Treating bone deterioration associated with chronic kidney disease

治疗与慢性肾病相关的骨质恶化

• 批准号: 9142786
• 负责人: Matthew R Allen
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142786
• 关键词: Affect; Age; Animal Model; Animals; Architecture; Binding; Biochemical; Biomechanics; Bolus Infusion; Bone Density; Bone Diseases; Bone Matrix; Bone Resorption; Bone Surface; Bone remodeling; Cessation of life; Chronic Kidney Failure; Clinic; Clinical; Clinical Data; Clinical Research; Collagen; Data; Deterioration; Development; Disease; Dose; Effectiveness; FDA approved; Fracture; General Population; Goals; Gold; Health; Homeostasis; Human; Hydration status; Kidney; Kidney Diseases; Lead; Maps; Measurement; Mechanics; Metabolic; Metabolic Bone Diseases; Minerals; Modeling; Morphology; Musculoskeletal System; Osteoclasts; Osteoporosis; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Physiologic calcification; Population; Postmenopausal Osteoporosis; Postmenopause; Pre-Clinical Model; Prevalence; Property; Quality of life; Raloxifene; Rattus; Regimen; Renal function; Risk; Safety; Saline; Series; Serum; Skeleton; Surface; Testing; Time; Tissues; Toxic effect; Urine; Veterans; Work; Working Women; base; bisphosphonate; bone; bone loss; bone mass; bone quality; clinically relevant; comparison group; crosslink; design; drug distribution; geometric structure; human disease; improved; long bone; mortality; pre-clinical; primary outcome; public health relevance; research study; skeletal; skeletal disorder; spine bone structure; standard care

 DESCRIPTION (provided by applicant): Veterans develop chronic kidney disease (CKD) at a significantly higher rate than the general population. The metabolic derangements associated with CKD lead to dramatic bone loss and a significant increased risk of fracture. More devastating than simply having increased fractures is that the risk of mortality associated with skeletal fracture, this is significantly higher in patiets with CKD compared to other patients that fracture. Collectively, this means our veterans are at risk of dying because of the skeletal complications of CKD. Clinical data regarding the effectiveness of controlling bone disease in CKD patients are limited and a call has been made for more data regarding safety and efficacy of bone agents in the setting of CKD. Surprisingly, there is also a paucity of pre-clinical data concerning how clinically relevant drugs affect skeletl properties in CKD. The goal of this project is to understand how potential clinical therapies affec skeletal health in a pre- clinical model of CKD. To achieve this goal we will use a slowly progressive animal model of kidney disease, the Cy/+ rat. Our group has shown that this pre-clinical model parallels the human disease in its development of disturbed mineral homeostasis and bone fragility. This means the results from this work will have high translational capacity to the clinic. In Aim 1 we will determine how altered kidney function associated with CKD (both high and low turnover disease) changes the skeletal distribution of bisphosphonate. Bisphosphonates are the most commonly used drug for treatment of metabolic bone disease yet they have not been used in CKD due to concern over drug accumulation. In a series of experiments we will administer fluorescent bisphosphonate to normal animals and those with CKD to allow mapping of drug distribution both at a bulk level (concentrations among bones) and at a tissue level (depth of penetration from bone surfaces). These experiments will help us to understand how altered kidney function influences drug accumulation and determine how this differs among dosing regimens. This will provide key data regarding dosing regimens of bisphosphonates. In Aim 2 we will determine if more frequent, low dose bisphosphonate treatment is more effective than a single dose in suppressing remodeling and preserving bone mass/mechanics. These experiments are based on our preliminary data showing that a single bolus dose of bisphosphonate is ineffective in controlling CKD-induced bone disease. Animals with CKD will be treated with a single dose of bisphosphonate, a weekly dose of bisphosphonate (which over the 10 week period equals the single bolus dose), or saline. The primary outcomes will be determined by skeletal analyses (bone density, architecture/geometry, structural/material biomechanical properties, histomorphometry). Biochemical measurements and renal function will also be assessed to assure these dose regimens do not adversely affect kidney function. Finally, in Aim 3 we will determine if combination treatment with bisphosphonates and raloxifene is more effective in normalizing bone of CKD animals compared to either monotherapy. Although bisphosphonate treatment is the goal-standard for treating various skeletal diseases, and we hypothesize they can be effective in the setting of CKD, their use is not expected to completely normalize bone mechanical properties in CKD because we have shown CKD leads to an intrinsic deficit in bones' material properties. We have further shown that raloxifene, a FDA-approved agent for treating bone, specifically benefits material properties and that when combined with bisphosphonate can improve mechanical properties more than either monotherapy alone. This experiment will treat CKD rats with bisphosphonate, raloxifene, bisphosphonate + raloxifene, or saline. The primary outcomes will match those of Aim 2 with additional in-depth analyses of tissue material properties (collagen cross-links, morphology, mechanics; bone hydration, bone mineralization). These data will serve as a platform on which to build a clinical regimen for reducing the skeletal burden and improving the quality of life of veterans suffering from CKD.

