The impact of glomerular disorders on bone quality and strength

肾小球疾病对骨质量和强度的影响

• 批准号: 10226160
• 负责人: Michelle Denburg
• 金额: $ 66.92万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226160
• 关键词: 18 year old; 3-Dimensional; Academic Medical Centers; Adolescent; Adult; Age; Age-Years; Biochemical; Biological Markers; Biomechanics; Biopsy; Biopsy Specimen; Body mass index; Bone Density; Bone Matrix; Bone Mineral Contents; Child; Childhood; Chronic Kidney Failure; Clinical; Cohort Studies; Competence; Data; Databases; Defect; Development; Devices; Diabetes Mellitus; Disease; Dose; Dual-Energy X-Ray Absorptiometry; Electronic Health Record; Exposure to; Finite Element Analysis; Fracture; Funding; Future; Generations; Glucocorticoids; Health; Health system; Hip Fractures; Hip region structure; Impairment; Inflammation; Inflammatory; Infrastructure; Intervention Trial; Knowledge; Label; Longitudinal Studies; Measures; Mechanics; Metabolism; Methods; Minerals; Morbidity - disease rate; Multi-Institutional Clinical Trial; Multicenter Studies; Nephrotic Syndrome; Neptune; Osteitis; Osteomalacia; Outcome; Participant; Pathogenesis; Pathogenicity; Patients; Pediatric Hospitals; Pennsylvania; Peripheral; Pharmaceutical Preparations; Philadelphia; Prevention strategy; Property; Prospective Studies; Prospective cohort study; Proteinuria; Race; Radial; Raman Spectrum Analysis; Recording of previous events; Renal Osteodystrophy; Renal function; Renal glomerular disease; Reporting; Resolution; Resources; Risk; Risk Factors; Seminal; Severities; Severity of illness; Skeleton; Spectrum Analysis; Spinal Fractures; Tetracyclines; Tissues; United States National Institutes of Health; Universities; Urine; Vertebral column; Vitamin D; Work; X-Ray Computed Tomography; base; bone; bone health; bone imaging; bone loss; bone mass; bone quality; bone strength; bone turnover; cohort; fracture risk; immunomodulatory therapies; insight; mechanical properties; microCT; mineralization; modifiable risk; nanoindentation; population based; prospective; sex; skeletal; tibia; young adult

PROJECT SUMMARY Children and adolescents with glomerular disease have unique and potentially modifiable risk factors for compromised bone health, but our current understanding of skeletal fragility in glomerular disease is lacking. In the first large population-based cohort study, we recently found that primary glomerular disease was independently associated with a >45% increased risk of incident spine and hip fracture, and that hip fracture risk was >1.5-fold greater in patients younger vs. older than 40 years of age. Mechanisms that drive increased fracture risk in glomerular disease are not clear but likely multifactorial. Our prior work in the Neptune cohort demonstrated that glomerular disease is associated with disturbances in vitamin D and mineral metabolism, and patients with glomerular disease are also exposed to medications which may negatively impact bone health. Identifying modifiable factors that compromise bone strength will facilitate the development of strategies to reduce fractures and other skeletal complications across the lifecourse. The primary objectives of this study are to: (1) determine the impact of glomerular disease on bone strength and (2) investigate the pathophysiologic underpinnings of impaired bone strength in glomerular disease. The proposed multi-center study will leverage the infrastructure of the NIH-funded CureGN prospective cohort study and the resources of two health systems [Children's Hospital of Philadelphia (CHOP)/University of Pennsylvania (Penn) and Columbia University Medical Center] with expertise in state-of-the-art high-resolution bone imaging and biopsy methods, to conduct the first prospective, longitudinal study to assess determinants of impaired bone quality and strength in glomerular disease. 150 CureGN participants (100 adults/50 children) and 120 age-, sex-, race-, and body mass index- matched healthy reference participants will be evaluated at baseline and 12 months. The new 2nd generation high-resolution peripheral quantitative computed tomography (HR-pQCT) device will be used to assess bone microarchitecture and generate micro-finite element analysis (µFEA) estimates of bone strength. We will also determine the DXA measures of areal BMD and bone mineral content (whole body, spine, hip and radius) that reflect bone deficits captured by HR-pQCT. Tetracycline double labeled transiliac crest bone biopsy specimens will be collected from a subset of 40 adult CureGN participants and analyzed by 2D histomorphometry; by microCT for 3D cortical and trabecular microarchitecture and estimated strength by finite element analysis; and by Nanoindentation/Raman spectroscopy for bone mechanical and matrix-level characterization. Concurrent clinical and biochemical profiling will allow for assessment of predictors of prospective changes in biomechanical competence and cortical and trabecular microarchitecture by HR-pQCT as well as tissue-level bone matrix and mechanical properties. The results of this study will serve specifically to inform future multicenter clinical trials of interventions to mitigate the effects of glomerular disease on bone health and fracture risk in children and adults with glomerular disease.

项目概要 患有肾小球疾病的儿童和青少年具有独特且潜在可改变的危险因素 骨骼健康受到损害，但我们目前对肾小球疾病中的骨骼脆弱性缺乏了解。在 在第一个基于人群的大型队列研究中，我们最近发现原发性肾小球疾病是 与发生脊柱和髋部骨折的风险增加 >45% 独立相关，并且髋部骨折风险增加 与 40 岁以上患者相比，年轻患者的患病率高出 1.5 倍以上。驱动机制增加 肾小球疾病中的骨折风险尚不清楚，但可能是多因素造成的。我们之前在海王星队列中的工作 证明肾小球疾病与维生素 D 和矿物质代谢紊乱有关，并且 肾小球疾病患者还会接触可能对骨骼健康产生负面影响的药物。 识别损害骨强度的可改变因素将有助于制定策略 减少整个生命过程中的骨折和其他骨骼并发症。本研究的主要目标是 目的：(1) 确定肾小球疾病对骨强度的影响；(2) 研究肾小球疾病的病理生理学 肾小球疾病中骨强度受损的基础。拟议的多中心研究将利用 NIH 资助的 CureGN 前瞻性队列研究的基础设施和两个卫生系统的资源 [费城儿童医院 (CHOP)/宾夕法尼亚大学 (Penn) 和哥伦比亚大学医学院 中心] 拥有最先进的高分辨率骨成像和活检方法的专业知识，首次进行 评估肾小球骨质量和强度受损的决定因素的前瞻性纵向研究 疾病。 150 名 CureGN 参与者（100 名成人/50 名儿童）和 120 名年龄、性别、种族和体重指数 - 将在基线和 12 个月时对匹配的健康参考参与者进行评估。新2代 高分辨率外周定量计算机断层扫描 (HR-pQCT) 设备将用于评估骨骼 微架构并生成骨强度的微有限元分析 (µFEA) 估计值。我们还将 确定 DXA 面积 BMD 和骨矿物质含量（全身、脊柱、髋部和桡骨）测量值， 反映 HR-pQCT 捕获的骨缺损。四环素双标记经髂嵴骨活检标本 将从 40 名成年 CureGN 参与者的子集中收集并通过 2D 组织形态计量学进行分析；经过 用于 3D 皮质和小梁微结构的 microCT，并通过有限元分析估计强度；和 通过纳米压痕/拉曼光谱进行骨机械和基质水平表征。并发 临床和生化分析将允许评估生物力学预期变化的预测因素 通过 HR-pQCT 以及组织水平骨基质和 机械性能。这项研究的结果将专门为未来的多中心临床试验提供信息 减轻肾小球疾病对儿童和成人骨骼健康和骨折风险影响的干预措施 患有肾小球疾病。