Successful treatment of patients with Ca containing kidney stones is a decrease in the rate of stone recurrence. While this is important, equally important is maintaining and improving the patient's bone mineral density (BMD) and bone quality, as stone formers have both a reduction in BMD and an increase in the rate of fracture compared to non-stone formers. Most humans with Ca-containing kidney stones are hypercalciuric when compared to non-stone formers and these patients often excrete more Ca than they absorb indicating a net loss of body Ca. The source of this additional urine (u) Ca is almost certainly the skeleton. BMD is correlated inversely with uCa excretion in patients with idiopathic hypercalcuria (IH) who have a reduction in BMD and an increase in fractures compared to controls. To help understand the mechanism of IH in man, we developed an animal model. Through >95 generations of successive inbreeding we have established a strain of rats that now consistently excrete ~10 times as much uCa as SD controls, all form kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These GHS rats have a systemic abnormality in Ca homeostasis: they absorb more intestinal Ca, resorb more bone, and do not adequately reabsorb filtered Ca similar to many humans with IH. We have found that the bone, kidney and intestine in GHS rats have an increased number of vitamin D receptors (VDR) which, in a series of recently published studies, have been shown to be biologically active, strongly suggesting a fundamental physiologic explanation for the hypercalciuria. We have demonstrated that compared to SD rats, GHS rats have reduced cortical and trabecular BMD even when fed an ample Ca diet. GHS rat bones are more brittle and fracture prone. Administration of the thiazide diuretic chlorthalidone increased trabecular bone strength in GHS rats. With added 1,25D we found a bone mineralization defect and a loss of BMD in GHS rats that exceeded changes in SD and contributed to increased hypercalciuria, suggesting that these bones would be more fracture-prone. The overall goal of this proposal is to study the relationship of hypercalciuria to BMD and bone quality in GHS rats.
Three specific aims will be addressed:
Aim 1. We will test the hypothesis that the decreased BMD and bone quality in GHS, compared to the parental SD, rats is due to changes in osteoblast activity.
Aim 2. We will test the hypothesis that the decreased BMD and quality in GHS rats, compared to SD rats, is due to changes in osteoclast activity.
Aim 3. We will test the hypothesis that the reduced BMD and bone quality in the GHS rats can be improved by dietary and pharmacologic treatments, including VDR inhibitor and VDR knockdown, directed toward reducing hypercalciuria. With the knowledge gained in these animal studies we hope to better understand the pathogenesis of hypercalciuria and decreased BMD. If the results from these animal studies are supported by studies in human IH stone formers, they will have a substantial influence on treatment paradigms that will not only reduce recurrent stone formation but improve bone quality in IH patients.
Patients with calcium containing kidney stones have reduced bone mineral density and an increased rate of fractures and bone of our genetic strain of hypercalciuric stone-forming rats also has reduction in bone density and quality. We will use these rats to study the mechanism of this bone disease and test potential dietary interventions to improve bone density and quality. If the results from these cellular and animal studies are supported by studies in human hypercalciuric stone formers, they will have a substantial effect on treatment paradigms that will not only reduce recurrent stone formation but improve bone quality in hypercalciuric patients.
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