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Influence of Fatigue Loading and Bone Turnover on Bone Strength and Pattern of Experimental Fractures of the Tibia in Mice

Abstract

Bone fragility depends on bone mass, structure, and material properties, including damage. The relationship between bone turnover, fatigue damage, and the pattern and location of fractures, however, remains poorly understood. We examined these factors and their integrated effects on fracture strength and patterns in tibia. Adult male mice received RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2×/week), or vehicle (Veh) 2 days prior to fatigue loading of one tibia by in vivo axial compression, with treatments continuing up to 28 more days. One day post fatigue, crack density was similarly increased in fatigued tibiae from all treatment groups. After 28 days, the RANKL group exhibited reduced bone mass and increased crack density, resulting in reduced bone strength, while the OPG-Fc group had greater bone mass and bone strength. Injury repair altered the pattern and location of fractures created by ex vivo destructive testing, with fractures occurring more proximally and obliquely relative to non-fatigued tibia. A similar pattern was observed in both non-fatigued and fatigued tibia of RANKL. In contrast, OPG-Fc prevented this fatigue-related shift in fracture pattern by maintaining fractures more distal and transverse. Correlation analysis showed that bone strength was predominantly determined by aBMD with minor contributions from structure and intrinsic strength as measured by nanoindentation and cracks density. In contrast, fracture location was predicted equally by aBMD, crack density and intrinsic modulus. The data suggest that not only bone strength but also the fracture pattern depends on previous damage and the effects of bone turnover on bone mass and structure. These observations may be relevant to further understand the mechanisms contributing to fracture pattern in long bone with different levels of bone remodeling, including atypical femur fracture.

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Acknowledgments

We thank Ms Madeleine Lachize and Juliette Cicchini for her technical assistance. Authors’s roles are as follows: Study design: NB and SF. Study conduct: NB. Data analysis: NB, MG. Data interpretation: NB, PA, PK, MO and SF. Drafting manuscript: NB and SF. Revising manuscript content and approving final version: NB, MG, PA, PK, MO, and SF.

Funding

This work was further supported by a grant from Amgen (to NB and SF) and by the SNF Grants No 310030-130550 (to SF).

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Correspondence to Nicolas Bonnet.

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Nicolas Bonnet, Maude Gerbaix, Michael Ominsky, Patrick Ammann, Paul J. Kostenuik and Serge L. Ferrari declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Bonnet, N., Gerbaix, M., Ominsky, M. et al. Influence of Fatigue Loading and Bone Turnover on Bone Strength and Pattern of Experimental Fractures of the Tibia in Mice. Calcif Tissue Int 99, 99–109 (2016). https://doi.org/10.1007/s00223-016-0124-8

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Keywords

  • Fatigue
  • Bone turnover
  • Cracks
  • Fracture pattern