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

描述（由申请方提供）：与一般人群相比，慢性肾脏病（CKD）患者的低骨量和骨折以及冠状动脉钙化和心血管死亡率增加。这种相关的骨骼疾病、骨外钙化和矿物质代谢紊乱的综合征被称为慢性肾病矿物质骨紊乱（CKD-MBD）。然而，这些重要临床表现相互关联的机制仍不清楚。双膦酸盐可有效预防多种非CKD骨病的骨折，还可改善动物模型中的动脉钙化。较新的双膦酸盐如唑来膦酸也通过下调血管内皮生长因子（VEGF）抑制血管生成。CKD患者中VEGF水平升高，并与死亡率增加相关。VEGF对正常骨重建也至关重要。唑来膦酸可通过改善骨和血管中的骨重建和VEGF表达来纠正CKD-MBD的异常。因此，我们的假设是CKD通过激活VEGF诱导CKD（CKD-MBD）中的骨骼和心脏疾病，这可以用唑来膦酸抑制。 为了检验这一假设，我们将使用Cy/+（CKD）大鼠，这是一种新型CKD动物模型，其发展为自然发生的缓慢进展的CKD-MBD，伴有高磷酸盐血症和继发性甲状旁腺功能亢进、骨重塑和骨丢失增加、动脉钙化和左心室肥大，准确反映了在CKD患者中观察到的临床疾病进展。在目的1中，在初始功效和毒性研究之后，我们将通过在早期和晚期时间点用唑来膦酸治疗CKD和正常大鼠来确定唑来膦酸对预防和治疗CKD-MBD的骨和心血管异常的功效，并确定矿物质稳态、骨转换、结构和生物力学以及动脉钙化的血清测量的影响，主动脉顺应性和左心室质量指数。在目标2中，我们将通过一系列离体和体外实验确定CKD是否增加骨和血管组织中的VEGF表达，以及是否可以用唑来膦酸阻断。最后，在目的3中，我们将通过用抗VEGF抗体治疗患有高转换性骨病或由增加的钙摄入诱导的低转换性骨病的CKD动物，确定体内VEGF抑制对在极端骨重建条件下CKD-MBD的骨和心血管异常的影响（贝伐珠单抗）或唑来膦酸，并测定与目标1相似的生化、骨骼和血管参数。这些研究将利用一种新的缓慢进展的CKD-MBD动物模型来测试VEGF是CKD-MBD发病机制中的关键机制参与者的创新假设。鉴于美国每9个人中就有1人患有CKD 3-5期，CKD-MBD导致的骨折和心血管疾病增加，这具有重要的公共卫生意义。 公共卫生相关性：慢性肾病患者存在骨骼异常和动脉硬化。这两个问题可能是有联系的。这项研究的目的是确定一组常用的药物，双膦酸盐，是否可以帮助骨骼和心脏/血管疾病，并确定药物的作用机制。

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. PUBLIC HEALTH RELEVANCE: In patients with chronic kidney disease there is abnormal bone and hardening of the arteries. Both of these problems may be linked. The purpose of this study is to determine if a commonly used group of drugs, bisphosphonates, may help both bone and heart/blood vessel disease and determine the mechanism the drugs work.