Hypercalciuria and Abnormal Bone in the Genetic Hypercalciuric Stone-Forming Rats - ABSTRACT Most patients who form calcium-containing kidney stones are hypercalciuric (excess calcium in urine), compared with non-stone formers. These patients are often in negative calcium (Ca) balance in that they excrete more Ca in their urine than they absorb from their diet, indicating a net loss of total body Ca. The source of the excessive urine Ca (uCa) is almost certainly the skeleton, the largest Ca repository in the body. Indeed these patients often have a reduction in bone mineral density, clinical osteoporosis, decreased bone strength and an increase in the rate of bone fracture. The primary endpoint for successful treatment of patients with Ca-containing kidney stones is a decrease in stone recurrence rate. Equally important, and often not as well recognized, is maintaining and improving the patient's bone mineral density (BMD) and bone quality. To study idiopathic hypercalciuria (IH) in ways that are impossible in man, we developed an animal model of this disorder. Through >100 generations of successive inbreeding of the most hypercalciuric SD rat progeny, we established a strain of rats that now consistently excrete ~8-10 times as much uCa as the founder SD rats. All of these rats spontaneously form kidney stones, and are termed Genetic Hypercalciuric Stone-forming (GHS) rats. In common with patients with IH, GHS rats have normal serum concentrations of Ca and 1,25D, increased intestinal Ca absorption, enhanced bone resorption, decreased renal tubule Ca reabsorption, and hypomineralization of bone with weakened mechanical properties. The overall goal of this proposed research project is to use the GHS rats to study the relationship of hypercalciuria to BMD and bone quality. We propose to determine if increased expression of vitamin D receptor (VDR) is responsible, at least in part, for the hypercalciuria and decreased BMD and bone quality in the GHS rats. We will then determine if pharmacologic interventions to reduce hypercalciuria will improve BMD and bone quality. We propose the following Specific Aims: 1. Test the hypothesis that the decreased BMD and bone quality in the GHS rats, compared to the founder SD rats, is due to an increased abundance of VDR in both osteoblasts and osteoclasts, resulting in an alteration in function. 2. Test the hypothesis that hypercalciuria, stone formation, reduced BMD and bone quality in the GHS rats can be improved by pharmacologic treatments, including bisphosphonates, RANKL ligand inhibitor and sclerostin inhibitor, directed toward reducing hypercalciuria. Results from these studies may lead to future clinical studies to reduce hypercalciuria and recurrent stone formation and improve bone quality.
