The impact of glomerular disorders on bone quality and strength

项目摘要 患有肾小球疾病的儿童和青少年有独特的和潜在的可改变的危险因素， 损害骨骼健康，但我们目前缺乏对肾小球疾病中骨骼脆弱性的了解。在 作为第一个大规模人群队列研究，我们最近发现原发性肾小球疾病是 与脊柱和髋部骨折发生风险增加>45%独立相关，且髋部骨折风险 在40岁以上的患者中，年轻患者比老年患者高1.5倍。推动增长的机制 肾小球疾病的骨折风险尚不清楚，但可能是多因素的。我们之前在海王星星系的研究 证明肾小球疾病与维生素D和矿物质代谢紊乱有关， 患有肾小球疾病的患者也暴露于可能对骨骼健康产生负面影响的药物。 确定影响骨强度的可变因素将有助于制定策略， 减少骨折和其他骨骼并发症的发生。本研究的主要目的是 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变化。 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， 一项前瞻性纵向研究，评估肾小球骨质量和强度受损的决定因素 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个月时评估匹配的健康参考参与者。新的第二代 将使用高分辨率外周定量计算机断层扫描（HR-pQCT）设备评估骨 微结构和生成骨强度的微观有限元分析（µFEA）估计。我们还将 确定DXA测量区域BMD和骨矿物质含量（全身、脊柱、髋关节和桡骨）， 反映HR-pQCT捕获的骨缺损。四环素双标记髂嵴间骨活检标本 将从40名成人CureGN参与者的亚组中收集，并通过2D组织形态计量学进行分析; 用于3D皮质和小梁微结构的microCT和通过有限元分析估计的强度;以及 通过纳米压痕/拉曼光谱进行骨机械和基质水平表征。并发 临床和生物化学分析将允许评估生物力学的预期变化的预测因子， 通过HR-pQCT以及组织水平骨基质测定的能力和皮质和小梁微结构， 力学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 肾小球疾病

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.