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

Abstract

Frick KK, Asplin JR, Culbertson CD, Granja I, Krieger NS, Bushinsky DA. Persistence of 1,25D-induced hypercalciuria in alendronatetreated genetic hypercalciuric stone-forming rats fed a low-calcium diet. Am J Physiol Renal Physiol 306: F1081-F1087, 2014. First published February 26, 2014 doi:10.1152/ajprenal.00680.2013.-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. vitamin D; calcium; kidney stones; intestinal absorption; bone resorption HYPERCALCIURIA IS THE MOST common metabolic abnormality observed in patients who form calcium-based kidney stones (14,49,50). The increased levels of urine (u) calcium (Ca) enhance the probability for nucleation and growth of calcium oxalate (CaOx) and/or calcium hydrogen phosphate (CaHPO 4 , brushite) crystals into clinically relevant kidney stones (14). Patients with idiopathic hypercalciuria (IH), defined as excessive uCa without a demonstrable metabolic cause, generally have normal serum (s) Ca, normal or elevated s1,25(OH) 2 D 3 (1,25D), normal or elevated serum parathyroid hormone (sPTH), normal or low serum phosphate (sP), and low bone mass (14,47,60). IH exhibits a polygenic mode of inheritance (47,48,60).We have established a strain of hypercalciuric rats by selectively inbreeding Sprague-Dawley (SD) rats for increased uCa excretion (2, 3, 5, 11-13, 15-22, 24, 25, 29, 33, 36, 37, 40 -42, 44, 52, 62, 66, 67). Our hypercalciuric rat colony has been maintained by continual selection and inbreeding for over 90 generations; each rat now con...

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria

“…28,29,33,34,37,40,43,48,[67][68][69] Ratios of 1 denote a urine at equilibrium, those .1 denote supersaturation, and those ,1 denote undersaturation. We have found excellent correspondence between calculated and experimentally measured saturation in urine and blood and in bone culture medium.…”

Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones

“…Bisphosphonates inhibit bone resorption and are commonly used to treat reduced bone mineral density and prevent fracture (13). Bisphosphonate use has also been shown to lower urinary calcium excretion in animal models (18,19) and by 50-100 mg/d in small human studies (20)(21)(22)(23), an effect thought to be due to the reduction in bone resorption (19). These human studies were limited by small sample sizes and short follow-up, and did not examine risk of kidney stone formation.…”

Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat

“…This partial resistance to alen may be due to the increased VDR in GHS tissues. While decreased renal tubular Ca reabsorption would contribute to the hypercalciuria in GHS rats fed LCD and given alen, there were no consistent differences in mRNA expression of renal transcellular or paracellular Ca transporters between GHS and SD(59*). If these results can be confirmed in humans with IH, the use of bisphosphonates, such as alen, may not completely prevent the decreased bone density observed in these patients (3, 6, 15-28).…”

“…To eliminate the component of bone resorption in 1,25D-stimulated hypercalciuria in GHS rats, we utilized the bisphosphonate alendronate (alen)(59*). SD and GHS rats were fed LCD and half were injected daily with 1,25D.…”