 描述（由申请人提供）： 退伍军人患慢性肾病 (CKD) 的几率明显高于普通人群，与 CKD 相关的代谢紊乱会导致骨质流失和骨折风险显着增加，而死亡风险比单纯增加骨折更具破坏性。与骨骼骨折相关，与其他骨折患者相比，慢性肾病患者的这一比例明显更高，这意味着我们的退伍军人由于 CKD 骨骼并发症的有效性而面临死亡风险。 CKD 患者的疾病有限，因此需要更多有关骨制剂在 CKD 治疗中的安全性和有效性的数据。令人惊讶的是，关于临床相关药物如何影响 CKD 骨骼特性的临床前数据也很少。该项目的目标是了解潜在的临床疗法如何影响 CKD 临床前模型中的骨骼健康。为了实现这一目标，我们将使用缓慢进展的肾脏疾病动物模型。 Cy/+ 大鼠。我们的研究小组已经证明，这种临床前模型与人类疾病的矿物质稳态紊乱和骨骼脆性的发展相似，这意味着这项工作的结果将具有很高的临床转化能力。将确定与 CKD（高周转疾病和低周转疾病）相关的肾功能改变如何改变双磷酸盐的骨骼分布，双磷酸盐是治疗代谢性骨病最常用的药物，但尚未用于治疗。由于担心药物蓄积而导致 CKD，在一系列实验中，我们将对正常动物和患有 CKD 的动物施用荧光双膦酸盐，以绘制总体水平（骨骼中的浓度）和组织水平（渗透深度）的药物分布图。这些实验将帮助我们了解肾功能的改变如何影响药物蓄积，并确定给药方案之间的差异，这将提供有关我们将在目标 2 中确定的双膦酸盐给药方案的关键数据。如果更频繁，低剂量的双膦酸盐治疗在抑制重塑和保持骨量/力学方面比单剂量更有效。这些实验基于我们的初步数据，表明单次推注剂量的双膦酸盐在控制 CKD 诱发的骨疾病方面无效。患有 CKD 的动物将接受单剂量双膦酸盐、每周剂量的双膦酸盐（10 周内等于单次推注剂量）或盐水治疗。通过骨骼分析（骨密度、结构/几何形状、结构/材料生物力学特性、组织形态计量学）来确定，还将评估生化测量和肾功能，以确保这些剂量方案不会对肾功能产生不利影响。确定双磷酸盐和雷洛昔芬的联合治疗是否比任一单一疗法更有效地使 CKD 动物的骨骼正常化，尽管双磷酸盐治疗是治疗各种疾病的目标标准。骨骼疾病，我们渴望它们能够有效治疗 CKD，但预计它们的使用不会使 CKD 中的骨机械特性完全正常化，因为我们已经表明 CKD 会导致骨骼材料特性的内在缺陷。雷洛昔芬是 FDA 批准的一种治疗骨骼的药物，特别有利于材料特性，与双膦酸盐联合使用可以比单独使用单一疗法更能改善机械特性。该实验将用双膦酸盐治疗 CKD 大鼠。主要结果将与目标 2 的结果相匹配，并进一步深入分析组织材料特性（胶原交联、形态、力学；骨水合、骨矿化）。一个平台，用于建立临床治疗方案，以减轻患有 CKD 的退伍军人的骨骼负担并提高生活质量。