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: 8646101
• 负责人: Chris Newman
• 金额: $ 3.16万
• 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 2018-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646101
• 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; Environment; Epidemic; Exhibits; Extracellular Matrix Proteins; Figs - dietary; Fracture; Gene Expression; Goals; Histology; Histopathology; Homeostasis; Hormones; Human; Hydration status; Intervention; Kidney; Kidney Diseases; Laboratories; Learning; Left Ventricular Mass; Life; Measurement; Measures; Mechanics; Metabolic; Minerals; Modeling; Morphology; Outcome; Parathyroid gland; Pathogenesis; Patients; Phenotype; 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; improved; kidney vascular structure; male; mineralization; physical property; prevent; primary outcome; public health relevance; 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-矿物质和骨疾病（CKD-MBD）导致复杂的骨骼和代谢表型。因此，晚期肾病患者骨折的风险增加。在与年龄相关的骨丢失患者中，骨矿物质密度（BMD）估计值是骨折发展的有用预测因素。然而，在CKD中，情况尚不清楚。虽然它可能是有用的，但其他代谢紊乱的存在表明，骨质量可能在CKD相关骨折的发病机制中发挥更大的作用，而不是与年龄相关的骨丢失。目前对CKD-MBD患者的治疗集中在抑制甲状旁腺激素升高。这是通过补充骨化三醇来实现的。虽然骨化三醇在骨质疏松患者中的作用已被研究，但其对CKD患者骨质量和骨折风险的影响目前尚不清楚。此外，最近的分析表明，雷洛昔芬，一种选择性雌激素受体调节剂，可能是一个有用的干预晚期肾病患者。这一点得到了雷洛昔芬治疗患者的有益肾脏结局以及证明改善骨质量的额外非细胞机制的证据的支持。因此，我们假设CKD导致骨质量改变，可以通过雷洛昔芬及其与骨化三醇的联合治疗来纠正。这将通过使用慢性进展性CKD-MBD模型（Cy/+大鼠）进行测试。本研究将比较正常和Cy/+大鼠的骨骼组织质量（与质量无关）。这将通过检查30周龄大鼠的骨质量变化来完成。具体而言，结局将包括组织水平的机械性能、矿化、胶原成分（交联、形态学和力学）和骨基质水合作用（MRI）。我们预期CKD大鼠表现出较低的骨强度、较低的矿化、较低的胶原硬度、较低的基质结合水和较高的胶原非酶交联。第二个主要目标是检查雷洛昔芬对Cy/+大鼠骨异常的影响。25周龄动物将接受5周治疗（相当于一个骨重建周期）。主要结局将通过骨骼分析（组织学、microCT、骨密度、力学测试和骨质量测量）确定，但也将评估CKD-MBD的生化、肾脏和血管成分。将进行基因表达分析，以开始识别参与生物力学骨质量变化的信号通路。我们预测雷洛昔芬将通过改善骨质量来改善骨的机械性能，而骨化三醇将通过增加骨量来改善机械性能。联合治疗应该通过积极影响质量和质量而超过所有其他治疗。了解CKD对骨质量的不利影响是预防这些患者骨折的关键一步。本研究通过在慢性肾脏疾病自发和进行性发展的大鼠模型中检查这些变化及其潜在的校正，为实现这一目标迈出了重要的一步。