Treating bone deterioration associated with chronic kidney disease

我们的退伍军人中慢性肾脏疾病（CKD）的患病率使他们面临骨折的风险增加， 与死亡相关的死亡每3名退伍军人中就有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，骨折伴CKD的人有更长的 住院率和死亡率高于无CKD的骨折患者。简单地说，干预措施 旨在减少CKD相关骨折的治疗将对退伍军人的健康产生重大影响。骨骼脆性 在CKD中是不同于骨质疏松症等疾病的。CKD相关骨改变的标志是， 皮质骨形成多孔性（孔）并且还对骨材料性质具有明显的变化。向前发展， 减少CKD患者骨骼脆弱性的方法需要解决皮质多孔性的逆转， 材料性能的改善。本提案的目的是提供有关皮质骨的基础数据 在CKD的设置中填充。我们将测试整体假设，即皮质孔隙度的逆转与增强 材料质量可以联合收割机改善CKD的骨力学性能。为了实现这一目标，我们将使用 两种互补的肾脏疾病动物模型，一种是Cy/+大鼠，以允许动态跟踪孔隙度 随着时间的推移而改变。第二种是腺嘌呤诱导模型，允许基于性别的孔隙度差异 动力学和治疗效果有待研究。这两种模型都与人类疾病相似， 矿物质平衡紊乱和骨脆性的发展。这意味着这项工作的结果将 有很强的临床应用能力。在目标1中，我们将确定抑制骨的有效性 在CKD中，有和没有同时抑制PTH的骨吸收对皮质孔隙填充的影响。两个临床- 将研究相关的方法-西那卡塞（减少甲状旁腺激素）和 二膦酸盐（减少骨吸收）。使用两种互补的动物模型， CKD发展出强大的皮质孔隙，我们将用低剂量或低剂量 二膦酸盐或西那卡塞。关键结果将是皮质孔隙率，使用重复的体内microCT扫描， 结合允许随时间跟踪单个皮质孔的新颖分析方法。这些 实验将帮助我们了解如何孔填充发生使用临床方法和如何这可能 不同性别之间的差异。在目标2中，我们将确定孔隙填充对组织和结构的影响 力学性能将使用拉曼光谱和纳米压痕测量来自目标1的组织 以表征新填充的孔隙组织的矿物质和胶原性质/力学。全骨 机械性能（单调性和断裂韧性）将用于评估整体骨性能， 抗断裂性的替代测量。最后，在目标3中，我们将确定联合治疗， 以孔填充和填充基质的改性为目标在改善机械性能方面更有效 CKD动物与任一单药治疗相比的特性。我们已经证明，雷洛昔芬，一种FDA批准的 用于治疗骨的试剂，特别有益于材料性能。此外，我们还开发了一种新的 雷洛昔芬的类似物，其维持对骨基质的有益作用，同时减少传统细胞介导的 方面的影响.所提出的实验将确定填充孔隙与增强性能的组合是否 将带来整体效益。总的来说，提出的实验和要生成的数据 将提供有关孔隙填充的基础数据，并作为建立临床方案的平台， 减轻骨骼负担，改善CKD退伍军人的生活质量。

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.