciuria (chemically induced, drug therapy, genetics, urine)
• Intestinal Absorption
• Intestinal Mucosa (metabolism)
• Kidney (metabolism)
• Kidney Calculi (chemically induced, drug therapy, genetics, urine)
• Male
• Phenotype
• Rats
• Rats, Sprague-Dawley
• Time Factors