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Effects of Loading Duration and Short Rest Insertion on Cancellous and Cortical Bone Adaptation in the Mouse Tibia.

ABSTRACT: The skeleton's osteogenic response to mechanical loading can be affected by loading duration and rest insertion during a series of loading events. Prior animal loading studies have shown that the cortical bone response saturates quickly and short rest insertions between load cycles can enhance cortical bone formation. However, it remains unknown how loading duration and short rest insertion affect load-induced osteogenesis in the mouse tibial compressive loading model, and particularly in cancellous bone. To address this issue, we applied cyclic loading (-9 N peak load; 4 Hz) to the tibiae of three groups of 16 week-old female C57BL/6 mice for two weeks, with a different number of continuous load cycles applied daily to each group (36, 216 and 1200). A fourth group was loaded under 216 daily load cycles with a 10 s rest insertion after every fourth cycle. We found that as few as 36 load cycles per day were able to induce osteogenic responses in both cancellous and cortical bone. Furthermore, while cortical bone area and thickness continued to increase through 1200 cycles, the incremental increase in the osteogenic response decreased as load number increased, indicating a reduced benefit of the increasing number of load cycles. In the proximal metaphyseal cancellous bone, trabecular thickness increased with load up to 216 cycles. We also found that insertion of a 10 s rest between load cycles did not improve the osteogenic response of the cortical or cancellous tissues compared to continuous loading in this model given the age and sex of the mice and the loading parameters used here. These results suggest that relatively few load cycles (e.g. 36) are sufficient to induce osteogenic responses in both cortical and cancellous bone in the mouse tibial loading model. Mechanistic studies using the mouse tibial loading model to examine bone formation and skeletal mechanobiology could be accomplished with relatively few load cycles.

SUBMITTER: Yang H

PROVIDER: S-EPMC5226737 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Effects of Loading Duration and Short Rest Insertion on Cancellous and Cortical Bone Adaptation in the Mouse Tibia.

Yang Haisheng H Embry Rachel E RE Main Russell P RP

PloS one 20170111 1

The skeleton's osteogenic response to mechanical loading can be affected by loading duration and rest insertion during a series of loading events. Prior animal loading studies have shown that the cortical bone response saturates quickly and short rest insertions between load cycles can enhance cortical bone formation. However, it remains unknown how loading duration and short rest insertion affect load-induced osteogenesis in the mouse tibial compressive loading model, and particularly in cancel ...[more]

PMID: 28076363

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Project description:Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4?Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1,200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p?<?0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. -1,000??? and a transition from lamellar-woven bone near -2,000???. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1,200 to 300 to 60 did not diminish the bone formation response (p?>?0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p?<?0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to -1,800??? peak strain, at 4?Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month-old C57Bl/6 female mice. Our results provide a basis for reduction of loading duration (daily cycles and study length) without loss of anabolic effect as measured by dynamic histomorphometry. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:682-691, 2018.

Project description:Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 ?? at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 ?? at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Dataset Information

Effects of Loading Duration and Short Rest Insertion on Cancellous and Cortical Bone Adaptation in the Mouse Tibia.

Publications

Effects of Loading Duration and Short Rest Insertion on Cancellous and Cortical Bone Adaptation in the Mouse Tibia.

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