Mechano-Regulation of Trabecular Bone Adaptation Is Controlled by the Local in vivo Environment and Logarithmically Dependent on Loading Frequency

Abstract

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 trabecular 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 2, 5, or 10 Hz, respectively, or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of trabecular bone formation and a decreased probability of trabecular 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 (re)modeling 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 2, 5, and 10 Hz (+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 4 week observation period ( R 2 = 0.74). In conclusion, these results suggest that trabecular 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 toward a better understanding of the mechanical signals influencing trabecular bone formation and resorption in the local in vivo environment.

Cortical Thickness Adaptive Response to Mechanical Loading Depends on Periosteal Position and Varies Linearly With Loading Magnitude

“…Bone adaptation is a local phenomenon. This has been demonstrated previously along the axis of the tibia or in discrete segments of the tibia (Sugiyama et al, 2010;Lu et al, 2016; Galea et al, 2020;Roberts et al, 2020;Scheuren et al, 2020). However, this work is the first to demonstrate the link between magnitude of axial load and adaptive response around the periosteum of the tibia at a cross-section level.…”

Bone mechanoregulation allows subject-specific load estimation based on time-lapsed micro-CT and HR-pQCTin vivo

“…The median age of the included patients was 33 years and ranged between 27 and 65 years. This is a provisional file, not the final typeset article μ A, integration time of 350 ms, 500 projections) were acquired from a previously published mouse tail loading study (Scheuren et al, 2020b). Two groups (n = 8, each) of 11-week old female C57BL/6J strain mice were scanned at the 6th caudal vertebrae (CV6) at weekly intervals for five weeks.…”

“…The sixth caudal vertebra of the animals in the loaded group was subject to mechanical loading through stainless steel pins inserted into the adjacent vertebrae (Figure 1). Compressive loading was applied three times per week for five minutes at 10 Hz and 8 N. Animals in the control group were subject to sham loading (0 N) (see Scheuren et al, 2020b).…”

“…First, to calculate sensitivity, specificity and accuracy, MR and LH algorithms were applied to synthetic remodelling data derived from HR-pQCT images (Badilatti et al, 2016;Ohs et al, 2020a). Second, to test whether the algorithms are capable of predicting the loading conditions in a controlled experimental setup, both algorithms were applied to micro-CT scans of two groups of mice that had their caudal vertebra either loaded (8 N) or sham loaded (0 N) from a previous study (Scheuren et al, 2020b). Third, to assess the method's fidelity in patients, MR and LH algorithms were applied to time-lapsed HR-pQCT scans and compared to patient-specific handgrip force measured using a dynamometer.…”

Technologies and Sensor Design for the Measurement of Ground Reaction Forces in Mice: A Review

“…Consequently, researchers are increasingly interested in applying movement analysis in animal models whenever it is ethical-particularly in mice-which represent about 95% of animal models. At our institute, researchers are investigating the effects of mechanical intervention therapies for improving bone properties and musculoskeletal regeneration [13,14]; measuring the GRFs per paw in mice before and after the interventions can help better qualify the results. While GRF measurement devices for human studies are plentiful and highly developed, options for mice and other small animals remain rare and inadequate.…”