title: 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.
authors.affiliation: Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland. nicolas.bonnet@unige.ch.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonnet
authors.affiliation: Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland.
authors.forename: Maude
authors.initials: M
authors.lastname: Gerbaix
authors.affiliation: Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ominsky
authors.affiliation: Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ammann
authors.affiliation: Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.affiliation: Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland.
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D050723:Fractures, Bone / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013977:Tibia / Q000098:blood supply / Q000187:drug effects*
keywords: Bone turnover; Cracks; Fatigue; Fracture pattern