Assessing and modifying bone quality in chronic kidney disease

评估和改变慢性肾病患者的骨质量

• 批准号: 9137684
• 负责人: Chris Newman
• 金额: $ 4.05万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2017-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137684
• 关键词: Affect; Age-Related Bone Loss; Animal Model; Animals; Binding; Biochemical; Biology; Biomechanics; Blood Pressure; Bone Density; Bone Diseases; Bone Matrix; Bone remodeling; Calcitriol; Cardiovascular Diseases; Chronic Kidney Failure; Clinical Research; Clinical Trials; Collagen; Combined Modality Therapy; Complex; Creatinine; Development; Epidemic; Exhibits; Extracellular Matrix Proteins; Figs - dietary; Fracture; Gene Expression; Goals; Health; Histology; Histopathology; Homeostasis; Human; Hydration status; Intervention; Kidney; Kidney Diseases; Laboratories; Left Ventricular Mass; Life; Measurement; Measures; Mechanics; Metabolic; Minerals; Modeling; Morphology; Osteoporotic; Outcome; PTH gene; Pathogenesis; Patients; Plasma; Play; Property; Proteinuria; Raloxifene; Rattus; Renal function; Risk; Role; Safety; Secondary Hyperparathyroidism; Selective Estrogen Receptor Modulators; Signal Pathway; Staging; Supplementation; Testing; Tissues; Vascular calcification; Vitamin D; Water; Work; bone; bone cell; bone mass; bone quality; bone strength; calcification; calcium phosphate; chemical property; crosslink; drug efficacy; educational atmosphere; improved; kidney vascular structure; male; metabolic phenotype; microCT; mineralization; physical property; prevent; primary outcome; response; skeletal; skeletal abnormality; skeletal tissue

DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) results in complex skeletal and metabolic phenotypes. Because of this, patients with advanced kidney disease have an increased risk of fractures. In patients with age-related bone loss, bone mineral density (BMD) estimates are a helpful predictor of fracture development. In CKD, however, the picture is unclear. While it may be of use, the presence of other metabolic derangements indicate that bone quality likely plays a greater role in the pathogenesis of CKD-related fractures than in those associated with age-related bone loss. Current treatment in patients with CKD-MBD is focused on suppressing elevations in parathyroid hormone. This is accomplished by calcitriol supplementation. While the effect of calcitriol in osteoporotic patients has been studied, its impact on bone quality and fracture risk n CKD patients is currently unknown. Also, recent analyses suggest that raloxifene, a selective estrogen receptor modulator, might be a useful intervention for patients with late stage kidney disease. This is supported by beneficial renal outcomes in patients on raloxifene as well as evidence demonstrating an additional non-cellular mechanism by which to improve bone quality. So, we hypothesized that CKD leads to alterations in bone quality that can be corrected by raloxifene and its combination with calcitriol. This will be tested through the use of a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will compare the quality of skeletal tissue (independently of mass) in normal and Cy/+ rats. This will be accomplished by examining bones from 30-week-old rats for changes in bone quality. Specifically, outcomes will include tissue-level mechanical properties, mineralization, collagen composition (cross-linking, morphology, and mechanics), and bone matrix hydration (MRI). We expect rats with CKD to display lower bone strength, lower mineralization, lower collagen stiffness, lower matrix-bound water, and higher non-enzymatic cross-linking of collagen. The second major goal is to examine the effects of raloxifene on bone abnormalities present in Cy/+ rats. 25-week-old animals will be treated for 5 weeks (equivalent to one bone remodeling cycle). Primary outcomes will be determined by skeletal analyses (histology, microCT, bone density, mechanical testing, and bone quality measures), though the biochemical, renal, and vascular components of CKD-MBD will be assessed as well. Gene expression analyses will be performed to begin to identify signaling pathways involved in changes in biomechanical bone quality. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality, while calcitriol will improve mechanical properties by increasing bone mass. Combination therapy should exceed all other treatments by positively impacting both quality and mass. An understanding of the detrimental impact of CKD on bone quality is a crucial step in preventing fractures in these patients. This study provides an important step in achieving this goal by examining these changes and their potential corrections in a rat model with the spontaneous and progressive development of chronic kidney disease.

描述（由申请人提供）：慢性肾脏疾病矿物质和骨病（CKD-MBD）导致复杂的骨骼和代谢表型。因此，晚期肾脏疾病患者的骨折风险增加。在与年龄相关的骨质流失的患者中，骨矿物质密度（BMD）估计值是断裂发育的有助于预测指标。但是，在CKD中，图片尚不清楚。虽然它可能使用，但其他代谢紊乱的存在表明，与与年龄相关的骨质流失相关的骨骼质量在与CKD相关骨折的发病机理中可能起更大的作用。当前在CKD-MBD患者中的治疗集中于抑制甲状旁腺激素的升高。这是通过补充钙三醇来完成的。尽管已经研究了骨化三醇对骨质疏松患者的影响，但目前尚不清楚其对骨质质量和骨折风险N CKD患者的影响。此外，最近的分析表明，选择性雌激素受体调节剂Raloxifene可能是晚期肾脏疾病患者的有用干预措施。这得到了雷昔芬患者的有益肾脏结局的支持，以及证明了提高骨质质量的其他非细胞机制。因此，我们假设CKD会导致骨质量的改变，这可以通过雷昔芬及其与钙三醇的结合来纠正。这将通过使用CKD-MBD（CY/+大鼠）缓慢进行的模型来测试。这项研究将比较正常和CY/+大鼠骨骼组织（与质量无关）的质量。这将通过检查30周龄大鼠的骨骼来实现这一目标，以改变骨质的变化。具体而言，结果将包括组织级的力学特性，矿化，胶原蛋白组成（交联，形态和力学）以及骨基质水合（MRI）。我们期望具有CKD的大鼠显示出较低的骨强度，较低的矿化，较低的胶原蛋白刚度，较低的基质结合水以及胶原蛋白的较高的非酶交联。第二个主要目标是检查雷昔芬对CY/+大鼠中存在的骨异常的影响。 25周大的动物将进行5周（相当于一个骨重塑周期）。主要结果将通过骨骼分析（组织学，微观骨骼密度，机械测试以及骨质质量测量）来确定，尽管也将评估CKD-MBD的生化，肾脏和血管成分。将进行基因表达分析，以开始识别与生物力学骨质变化有关的信号通路。我们预测，雷昔芬将通过改善骨骼质量来改善骨骼的机械性能，而钙三醇将通过增加骨骼质量来改善机械性能。联合疗法应通过积极影响质量和质量来超越所有其他治疗方法。了解CKD对骨质质量的有害影响是防止这些患者骨折的关键步骤。这项研究通过检查这些变化及其在大鼠模型中的潜在校正来实现这一目标的重要一步，并通过慢性肾脏疾病的自发和渐进发展。