Claudia Weigt

Trabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates.

Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this study was to assess the long-term effect (>10 weeks) of cyclic mechanical loading on the bone microstructure, bone stiffness, and bone remodeling rates. Mice were subjected to cyclic mechanical loading at the sixth caudal vertebra with 8N or 0N (control) three times per week for a total period of 14 weeks. Structural bone parameters were determined from in vivo micro-computed tomography (micro-CT) scans performed at week 0, 4, 6, 8, 10, 12, and 14. Mechanical parameters were derived from micro-finite element analysis. Dynamic bone morphometry was calculated using registration of serial micro-CT scans. Bone volume fraction and trabecular thickness increased significantly more for the loaded group than for the control group (p = 0.006 and p = 0.002 respectively). The trabecular bone microstructure adapted to the load of 8N in approximately ten weeks, indicated by the trabecular bone volume fraction, which increased from 16.7% at 0 weeks to 21.6% at week 10 and only showed little change afterwards (bone volume fraction of 21.5% at 14 weeks). Similarly bone stiffness - (at the start of the experiment 649N/mm) - reached 846N/mm at 10 weeks in the loaded group and was maintained to the end of the experiment (850N/mm). At 4 weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8N compared to 0N. This difference was significantly reduced as the bone adapted to 8N, with 8N remodeling rates returning to the values of the 0N group at approximately 10 weeks. Together these data suggest that once bone has adapted to a new loading state, the remodeling rates reduce gradually while maintaining bone volume fraction and stiffness.

The Clinical Biomechanics Award 2012 — Presented by the European Society of Biomechanics: Large scale simulations of trabecular bone adaptation to loading and treatment

BACKGROUND Microstructural simulations of bone remodeling are particularly relevant in the clinical management of osteoporosis. Before a model can be applied in the clinics, a validation against controlled in vivo data is crucial. Here we present a strain-adaptive feedback algorithm for the simulation of trabecular bone remodeling in response to loading and pharmaceutical treatment and report on the results of the large-scale validation against in vivo data. METHODS The algorithm follows the mechanostat principle and incorporates mechanical feedback, based on the local strain-energy density. For the validation, simulations of bone remodeling and adaptation in 180 osteopenic mice were performed. Permutations of the conditions for early (20th week) and late (26th week) loading of 8N or 0N, and treatments with bisphosphonates, or parathyroid hormone were simulated. Static and dynamic morphometry and local remodeling sites from in vivo and in silico studies were compared. FINDINGS For each study an individual set of model parameters was selected. Trabecular bone volume fraction was chosen as an indicator of the accuracy of the simulations. Overall errors for this parameter were 0.1-4.5%. Other morphometric indices were simulated with errors of less than 19%. Dynamic morphometry was more difficult to predict, which resulted in significant differences from the experimental data. INTERPRETATION We validated a new algorithm for the simulation of bone remodeling in trabecular bone. The results indicate that the simulations accurately reflect the effects of treatment and loading seen in respective experimental data, and, following adaptation to human data, could be transferred into clinics.

Longitudinal in vivo imaging of bone formation and resorption using fluorescence molecular tomography

Bone research often focuses on anatomical imaging of the bone microstructure, but in order to gain better understanding in how bone remodeling is modulated through interventions also bone formation and resorption processes should be investigated. With this in mind, the purpose of this study was to establish a longitudinal in vivo imaging approach of bone formation and resorption using fluorescence molecular tomography (FMT). In this study the reproducibility, accuracy and sensitivity of FMT for bone imaging were assessed by performing longitudinal measurements with FMT and comparing it to in vivo micro-computed tomography on a set of control mice, and mice in which load-adaptation was induced in the sixth caudal vertebra. The precision error for FMT measurements, expressed as coefficient of variation, was smaller than 16%, indicating acceptable reproducibility. A correlation was found between bone resorption measured with FMT and bone resorption rate measured with in vivo micro-computed tomography only over the first 14days (R=0.81, p<0.01), but not between bone formation measured with FMT and bone formation rate measured with in vivo micro-CT. Bone formation measured by FMT was 89-109% greater (p<0.05) for mice subjected to mechanical loading than control mice. Bone resorption was 5-8% lower, but did not reach a significant difference between groups, indicating moderate sensitivity for FMT. In conclusion, in vivo FMT in mouse tail bones is feasible but needs to be optimized for monitoring load adaptation in living mice.

Bone adaptation to cyclic loading in murine caudal vertebrae is maintained with age and directly correlated to the local micromechanical environment

The ability of the skeleton to adapt to mechanical stimuli (mechanosensitivity) has most often been investigated at the whole-bone level, but less is known about the local mechanoregulation of bone remodeling at the bone surface, especially in context of the aging skeleton. The aim of this study was to determine the local and global mechanosensitivity of the sixth caudal vertebra during cyclic loading (8 N, three times per week, for six weeks) in mice aged 15, 52, and 82 weeks at the start of loading. Bone adaptation was monitored with in vivo micro-computed tomography. Strain energy density (SED), assumed as the mechanical stimulus for bone adaptation, was determined with micro-finite element models. Mechanical loading had a beneficial effect on the bone microstructure and bone stiffness in all age groups. Mineralizing surface was on average 13% greater (p<0.05) in loaded than control groups in 15- and 82-week-old mice, but not for 52-week-old mice. SED at the start of loading correlated to the change in bone volume fraction in the following 6 weeks for loaded groups (r(2)=0.69-0.85) but not control groups. At the local level, SED was 14-20% greater (p<0.01) at sites of bone formation, and 15-20% lower (p<0.01) at sites of bone resorption compared to quiescent bone surfaces for all age groups, indicating SED was a stimulus for bone adaptation. Taken together, these results support that mechanosensitivity is maintained with age in caudal vertebrae of mice at a local and global level. Since age-related bone loss was not observed in caudal vertebrae, results from the current study might not be translatable to aged humans.

PARATHYROID HORMONE INTERFERES WITH THE MECHANOREGULATION OF BONE REMODELING

The human parathyroid peptide fragment hPTH 134 is an anabolic drug which, given intermittently, turns on bone remodeling by increasing bone formation. Its exact mode of action is however still unclear to date. In an earlier study, we found that in mechanically loaded animals, formation occurs preferentially at highly loaded areas, and resorption at lowly strained areas [1]. Here we investigate if and how PTH combined with mechanical loading alters the mechanoregulation of bone remodeling. With this, we aimed at a better understanding of the effectiveness of PTH in the treatment of bone diseases such as osteoporosis.