Identification of Key Loading Parameters for Bone Functional Adaptation

骨功能适应关键负载参数的识别

• 批准号: 8084246
• 负责人: Gary Beaupre
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084246
• 关键词: Affect; American; Animal Model; Animals; Biomechanics; Bone remodeling; C57BL/6 Mouse; Characteristics; Complex; Dose; Elderly; Exercise; Female; Forelimb; Fracture; Frequencies; Future; Goals; Health; Human; Investigation; Knowledge; Lead; Life; Life Style; Maintenance; Measures; Mechanics; Minerals; Mouse Strains; Mus; Osteogenesis; Osteoporosis; Physical activity; Physiological; Process; Protocols documentation; Quality of life; Recommendation; Relative (related person); Reporting; Research; Rest; Risk; Skeleton; Stimulus; Surgeon; Testing; Time; Tissues; Veterans; Weight; Weight-Bearing state; base; bone; bone health; bone mass; combat; design; improved; intervention program; male; mouse model; novel strategies; research study; response; skeletal

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. PUBLIC HEALTH RELEVANCE: Osteoporosis is a major US heath concern that affects both males and females and both veterans and non- veterans alike. It is estimated that 1.2 million male veterans over the age of 65 has osteoporosis. One out of two female veterans and one out of four male veterans will sustain an osteoporosis-related fracture in their lifetime. Maintaining a physically active lifestyle is the most common recommendation for reducing the risk of osteoporosis. The US Surgeon General recently concluded that the current state of scientific "evidence does not lead to a specific set of exercises or practices" for promoting skeletal health. The minimal or optimal amount and type of physical activity for maintaining skeletal health is unknown. The proposed study will add to our knowledge of the biomechanical factors that affect bone maintenance and adaptation. The results of this research have the potential to influence the design of future exercise intervention programs to combat osteoporosis, reduce the risk of fragility fractures, and improve the quality of life of veterans.

描述（由申请人提供）： 骨质疏松症是一个主要的和日益增长的美国健康问题。目前约有4400万美国人患有骨质疏松症或低骨量，并且脆性骨折的风险增加。每两名女性退伍军人中就有一人，每四名男性退伍军人中就有一人在一生中会发生与骨质疏松症有关的骨折。根据男女退伍军人的比例（12比1），预计男性退伍军人在一生中遭受脆性骨折的人数是女性退伍军人的近六倍。保持一种包括足够的日常负重活动的生活方式是降低骨质疏松症风险的最常见建议。在2004年的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，“证据并不导致一套特定的锻炼或实践”来保持骨骼健康。因此，用于维持健康骨骼的身体活动的量、类型和强度是未知的。 动物研究中，所有方面的外部负荷可以有条不紊地控制提供了最强大的方法来了解复杂的机械生物学过程，控制骨重建和骨骼适应。对活体动物骨骼施加外部载荷提供了大量关于骨骼如何适应日常机械载荷的基本信息。然而，在我们对定义任何负荷或锻炼方案的各种参数之间的关系的了解中，仍然存在关键的差距（例如，每日负荷循环次数、负荷幅度、负荷频率）及其对骨适应性反应的影响。本研究的目的是更好地了解调节骨功能适应的外源性负荷方案的关键参数之间的关系。 以前的外源性载荷动物研究的一个重要问题是，由于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，因此不同研究的结果往往难以比较。由于已知此类研究中的骨形成随着每天循环次数的增加和应变幅度的增加而增加，因此这两个载荷参数的不同组合可以产生相当的结果，因此难以或不可能确定每个参数的相对贡献。最近，我们的研究小组已经表明，具有看似不同结果的多个动物研究可以使用称为每日应变刺激（DSS）的单个参数来统一，该参数使用加权指数将每日负荷循环次数和应变幅度结合起来，该指数确定每个对总骨刺激的相对贡献。拟议的研究将使用这种统一的方法来分析一组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。 将16周龄雌性小鼠暴露于右前肢的非侵入性外源性负荷。将根据每日应变刺激对加载方案进行量化。将对五种实验方案进行研究。在第一个实验中，外源载荷将以2 Hz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载荷幅度。第二个方案旨在复制方案1中选定的DSS值，但每天循环次数和应变幅度的组合明显不同，以测试循环次数和应变幅度之间的预期二元性。第三个方案将研究在每个加载循环之间插入10 s休息期的影响。第四个方案将研究在10 Hz下加载的影响。最终方案将联合收割机结合10 Hz负载和其余插入设计。在所有情况下，我们预计DSS将是骨适应的强有力预测因素。这项拟议中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，以对抗人类骨质疏松症。 公共卫生相关性： 骨质疏松症是一个主要的美国健康问题，影响男性和女性，退伍军人和非退伍军人一样。据估计，120万65岁以上的男性退伍军人患有骨质疏松症。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其一生中会遭受与糖尿病有关的骨折。保持身体活跃的生活方式是降低骨质疏松症风险的最常见建议。美国卫生局局长最近得出结论，目前的科学“证据并没有导致一套特定的运动或实践”，以促进骨骼健康。维持骨骼健康的最小或最佳体力活动量和类型尚不清楚。这项研究将增加我们对影响骨维持和适应的生物力学因素的认识。这项研究的结果有可能影响未来运动干预计划的设计，以对抗骨质疏松症，降低脆性骨折的风险，并提高退伍军人的生活质量。