Augmentation of Peak Bone Mass

与骨质疏松性骨折相关的主要危险因素之一是未能在成年早期获得足够的骨量。运动具有非侵入性骨吸收的巨大潜力，但一般运动方案仅在正常水平上最小限度地增加骨量，并依赖于高冲击、高幅度的负荷来实现这些骨积累。最近，我们发现，在低强度负荷方案的每个负荷周期之间插入短暂的休息间隔，就足以将方案从不影响骨细胞群体的方案转变为具有潜在成骨能力的信号。因此，在需要增强骨骼性能，但不能进行高冲击性运动的情况下，这种疗法可能特别适用。根据我们的初步数据和文献回顾，我们假设在骨骼生长过程中启动的低幅度、静止插入的机械载荷将增强成年哺乳动物的皮质骨特性。为了探索这一假设，我们将利用我们最近开发的非侵入性小鼠胫骨加载设备。设计了一系列五个特定的目标，以确定休息插入、低幅度负荷是否可以在雌性C57BLI6J小鼠中建立和维持增强的胫骨皮质骨特性。这些研究的最终目标是，我们将评估由静息插入负荷引起的皮质骨性能增强是否足以抵消衰老和雌激素耗竭引起的退化。在基础水平上，这些研究将为年轻的生长骨骼如何对机械负荷做出反应提供独特的见解，并将提供信息的基线，我们将在未来开始探索特定的基因改变(例如，通过转基因或基因敲除小鼠)如何影响骨骼中的机械转导。在应用层面上，休息插入、低幅度、非侵入性负荷显著增加并保持小鼠皮质骨特性的结果将使我们的团队处于开始探索这一概念在人类受试者中的有效性的位置。

One of the primary risk factors associated with osteoporotic fractures is the failure to achieve sufficient bone mass during early adulthood. Exercise holds substantial potential for non-invasive bone accretion, but general exercise protocols only minimally enhance bone mass over normal levels and rely upon high impact, high magnitude loading to achieve these bone gains. Recently, we found that inserting a brief rest interval between each load cycle of a low magnitude loading regimen is sufficient to transform the protocol from one that does not influence bone cell populations into a signal that is potently osteogenic. This regimen may therefore be particularly amenable to application in conditions where enhanced bone properties are desirable, but high impact exercise is not feasible. Based upon our preliminary data and a review of the literature, we hypothesize that low magnitude, rest-inserted, mechanical loading initiated during skeletal growth will enhance the cortical bone properties of adult mammals. To explore this hypothesis, we will capitalize on our recently developed non-invasive murine tibia loading device. A series of five Specific Aims have been designed to determine if rest-inserted, low magnitude loading can serve to build and maintain augmented tibial cortical bone properties in female C57BLI6J mice. The studies culminate with our final Aim, in which we will assess whether enhanced cortical bone properties induced by the rest-inserted loading are sufficient to counteract the degradation caused by aging and estrogen depletion. At a basic level, these studies will provide unique insight toward how young growing bones respond to mechanical loading, and will provide a baseline of information from which we will, in the future, begin to explore how specific genetic alterations (e.g., via transgenic or knockout mice) affect mechanotransduction in bone. At the applied level, an outcome in which rest-inserted, low magnitude, non-invasive loading significantly augments and maintains murine cortical bone properties would place our group in position to begin to explore the efficacy of this concept in human subjects.