Treating bone deterioration associated with chronic kidney disease

退伍军人中慢性肾脏疾病(CKD)的流行使他们面临更高的骨折风险和 骨折相关死亡。几乎每3名退伍军人中就有1人患有CKD，CKD患者的骨折风险是4倍 高于年龄匹配的普通人群，CKD骨折患者的寿命更长 住院时间和病死率高于无CKD骨折患者。简单地说，干预 旨在减少CKD相关性骨折将对退伍军人的健康产生重大影响。骨骼脆性 慢性肾脏病是与骨质疏松症等疾病相区别的。CKD相关骨质改变的特点是 皮质骨形成孔洞，并对向前移动的骨材料特性有明显的变化， 降低慢性肾脏病骨骼脆性的方法需要同时解决皮质孔隙度的逆转和 材料特性的改进。这项建议的目标是提供有关皮质骨的基础数据 在CKD的背景下进行填充。我们将测试总体假设，即增强的 材料质量可以结合起来改善CKD的骨力学性能。为了实现这一目标，我们将利用 两种互补的肾脏疾病动物模型，一种是Cy/大鼠，允许动态追踪孔隙度 随着时间的推移而改变。第二种是腺嘌呤诱导的模型，允许基于性别的孔隙度差异 动力学和治疗效果有待研究。这两个模型都与人类疾病在其 矿物质动态平衡失调和骨脆性的发展。这意味着这项工作的结果将 对临床有较高的翻译能力。在目标1中，我们将确定抑制骨骼的有效性 慢性肾脏病伴或不伴甲状旁腺素同时抑制时的吸收对皮质孔洞填充的影响。两个临床上- 将研究相关的方法--Cinacalcet(减少甲状旁腺激素)和 双磷酸盐(减少破骨细胞性骨吸收)。使用两种互补的动物模型 CKD发展成强大的皮质多孔性，我们将对雄性和雌性动物使用低剂量 双磷酸盐或金刚石粉。关键的结果将是皮质孔隙率，使用体内重复的微型CT扫描， 与一种新的分析方法相结合，允许随着时间的推移跟踪单个皮质毛孔。这些 实验将帮助我们了解毛孔填充是如何使用临床方法发生的，以及这可能是如何发生的 不同性别之间的差异。在目标2中，我们将确定孔洞填充对组织和结构的影响 机械性能。来自Aim 1的组织将用拉曼光谱和纳米压痕进行测量 以表征新填充的毛孔组织的矿物质和胶原特性/力学。整块骨头 力学性能(单调和断裂韧性)将用于评估整体骨骼性能，如下所示 断裂抗力的替代措施。最后，在目标3中，我们将确定联合治疗， 靶向孔填充和填充基质的改性在改善力学性能方面更有效 CKD动物的特性与任何一种单一疗法相比较。我们已经证明，FDA批准的雷洛昔芬 骨治疗剂，特别有益于材料性能。此外，我们还开发了一部小说 雷洛昔芬的类似物，在减少传统细胞介导的基础上保持对骨基质的有利影响 效果。提议的实验将确定填充具有增强性能的孔的组合 将会带来整体的好处。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，并作为建立临床方案的平台 减轻退伍军人慢性肾脏病骨骼负担，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.