Systemic Bone Loss Following Fracture in Humans

项目概要/摘要： 骨折风险最可靠的预测因素是任何骨骼部位的既往骨折。这种疾病的病因 这种关系尚不完全清楚，但一种促成机制是骨折引发全身性骨丢失 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的全身性骨丢失反应。然而时过境迁 人类全身性骨丢失和恢复的过程和程度尚未研究， 目前尚不清楚系统性骨丢失是否对老年人和年轻人有不同的影响。解决 这些知识差距，我们将使用标准的临床和尖端的高分辨率成像， 表征人类受试者中肱骨骨折后的全身性骨丢失反应。我们假设 骨折后全身性骨丢失：1）肱骨骨折后将持续6个月或更长时间， 部分恢复，2）对松质骨的影响大于对皮质骨的影响，3）将延迟 并且相对于年轻受试者，老年受试者的恢复减少。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 在年轻（20-40岁）和老年（60-80岁）患者肱骨骨折后， 基线、3、6、18和36个月时的无脊椎骨骼部位（腰椎、双侧髋关节、胫骨和前臂） 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，我们还将 通过测量骨重建的血清生物标志物来研究全身性骨丢失的机制， 炎症和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 骨小梁和骨皮质间室在全身性骨丢失和恢复过程中的生物力学变化 在相同的患者骨折后，以及这些患者在年龄上的差异。使用临床定量计算 在同侧和对侧近端进行断层扫描（QCT）和高分辨率外周QCT（HR-pQCT） 股骨，胫骨和桡骨，我们将测量骨小梁和皮质密度和显微结构，并使用有限元 分析以估计骨的机械特性。总而言之，这些新的研究将揭示， 骨折后的骨丢失和恢复：1）发生在人类患者中类似于我们在小鼠中所示的情况， 但在更长的时间轴上，2）在轴向与非轴向骨骼部位和骨小梁部位具有不同的作用 vs.皮质骨，和3）影响老年人与年轻人不同，可能使老年受试者 骨质和强度永久性不足这些研究的结果可能最终会帮助我们 确定骨折后全身性骨丢失的机制，并将为治疗策略提供信息， 为骨折后保持患者骨骼健康提供了机会。

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.