The impact of glomerular disorders on bone quality and strength

项目总结 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 损害了骨骼健康，但我们目前对肾小球疾病中骨骼脆性的了解还很缺乏。在……里面 第一项基于人群的大型队列研究，我们最近发现，原发性肾小球疾病是 独立与脊柱和髋部骨折风险增加45%，以及髋部骨折风险 年龄小于40岁的患者比年龄大于40岁的患者多1.5倍。驱动机制增加 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，以及 肾小球疾病患者也会接触到可能对骨骼健康产生负面影响的药物。 确定影响骨骼强度的可修改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。这项研究的主要目标是 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 肾小球疾病中骨质强度受损的基础。拟议的多中心研究将利用 美国国立卫生研究院资助的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(宾夕法尼亚)和哥伦比亚大学医学院 中心]拥有最先进的高分辨率骨骼成像和活组织检查方法的专业知识，进行第一次 评估肾小球骨质质量和强度受损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- 匹配的健康参考参与者将在基线和12个月时进行评估。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)设备来评估骨骼 微体系结构和生成骨强度的微有限元分析(µFEA)估计。我们还将 确定区域骨密度和骨矿含量(全身、脊柱、髋部和桡骨)的DXA测量 反映HR-pQCT捕捉到的骨量不足。四环素双标记胸骨活检骨标本 将从40名成年CureGN参与者中收集，并通过2D组织形态计量学进行分析； 三维皮质和骨小梁微结构的微CT和通过有限元分析估计的强度；以及 通过纳米压痕/拉曼光谱进行骨力学和基质水平的表征。并发 临床和生化分析将允许评估生物力学未来变化的预测因素 HR-pQCT和组织水平的骨基质和骨小梁微结构的能力 机械性能。这项研究的结果将特别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。

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.