It is well established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment (strain energy density (SED) and SED gradient) of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2Hz, 5Hz, or 10Hz, respectively or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of bone formation and a decreased probability of bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net remodeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2Hz, 5Hz and 10Hz (+15%, +21% and +24%, p<0.0001), while static loading led to a decrease in bone volume fraction (-9%, p≤0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the four week observation period (R²=0.74). In conclusion, these results suggest that bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights towards a better understanding of the mechanical signals influencing bone formation and resorption in the local in vivo environment.

中文翻译：

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骨骼适应的机械调节受局部体内环境控制，并且对数依赖于加载频率

众所周知，周期性的而不是静态的机械负载对骨骼具有合成代谢作用。但是，描述加载频率与骨骼适应量之间关系的功能仍然不清楚。本研究采用实验和计算相结合的方法，旨在研究在体内局部环境中机械信号是否受机械信号控制并取决于负荷频率。具体来说，通过结合体内微计算机断层扫描（micro-CT）成像和微有限元（micro-FE）分析，我们可以监测体内微结构以及机械力学的变化在分别以2Hz，5Hz或10Hz的不同频率周期性加载或静态加载4周后，小鼠尾椎的环境（应变能密度（SED）和SED梯度）。SED和SED梯度在局部组织水平上的较高值导致增加的骨形成概率和降低的骨吸收概率。与SED相比，在所有负荷组中，SED梯度在确定局部骨形成和吸收事件方面均优越。与假装和静态载荷相比，循环载荷引起的净重塑率为正，主要是由于矿化表面的增加和侵蚀表面的减少。因此，骨骼体积分数随时间以2Hz，5Hz和10Hz增大（+15％，+ 21％和+ 24％，p <0.0001），而静态负荷导致骨体积分数减少（-9％，p≤0.001）。此外，回归分析显示，在四个星期的观察期内，负荷频率与骨体积分数的净变化之间呈对数关系（R² = 0.74）。总之，这些结果表明，骨骼的适应性受局部体内环境中的机械信号调节，此外，机械调节对数依赖于负载频率，该频率低于某个阈值且具有分解代谢作用，而高于分解代谢作用。因此，这项研究为更好地了解影响局部体内环境中骨骼形成和吸收的机械信号提供了宝贵的见识。