A prospective study of human bone adaptation using a novel in-vivo loading model

描述（由申请人提供）：体力活动和运动导致骨内发生机械应变，从而启动适应性成骨反应。由于这一过程，在生长期和青年期进行锻炼已被证明可以增加峰值骨量并改善骨机械性能，从而提供终身保护，防止骨质疏松症。在动物中，机械应变量和应变率是与骨适应程度相关的两个关键变量，随着这些变量中的每一个的增加，发生成骨反应增加。虽然相同的机制可能会影响人类的骨骼适应，但这种动物数据的翻译方式尚未经过严格的测试。本申请的目的是首次在人类中定量定义应变幅度和应变率与桡骨远端骨结构和强度变化之间的关系。我们的总体假设是，更大的应变幅度和速率将引起更大的成骨反应。该假设基于啮齿动物负荷模型中描述的相似关系。同样，我们假设骨骼内经历高应变量或应变率的局部区域将经历局部骨密度增加，并且高水平的身体活动、强度或骨量可能会降低成骨反应。我们的理由是，骨质疏松症可以最有效地解决预防，所获得的知识是必不可少的，以便未来的临床试验运动，以改善骨骼健康可以系统地设计，以最大限度地发挥干预的潜在作用。我们已经开发了一个简单的体内人体负荷模型，其中受试者通过靠在手掌上向桡骨施加力，并且我们已经验证了非侵入性方法来量化该部位内的应变幅度和速率、骨强度和骨结构。利用这个模型，我们提出了三个目标来测试骨适应性反应和骨力学应变环境之间的关系。前两个目标分别是独立的12个月随机临床实验，包括两个实验组和一个对照组（每组20名受试者，每个目标60名受试者）。对于第一个目标，应变幅度将是 在恒定应变速率下指定为低（1800毫微英寸）或高（3600毫微英寸）。对于第二个目标，在恒定应变幅度下，应变速率将被指定为低（4500 me/s）或高（36，000 me/s）。在每个目标中，女性将在12个月内每周对其桡骨施加三次负荷（共156次），并使用定量计算机断层扫描和特定受试者的有限元模型测量骨结构和强度的变化。第三个目标是对目标1和2中入组的受试者进行12个月随访。这项研究是新颖的，因为它直接将先前在动物身上证明的关系转化为人类。该研究在使用非侵入性方法来表征载荷暴露和骨强度方面具有创新性。 公共卫生相关性：拟议的项目研究施加到女性前臂的机械信号之间的关系，以及由此产生的前臂骨强度和结构的改善。类似的研究已经在小动物身上进行过，但这个项目是第一个在人类身上严格测试这种关系的项目。通过了解机械信号（输入）和骨骼改善（输出）之间的输入/输出关系，可以开发最大限度地改善骨骼健康的运动，从而预防骨质疏松症和骨折。

DESCRIPTION (provided by applicant): Physical activity and exercise cause mechanical strain to occur within bone, thereby initiating an adaptive osteogenic response. Owing to this process, exercise during growth and young adulthood has been shown to increase peak bone mass and improve bone mechanical properties, providing life-long protection against osteoporosis. In animals, mechanical strain magnitude and strain rate are two key variables that are related to the degree of bone adaptation, with increasing osteogenic response occurring as each of these variables increases. Although the same mechanisms likely influence bone adaptation in humans, the manner in which this animal data may be translated has not been rigorously tested. The objective of this application is to quantitatively define, for the first tim in humans, the relationship between strain magnitude and strain rate to changes in distal radius bone structure and strength. Our global hypothesis is that larger strain magnitudes and rates will elicit a greater osteogenic response. This hypothesis is based on similar relationships that have been described in rodent loading models. Similarly, we hypothesize that local regions experiencing high strain magnitudes or rates within a bone will experience local increases in bone density, and that high levels of physical activity, strength, or bone mass may decrease the osteogenic response. Our rationale is that osteoporosis can be most effectively addressed with prevention, and the knowledge gained is essential so that future clinical trials of exercise to improve bone health can be systematically designed to maximize the potential effect of the intervention. We have developed a simple in vivo human loading model in which subjects apply a force to the radius by leaning onto the palm of the hand, and we have validated noninvasive methods to quantify strain magnitude and rate, bone strength, and bone structure within this site. Using this model, we propose three aims to test the relationship between bone adaptive response and bone mechanical strain environment. The first two aims are each independent 12-month randomized clinical experiments that include two experimental groups and one control group (20 subjects per group, for 60 subjects per aim). For the first aim, strain magnitude will be assigned as either low (1800 me) or high (3600 me) at a constant strain rate. For the second aim, strain rate will be assigned as either low (4500 me/s) or high (36,000 me/s) at a constant strain magnitude. In each of these aims women will apply three bouts of loading to their radii per week for 12 months (156 bouts total) and changes to bone structure and strength will be measured using quantitative computed tomography and subject-specific finite element models. The third aim is the 12-month follow-up of subjects enrolled in Aims 1 and 2. The research is novel because it directly translates relationships previously demonstrated in animals to humans. The research is innovative in its use of noninvasive methods to characterize loading exposure and bone strength. PUBLIC HEALTH RELEVANCE: The proposed project examines the relationship between mechanical signals applied to the forearm of women, and the resulting improvements to forearm bone strength and structure. Similar studies have been undertaken in small animals, but this project is the first to rigorously test this relationship in humans. By understanding the input/output relationship between mechanical signals (input) and bone improvements (output), exercises can be developed to maximally improve bone health, thereby preventing osteoporosis and fractures.