Bisphosphonates in the treatment of chronic kidney disease-mineral bone disease

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DESCRIPTION (provided by applicant): In patients with chronic kidney disease (CKD), there is an increased incidence of low bone mass and fractures and coronary artery calcification and cardiovascular mortality compared to the general population. This syndrome of interrelated bone disease, extraskeletal calcification, and disordered mineral metabolism is called Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). However, the mechanism by which these important clinical manifestations are inter-related remains unknown. Bisphosphonates are effective in preventing fractures in multiple non-CKD bone diseases, and can also improve arterial calcification in animal models. Newer bisphosphonates such as zoledronic acid also inhibit angiogenesis through down regulation of vascular endothelial growth factor (VEGF). VEGF levels are elevated in CKD patients and associated with increased mortality. VEGF is also critical for normal bone remodeling. Zoledronic acid, by improving both bone remodeling and VEGF expression in bone and vasculature, may correct the abnormalities of CKD-MBD. Thus, our hypothesis is that CKD induces bone and cardiac disease in CKD (CKD-MBD) through activation of VEGF and this can be inhibited with zoledronic acid. To test this hypothesis we will use the Cy/+ (CKD) rat, a novel animal model of CKD that develops a naturally-occurring, slowly-progressive CKD-MBD with hyperphosphatemia and secondary hyperparathyroidism, increased bone remodeling and bone loss, arterial calcification, and left ventricular hypertrophy, accurately reflecting the clinical disease progression observed in humans with CKD. In Aim 1, after initial efficacy and toxicity studies, we will determine the efficacy of zoledronic acid on the prevention and treatment of the bone and cardiovascular abnormalities of CKD-MBD by treating CKD and normal rats with zoledronic acid at early and late time points and determine the effect of serum measures of mineral homeostasis, bone turnover, architecture and biomechanics, and arterial calcification, aorta compliance and left ventricular mass index. In Aim 2, we will determine if CKD increases VEGF expression in bone and vascular tissue and if this can be blocked with zoledronic acid through a series of ex vivo and in vitro experiments. Lastly, in Aim 3, we will determine the effect of VEGF inhibition in vivo on the bone and cardiovascular abnormalities of CKD-MBD in conditions of extremes of bone remodeling by treating CKD animals with high turnover bone disease, or low turnover bone disease induced by increased calcium intake, with an anti-VEGF antibody (bevacizumab) or zoledronic acid in a 2 x 2 design, and biochemical, skeletal, and vascular parameters similar to Aim 1 determined. These studies will utilize a novel animal model of slowly progressive CKD-MBD to test the innovative hypothesis that VEGF is a key mechanistic player in the pathogenesis of CKD-MBD. Given that 1 in 9 individuals in the U.S. have CKD stages 3-5 with increased fractures and cardiovascular disease from CKD-MBD, this has important public health implications.