Treating bone deterioration associated with chronic kidney disease

退伍军人中慢性肾病 (CKD) 的患病率使他们面临更高的骨折和骨折风险 骨折相关死亡。近每 3 名退伍军人中就有 1 名患有 CKD，患有 CKD 的人骨折风险是 4 倍 高于同龄一般人群，并且患有 CKD 的骨折者的寿命更长 住院和死亡率高于无 CKD 骨折的患者。简单来说，干预 旨在减少 CKD 相关骨折的目标将对退伍军人的健康产生重大影响。骨骼脆弱 CKD 的发病率与骨质疏松症等疾病不同。 CKD 相关骨变化的特点是 皮质骨出现孔隙（孔），并且骨材料特性也发生明显变化展望未来， 减少 CKD 骨骼脆弱性的方法需要同时解决皮质孔隙度的逆转和 材料性能的改进。该提案的目标是提供皮质骨的基础数据 填充 CKD 的设置。我们将检验总体假设，即皮质孔隙度的逆转随着增强 材料质量可以结合起来改善 CKD 中的骨机械性能。为了实现这个目标，我们将使用 两种互补的肾脏疾病动物模型，一种是 Cy/ 大鼠，可动态跟踪孔隙率 随着时间的推移而变化。第二种是腺嘌呤诱导模型，允许孔隙率存在性别差异 动力学和治疗效果有待研究。这两种模型都与人类疾病有相似之处 矿物质稳态紊乱和骨脆性的发展。这意味着这项工作的结果将 具有较高的临床转化能力。在目标 1 中，我们将确定抑制骨的有效性 CKD 中皮质孔隙填充的同时 PTH 抑制的吸收。临床上有两种—— 将研究相关方法——西那卡塞（减少甲状旁腺激素）和 双膦酸盐（减少破骨细胞骨吸收）。使用两种互补的动物模型 CKD 会形成强大的皮质孔隙，我们将用低剂量治疗雄性和雌性动物 双膦酸盐或西那卡塞。主要结果将是皮质孔隙度，使用重复的体内 microCT 扫描， 结合一种新颖的分析方法，可以随着时间的推移跟踪各个皮质孔。这些 实验将帮助我们了解使用临床方法如何发生毛孔填充以及这如何可能 性别之间存在差异。在目标 2 中，我们将确定孔隙填充对组织和结构的影响 机械性能。来自 Aim 1 的组织将通过拉曼光谱和纳米压痕进行测量 表征新填充的毛孔组织的矿物质和胶原蛋白特性/力学。全骨 机械性能（单调和断裂韧性）将用于评估整体骨骼性能： 抗断裂性的替代指标。最后，在目标 3 中，我们将确定是否联合治疗， 针对孔隙填充和填充基质的改性可以更有效地提高机械性能 与任一单一疗法相比，CKD 动物的特性。我们已经证明雷洛昔芬是 FDA 批准的一种药物 用于治疗骨骼的药剂，特别有利于材料特性。此外，我们还开发了一种新颖的 雷洛昔芬的类似物，可保持对骨基质的有益作用，同时减少传统的细胞介导的 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 矩阵的整体效益。总的来说，提出的实验和要生成的数据 将提供有关毛孔填充的基础数据，并作为构建临床方案的平台 减轻患有 CKD 的退伍军人的骨骼负担并提高生活质量。

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.