Identification of Key Loading Parameters for Bone Functional Adaptation

描述(由申请人提供)： 骨质疏松症是美国一个主要且日益严重的健康问题。目前约有4400万美国人患有骨质疏松症或骨量减少，并面临更高的脆性骨折风险。每两名女性退伍军人中就有一名，每四名男性退伍军人中就有一名在有生之年患上骨质疏松症相关骨折。根据男性和女性退伍军人的比例(12：1)，预计男性退伍军人一生中遭受脆性骨折的人数几乎是女性退伍军人的六倍。保持一种包括足够的日常负重活动的生活方式是最常见的降低骨质疏松风险的建议。在2004年一份关于骨骼健康和骨质疏松症的报告中，美国卫生局局长得出结论，“证据并没有导致一套特定的锻炼或实践”来维持骨骼健康。因此，维持健康骨骼的体力活动的数量、类型和强度尚不清楚。在动物实验中，外部负荷的所有方面都可以被有条不紊地控制，这为理解控制骨重塑和骨骼适应的复杂机械生物学过程提供了最可靠的方法。在活体动物骨骼上施加外部载荷已经提供了关于骨骼如何适应日常机械载荷的丰富的基本信息。然而，在定义任何负荷或运动方案的各种参数之间的关系(例如，每天负荷循环的次数、负荷大小、负荷频率)以及它们对骨适应性反应的影响方面，我们仍然存在关键的差距。该研究的目的是为了更好地了解外源性负荷方案中调节骨功能适应的关键参数之间的关系。以前关于外源性载荷的动物研究的一个重要问题是，不同研究的结果往往很难比较，因为每天的载荷循环和施加的载荷或应变大小有许多不同的组合。由于这类研究中的骨形成随着每天循环次数的增加和应变大小的增加而增加，这两个加载参数的不同组合可以产生类似的结果，因此很难或不可能确定每个参数的相对贡献。最近，我们的研究小组发现，使用一个名为每日应变刺激(DSS)的参数可以统一多个动物研究，结果似乎不同，DSS使用加权指数将每日载荷循环的次数和应变大小结合在一起，该加权指数确定了每个参数在总骨骼刺激中的相对贡献。这项拟议的研究将使用这种统一的方法来分析一套全面和系统的实验结果，以研究小鼠模型中的外源性负荷和骨适应。16周龄的雌性小鼠将暴露在非侵入性的、外源性的右前肢负载中。加载方案将根据每日的应变刺激进行量化。我们将研究五个实验方案。在第一个实验中，外源负载将以2赫兹的频率每天施加100个循环，使用跨越DSS值目标范围的五个不同的负荷量。第二个方案旨在复制方案1中选定的DSS值，但使用明显不同的每天循环和应变大小的组合来测试循环和应变大小之间的预期二元性。第三个方案将研究在每个加载周期之间插入10s休息期的效果。第四个方案将研究10赫兹负载的影响。最终的协议将结合10赫兹加载和静止插入设计。在所有情况下，我们预计DSS将是骨适应的有力预测指标。这项拟议的研究将增加我们对影响骨骼健康的生物力学因素的了解。这项研究的结果有可能影响未来运动干预计划的设计，以对抗人类的骨质疏松症。

DESCRIPTION (provided by applicant): Osteoporosis is a major and growing US heath concern. Approximately 44 million Americans currently have osteoporosis or low bone mass and are at an increased risk of a fragility fracture. One out of every two female veterans and one out of every four male veterans will have an osteoporosis-related fracture in their lifetime. Based on the ratio of male to female veterans (12 to 1), nearly six times as many male veterans as female veterans can be expected to sustain a fragility fracture in their lifetime. Maintaining a lifestyle that includes adequate daily weight-bearing activity is the most common recommendation for reducing the risk of osteoporosis. In a 2004 report on bone health and osteoporosis the US Surgeon General concluded that "the evidence does not lead to a specific set of exercises or practices" for maintaining skeletal health. Thus, the amount, type and intensity of physical activity for maintaining a healthy skeleton is not known. Animal studies in which all aspects of the external loading can be methodically controlled offer the most robust approach for understanding the complex mechanobiological processes that control bone remodeling and skeletal adaptation. The application of external loads to the bones of living animals has provided a wealth of fundamental information about how bone adapts to daily mechanical loading. There remain critical gaps, however, in our knowledge of the relationships among the various parameters that define any loading or exercise protocol (e.g., number of daily loading cycles, loading magnitude, loading frequency) and their influence on the bone adaptive response. The objective of the proposed study is to better understand the relationships among key parameters of exogenous loading protocols that modulate bone functional adaptation. An important concern with previous animal studies with exogenous loading is that the results from different studies are often difficult to compare because of the many different combinations of load cycles per day and applied loading or strain magnitudes. Since bone formation in such studies is known to increase with increasing number of cycles per day and increasing strain magnitude, different combinations of these two loading parameters can yield comparable results, thus making it difficult or impossible to determine the relative contribution of each parameter. Recently, our research group has shown that multiple animal studies with seemingly disparate results can be unified using a single parameter called the daily strain stimulus (DSS), which combines the number of daily load cycles and the strain magnitude using a weighting exponent that determines the relative contribution of each to the total bone stimulus. The proposed study will use this unifying approach to analyze the results of a comprehensive and systematic set of experiments to study exogenous loading and bone adaptation in a mouse model. Sixteen-week old female mice will be exposed to non-invasive, exogenous loading of the right forelimb. Loading protocols will be quantified in terms of the daily strain stimulus. Five experimental protocols will be examined. In the first experiment, the exogenous loading will be applied for 100 cycles per day applied at a frequency of 2 Hz using five different load magnitudes that span the target range of DSS values. The second protocol is designed to duplicate selected DSS values from protocol 1, but with markedly different combinations of cycles per day and strain magnitude to test for the expected duality between cycles and strain magnitude. The third protocol will study the effect of a 10s rest period inserted between each loading cycle. The fourth protocol will study the effect of loading at 10 Hz. The final protocol will combine the 10 Hz loading with the rest insertion design. In all cases, we expect that the DSS will be a strong predictor of bone adaptation. The proposed study will add to our knowledge of the biomechanical factors that affect skeletal health. The results of this research have the potential to influence the design of future exercise intervention programs to combat osteoporosis in humans.