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）： 退伍军人患慢性肾脏疾病（CKD）的比率明显高于普通人群。与CKD相关的代谢紊乱导致显著的骨丢失和骨折风险的显著增加。比简单地增加骨折更具有破坏性的是，与骨折相关的死亡风险，与其他骨折患者相比，CKD患者的死亡风险明显更高。总的来说，这意味着我们的退伍军人由于CKD的骨骼并发症而面临死亡的风险。关于控制CKD患者骨病有效性的临床数据有限，呼吁获得更多关于骨制剂在CKD背景下的安全性和有效性的数据。令人惊讶的是，还缺乏关于临床相关药物如何影响CKD中的β 1性质的临床前数据。本项目的目标是了解潜在的临床治疗如何影响CKD临床前模型中的骨骼健康。为了实现这一目标，我们将使用慢性进展性肾病动物模型，Cy/+大鼠。我们的研究小组已经表明，这种临床前模型与人类疾病在矿物质稳态紊乱和骨脆性方面的发展相似。这意味着这项工作的结果将具有很高的临床转化能力。在目标1中，我们将确定与CKD（高转换和低转换疾病）相关的肾功能改变如何改变双膦酸盐的骨骼分布。双膦酸盐是治疗代谢性骨病最常用的药物，但由于担心药物蓄积，尚未用于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，以允许在整体水平（骨中的浓度）和组织水平（从骨表面的渗透深度）绘制药物分布。这些实验将帮助我们了解肾功能改变如何影响药物蓄积，并确定这在给药方案中的差异。这将提供有关双磷酸盐给药方案的关键数据。在目标2中，我们将确定更频繁的低剂量双膦酸盐治疗在抑制重塑和保留骨量/力学方面是否比单次剂量更有效。这些实验是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诱导的骨疾病中无效。CKD动物将接受单次双膦酸盐给药、每周一次双膦酸盐给药（在10周内等于单次推注给药）或生理盐水给药。主要结局将通过骨骼分析（骨密度、结构/几何形状、结构/材料生物力学特性、组织形态测量学）确定。还将评估生化测量和肾功能，以确保这些给药方案不会对肾功能产生不良影响。最后，在目标3中，我们将确定与单药治疗相比，双膦酸盐和雷洛昔芬联合治疗是否更有效地使CKD动物的骨正常化。虽然双膦酸盐治疗是治疗各种骨骼疾病的目标标准，我们假设它们在CKD的情况下是有效的，但它们的使用预计不会完全使CKD的骨机械性能正常化，因为我们已经证明CKD会导致骨材料性能的内在缺陷。我们进一步证明，雷洛昔芬（FDA批准的治疗骨骼的药物）特别有益于材料性能，并且与双膦酸盐联合使用时比单独使用任何一种单一药物都能更好地改善机械性能。本实验将用双膦酸盐、雷洛昔芬、双膦酸盐+雷洛昔芬或盐水治疗CKD大鼠。主要结局将与目标2的结局相匹配，并对组织材料特性（胶原交联、形态学、力学;骨水合作用、骨矿化）进行了额外的深入分析。这些数据将作为一个平台，在此基础上建立一个临床方案，以减轻骨骼负担，改善患有CKD的退伍军人的生活质量。