Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6mice were ovariectomized (OVX, n=11) or sham-operated (SHM, n=9) and monitored with in vivo μCT on the day of surgery and every 2weeks after, up to 12weeks. There was a significant decrease in bone volume fraction for OVX (−35%) compared to SHM (+16%) in trabecular bone (P<0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P<0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (−16%) compared to SHM (+11%, P<0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P<0.001) and a delayed increase in bone formation rate (P<0.001). Monitoring transient bone biology is a promising method for future researc

Bone morphology allows estimation of loading history in a murine model of bone adaptation

Bone adapts its morphology (density/micro- architecture) in response to the local loading conditions in such a way that a uniform tissue loading is achieved (‘Wolff’s law’). This paradigm has been used as a basis for bone remodeling simulations to predict the formation and adaptation of trabecular bone. However, in order to predict bone architectural changes in patients, the physiological external loading conditions, to which the bone was adapted, need to be determined. In the present study, we developed a novel bone loading estimation method to predict such external loading conditions by calculating the loading history that produces the most uniform bone tissue loading. We applied this method to murine caudal vertebrae of two groups that were in vivo loaded by either 0 or 8 N, respectively. Plausible load cases were sequentially applied to micro-finite element models of the mice vertebrae, and scaling factors were calculated for each load case to derive the most uniform tissue strain-energy density when all scaled load cases are applied simultaneously. The bone loading estimation method was able to predict the difference in loading history of the two groups and the correct load magnitude for the loaded group. This result suggests that the bone loading history can be estimated from its morphology and that such a method could be useful for predicting the loading history for bone remodeling studies or at sites where measurements are difficult, as in bone in vivo or fossil bones.ISSN:1617-7959ISSN:1617-794

Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

ISSN:0171-967XISSN:1432-082

The effects of tensile-compressive loading mode and microarchitecture on microdamage in human vertebral cancellous bone

The amount of microdamage in bone tissue impairs mechanical performance and may act as a stimulus for bone remodeling. Here we determine how loading mode (tension vs. compression) and microstructure (trabecular microarchitecture, local trabecular thickness, and presence of resorption cavities) influence the number and volume of microdamage sites generated in cancellous bone following a single overload. Twenty paired cylindrical specimens of human vertebral cancellous bone from 10 donors (47–78 years) were mechanically loaded to apparent yield in either compression or tension, and imaged in three dimensions for microarchitecture and microdamage (voxel size 0.7×0.7×5.0 μm3). We found that the overall proportion of damaged tissue was greater (p=0.01) for apparent tension loading (3.9±2.4%, mean±SD) than for apparent compression loading (1.9±1.3%). Individual microdamage sites generated in tension were larger in volume (p&lt;0.001) but not more numerous (p=0.64) than sites in compression. For both loading modes, the proportion of damaged tissue varied more across donors than with bone volume fraction, traditional measures of microarchitecture (trabecular thickness, trabecular separation, etc.), apparent Young׳s modulus, or strength. Microdamage tended to occur in regions of greater trabecular thickness but not near observable resorption cavities. Taken together, these findings indicate that, regardless of loading mode, accumulation of microdamage in cancellous bone after monotonic loading to yield is influenced by donor characteristics other than traditional measures of microarchitecture, suggesting a possible role for tissue material properties

Microdamage Caused by Fatigue Loading in Human Cancellous Bone: Relationship to Reductions in Bone Biomechanical Performance

<div><p>Vertebral fractures associated with osteoporosis are often the result of tissue damage accumulated over time. Microscopic tissue damage (microdamage) generated <i>in vivo</i> is believed to be a mechanically relevant aspect of bone quality that may contribute to fracture risk. Although the presence of microdamage in bone tissue has been documented, the relationship between loading, microdamage accumulation and mechanical failure is not well understood. The aim of the current study was to determine how microdamage accumulates in human vertebral cancellous bone subjected to cyclic fatigue loading. Cancellous bone cores (n = 32) from the third lumbar vertebra of 16 donors (10 male, 6 female, age 76±8.8, mean ± SD) were subjected to compressive cyclic loading at σ/E₀ = 0.0035 (where σ is stress and E₀ is the initial Young’s modulus). Cyclic loading was suspended before failure at one of seven different amounts of loading and specimens were stained for microdamage using lead uranyl acetate. Damage volume fraction (DV/BV) varied from 0.8±0.5% (no loading) to 3.4±2.1% (fatigue-loaded to complete failure) and was linearly related to the reductions in Young’s modulus caused by fatigue loading (r² = 0.60, p<0.01). The relationship between reductions in Young’s modulus and proportion of fatigue life was nonlinear and suggests that most microdamage generation occurs late in fatigue loading, during the tertiary phase. Our results indicate that human vertebral cancellous bone tissue with a DV/BV of 1.5% is expected to have, on average, a Young’s modulus 31% lower than the same tissue without microdamage and is able to withstand 92% fewer cycles before failure than the same tissue without microdamage. Hence, even small amounts of microscopic tissue damage in human vertebral cancellous bone may have large effects on subsequent biomechanical performance.</p></div

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

peer reviewedBone 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 8 N or 0 N (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 8 N 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 649 N/mm) - reached 846 N/mm at 10 weeks in the loaded group and was maintained to the end of the experiment (850 N/mm). At 4 weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8 N compared to 0 N. This difference was significantly reduced as the bone adapted to 8 N, with 8 N remodeling rates returning to the values of the 0 N 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. (C) 2013 Elsevier Inc. All rights reserved