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 uCa 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 8d all were also given alen until sacrifice at d16. At 8d, 1,25D increased uCa in SD and to a greater extent in GHS. At 16d, 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 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 alendronate, may not prevent the decreased bone density observed in these patients.