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： 骨折风险最可靠的预测因素是任何骨骼部位既往骨折史。此现象的病因学 关系尚不完全清楚，但其中一个机制是骨折引发全身性骨质流失 反应，这会增加所有骨骼部位未来骨折的风险。我们的实验室已经产生了多个临床前 研究描述了小鼠股骨骨折后这种全身性骨质流失反应。然而，时间 人类全身性骨质流失和恢复的过程和程度尚未得到研究，但 目前尚不清楚全身性骨质流失对老年人和年轻人的影响是否有所不同。致地址 为了弥补这些知识差距，我们将使用标准临床和尖端高分辨率成像来 表征人类肱骨骨折后的全身性骨质流失反应。我们假设 骨折后全身性骨质流失： 1) 肱骨骨折后会持续 6 个月或更长时间，然后 部分恢复，2) 对小梁骨的影响比对皮质骨的影响更大，3) 会延迟 与年轻受试者相比，老年受试者的恢复速度较慢。为了研究这些假设，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幅度 年轻（20-40 岁）和老年（60-80 岁）人类患者的肱骨骨折后，轴向和 基线、3、6、18 和 36 个月时的阑尾骨骼部位（腰椎、双侧髋部、胫骨和前臂） 骨折后并将这些患者与非骨折对照受试者进行比较。在每个时间点我们也会 通过测量骨重建的血清生物标志物来研究全身性骨质流失的机制 炎症并使用加速度计跟踪患者的身体活动。接下来，我们将确定微观结构 全身性骨质流失和恢复过程中小梁和皮质室的生物力学变化 同一患者骨折后的情况以及这些患者随年龄的不同有何不同。使用临床定量计算 同侧和对侧近端断层扫描 (QCT) 和高分辨率外周 QCT (HR-pQCT) 股骨、胫骨和桡骨，我们将测量小梁和皮质密度和微观结构，并使用有限元 分析来估计骨骼的机械特性。总而言之，这些新颖的研究将揭示系统性的 骨折后的骨质流失和恢复：1）在人类患者中发生的情况与我们在小鼠中所显示的情况类似， 但在更长的时间轴上，2）在轴向与附肢骨骼部位以及小梁上有不同的影响 与皮质骨相比，3）对老年人的影响与年轻人不同，可能会留下老年受试者 骨量和强度永久性缺陷。这些研究的结果最终可能会帮助我们 确定骨折后全身性骨质流失的机制，并将为治疗策略提供信息并建立 骨折后保持患者骨骼健康的机会之窗。