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: 10343760
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343760
• 关键词: Address; Adenine; Affect; Age; Animal Diseases; Animal Model; Animals; Area; Biological Assay; Bone Diseases; Bone Matrix; Bone Resorption; Bone Tissue; Cells; Cessation of life; Chronic Kidney Failure; Clinic; Clinical; Collagen; Data; Deterioration; Development; Disease Progression; Dose; Effectiveness; FDA approved; Female; Foundations; Fracture; General Population; Goals; Health; Homeostasis; Hospitalization; Individual; Intervention; Kidney Diseases; Laboratories; Measures; Mechanics; Mediating; Methods; Minerals; Modeling; Modification; Osteogenesis; Osteoporosis; Outcome; PTH gene; Patients; Persons; Pharmacology; Population; Porosity; Prevalence; Prevention; Property; Quality of life; Raloxifene; Raman Spectrum Analysis; Rattus; Regimen; Resistance; Risk; Scanning; Sex Differences; Testing; Time; Tissues; Treatment Efficacy; Veterans; Water; Work; analog; base; bisphosphonate; bone; bone fragility; bone mass; cinacalcet; clinically relevant; cortical bone; effectiveness evaluation; experimental study; fracture risk; human disease; improved; in vivo; male; mechanical properties; microCT; military veteran; mortality; mortality risk; nanoindentation; novel; novel strategies; pre-clinical; prevent; sex; skeletal; substantia spongiosa

The prevalence of chronic kidney disease (CKD) in our veterans is putting them at elevated risk of fracture and fracture-associated death. Nearly 1 of every 3 veterans has CKD, fracture risk in persons with CKD is 4x higher than the age-matched general population, and persons who fracture with CKD have longer hospitalization and higher mortality rates than patients without CKD who fracture. Simply stated, interventions aimed at reducing CKD-associated fracture would have a significant impact on veteran health. Skeletal fragility in CKD is unique from conditions such as osteoporosis. The hallmark of CKD-associated bone change is that cortical bone develops porosity (holes) and also has clear changes to bone material properties Moving forward, approaches to reduce skeletal fragility in CKD will need to address both reversal of cortical porosity and improvements in material properties. The goal of this proposal is to provide foundational data on cortical bone infilling in the setting of CKD. We will test the overall hypothesis that reversal of cortical porosity with enhanced material quality can combine to improve bone mechanical properties in CKD. To achieve this goal we will use two complementary animal models of kidney disease, one, the Cy/+ rat, to allow dynamic tracking of porosity changes over time. The second, an adenine-induced model, to allow sex-based differences in porosity dynamics and treatment efficacy to be studied. Both of these models have 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 the effectiveness of suppressing bone resorption with and without simultaneous PTH suppression on cortical porosity infilling in CKD. Two clinically- relevant approaches will be studied – cinacalcet (to reduce parathyroid hormone) and bisphosphonate (to reduce osteoclastic bone resorption). Using two complementary animal models of CKD that develop robust cortical porosity, we will treat both male and female animals with either low-dose bisphosphonate or cinacalcet. Key outcomes will be cortical porosity, using repeated in vivo microCT scans, combined with a novel analysis approach that permits tracking of individual cortical pores over time. These experiments will help us to understand how pore infilling occurs using clinical approaches and how this may differ between sexes. In Aim 2 we will determine the effects of porosity infilling on tissue and structural mechanical properties. Tissues from Aim 1 will be measured with Raman spectroscopy and nano-indentation to characterize the mineral and collagen properties/mechanics of the newly infilled pore tissue. Whole bone mechanical properties (monotonic and fracture toughness) will be used to assess overall bone properties as surrogate measures of fracture resistance. Finally, in Aim 3 we will determine if combination treatment, targeting both pore infilling and modification of the infilled matrix is more effective in improving mechanical properties of CKD animals compared to either monotherapy. We have shown that raloxifene, a FDA-approved agent for treating bone, specifically benefits material properties. Furthermore, we have developed a novel analog for raloxifene that maintains beneficial effects on bone matrix with reductions in traditional cell-mediated effects. The experiments proposed will determine if the combination of infilling pores with enhanced properties of the matrix will have overall benefits. Collectively, the experiments proposed and the data to be generated will provide foundational data on pore infilling and 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.

我们退伍军人中慢性肾脏疾病（CKD）的患病率正在使骨折的风险升高 裂缝相关死亡。每3名退伍军人中有近1人患有CKD，CKD患者的骨折风险为4倍 高于年龄匹配的一般人群，而与CKD骨折的人更长 与没有CKD骨折的患者相比，住院和死亡率更高。简而言之，干预措施 旨在减少与CKD相关的断裂将对退伍军人健康产生重大影响。骨骼脆弱性 在CKD中，诸如骨质疏松症之类的条件是独一无二的。 CKD相关的骨骼变化的标志是 皮质骨发育孔隙度（孔），并且对向前移动的骨骼材料特性有明显的变化， 减少CKD中骨骼脆弱性的方法需要解决皮质孔隙率的逆转和 材料特性的改进。该建议的目的是提供有关皮质骨的基本数据 在CKD的环境中填充。我们将测试总体假设，即具有增强的皮质孔隙度的逆转 材料质量可以结合起来改善CKD中的骨骼机械性能。为了实现这一目标，我们将使用 两种完整的肾脏疾病动物模型，一个Cy/+大鼠，以允许动态跟踪孔隙率 随着时间的变化。第二个是腺嘌呤诱导的模型，允许基于性别的孔隙率差异 动力学和治疗效率要研究。这两个模型都与人类疾病相似 矿物质稳态和骨骼脆弱性的发展。这意味着这项工作的结果将 具有高诊所的转化能力。在AIM 1中，我们将确定抑制骨骼的有效性 在CKD中填充皮质孔隙率上填充皮质孔隙率的同时抑制有或没有同时抑制。两个临床上 - 相关方法将进行研究 - cinacalcet（减少甲状旁腺激素）和 双膦酸盐（减少整骨骨骨分辨率）。使用两个完整的动物模型 CKD发展出强大的皮质孔隙率，我们将用低剂量治疗男性和雌性动物 双膦酸盐或cinacalcet。关键结果将是皮质孔隙度，使用体内微观扫描重复 结合一种新的分析方法，可以随着时间的流逝跟踪单个皮质孔。这些 实验将帮助我们了解如何使用临床方法进行毛孔填充以及如何进行。 性别之间的不同。在AIM 2中，我们将确定孔隙量填充对组织和结构的影响 机械性能。 AIM 1的组织将通过拉曼光谱和纳米调节测量 为了表征新填充的孔组织的矿物质和胶原特性/力学。全骨 机械性能（单调和断裂韧性）将用于评估整体骨特性 断裂抗性的替代度量。最后，在AIM 3中，我们将确定联合处理是否 针对填充孔和修饰填充矩阵的靶向更有效地改善机械 CKD动物的特性与任何一种单一疗法相比。我们已经证明了Raloxifene，是FDA批准的 治疗骨骼的药物，特别有益于材料特性。此外，我们已经开发了一本小说 对雷昔芬的类似物对骨基质保持有益影响，并降低了传统细胞介导的 效果。提出的实验将确定填充毛孔与增强特性的组合 矩阵的总体好处。共同提出了实验和生成数据 将提供有关孔填充的基本数据，并用作建立临床方案的平台 减少骨骼伯恩的骨骼，并改善患有CKD的退伍军人的生活质量。