Systemic Bone Loss Following Fracture in Humans

人类骨折后的全身性骨质流失

• 批准号: 10660721
• 负责人: Blaine A. Christiansen
• 金额: $ 79.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660721
• 关键词: Accelerometer; Address; Affect; Age; American; Automobile Driving; Bilateral; Biological Markers; Biomechanics; Bone Density; Bone Mineral Contents; Bone callus; Bone remodeling; Clinical; Clinical Data; Contralateral; Data; Dual-Energy X-Ray Absorptiometry; Elderly; Epidemiology; Etiology; Failure; Femoral Fractures; Femur; Finite Element Analysis; Forearm; Fracture; Future; Goals; Health; Hip region structure; Human; Humeral Fractures; Image; Individual; Ipsilateral; Knowledge; Limb structure; Measures; Minerals; Mus; Osteitis; Osteoporosis; Patients; Peripheral; Persons; Physical activity; Porosity; Process; Questionnaires; Radial; Recording of previous events; Recovery; Research; Resolution; Serum; Site; Skeleton; Structure; Testing; Therapeutic; Time; Tissues; Upper Extremity Fracture; Upper arm; Vertebral column; Width; X-Ray Computed Tomography; age related; aging population; bone; bone loss; bone mass; bone quality; bone strength; cortical bone; cost; density; fall risk; fracture risk; high resolution imaging; human subject; improved; mechanical properties; novel; osteoporosis with pathological fracture; partial recovery; preclinical study; recruit; response; response to injury; skeletal; skeletal preservation; substantia spongiosa; systemic inflammatory response; therapeutic target; therapeutically effective; tibia; timeline

Project Summary/Abstract: The most reliable predictor of fracture risk is a previous fracture at any skeletal site. The etiology of this relationship is not fully known, but one contributing mechanism is that fracture initiates a systemic bone loss response, which increases future fracture risk at all skeletal sites. Our lab has generated multiple preclinical studies characterizing this systemic bone loss response following femur fracture in mice. However, the time course and magnitude of systemic bone loss and recovery in humans has not been investigated, and it is currently unknown if systemic bone loss differentially affects older people compared to young people. To address these knowledge gaps, we will use both standard clinical and cutting-edge high-resolution imaging to characterize the systemic bone loss response following a humerus fracture in human subjects. We hypothesize that post-fracture systemic bone loss: 1) will persist for 6 months or more after a humerus fracture followed by partial recovery, 2) will have a greater effect on trabecular bone than on cortical bone, and 3) will have delayed and diminished recovery in older subjects relative to younger subjects. To investigate these hypotheses, we will first determine the time course and magnitude of systemic bone mineral density (BMD) loss and recovery following humerus fracture in young (20-40 years old) and old (60-80 years old) human patients at axial and appendicular skeletal sites (lumbar spine, bilateral hips, tibiae, and forearms) at baseline, 3, 6, 18, and 36 months post-fracture and compare these patients to non-fractured control subjects. At each time point we will also investigate mechanisms of systemic bone loss by measuring serum biomarkers of bone remodeling and inflammation and tracking patient physical activity using accelerometers. Next, we will determine microstructural and biomechanical changes in the trabecular and cortical compartments during systemic bone loss and recovery following fracture in the same patients and how these differ by age. Using clinical quantitative computed tomography (QCT) and high-resolution peripheral QCT (HR-pQCT) at the ipsilateral and contralateral proximal femur, tibia, and radius, we will measure trabecular and cortical density and microstructure and use finite element analysis to estimate mechanical properties of bone. Altogether, these novel studies will reveal that systemic bone loss and recovery following fracture: 1) occurs in human patients similar to what we have shown in mice, but on a much longer timeline, 2) has differential effects at axial vs. appendicular skeletal sites and in trabecular vs. cortical bone, and 3) affects older people differently than younger people, potentially leaving older subjects with permanent deficits in bone mass and strength. The findings from these studies may ultimately help us identify mechanisms of systemic bone loss following fracture, and will inform therapeutic strategies and establish windows of opportunity for preserving skeletal health of patients after a fracture.

项目摘要/摘要： 断裂风险的最可靠的预测因子是任何骨骼部位的骨折。这个病因 关系尚不清楚，但一种促成机制是断裂引发全身性骨质流失 反应，这会增加所有骨骼部位的未来断裂风险。我们的实验室已经产生了多个临床前 小鼠股骨断裂后这种全身性骨丢失反应的研究。但是，时间 尚未研究人类全身骨质流失和恢复的过程和幅度 目前，与年轻人相比，目前尚不清楚系统性骨质流失是否会影响老年人。解决 这些知识差距，我们将使用标准临床和尖端的高分辨率成像来 表征人类受试者肱骨骨折后的全身骨质损失反应。我们假设 裂缝后的全身骨质流失：1）肱骨骨折后将持续6个月或更长时间 部分恢复，2）对小梁骨有更大的影响，而对皮质骨的影响更大，而3）将延迟 相对于年轻受试者，老年受试者的恢复减少。为了调查这些假设，我们将 首先确定全身骨矿物质密度（BMD）损失和恢复的时间过程和大小 在年轻（20-40岁）和轴向和老年患者（60-80岁）的肱骨骨折之后 基线3、6、18和36个月的阑尾骨骼部位（腰椎，双侧臀部，胫骨和前臂） 骨折后并将这些患者与非裂缝对照受试者进行比较。在每个时间点，我们也会 通过测量骨骼重塑的血清生物标志物和 使用加速度计的炎症和跟踪患者体育锻炼。接下来，我们将确定微观结构 系统骨质流失和恢复期间小梁和皮质隔室的生物力学变化 在同一患者的骨折之后以及这些因年龄的差异。使用临床定量计算 在同侧和对侧近端，断层扫描（QCT）和高分辨率外围QCT（HR-PQCT） 股骨，胫骨和半径，我们将测量小梁和皮质密度和微观结构，并使用有限元素 分析以估计骨骼的机械性能。这些新颖的研究总之将揭示系统性 骨折后的骨质流失和恢复：1）发生在人类患者中，类似于我们在小鼠中所显示的类似 但是在更长的时间表上，2）在轴向与阑尾骨骼部位和小梁中具有差异效应 与皮质骨头，3）对老年人的影响不同于年轻人，可能会留下老年人 骨骼质量和力量的永久缺陷。这些研究的发现最终可能会帮助我们 确定裂缝后全身骨质流失的机制，并将为治疗策略提供信息并建立 骨折后保存患者骨骼健康的机会窗口。