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Clin Rev Bone Miner Metab. 2018;16(4):142-158. doi: 10.1007/s12018-018-9256-x. Epub 2018 Dec 29.

Bone Fracture Acute Phase Response-A Unifying Theory of Fracture Repair: Clinical and Scientific Implications.

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1Department of Orthopaedics, Mayo Clinic, 200 1st Ave SW, Rochester, MN 55903 USA.
2Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave. South, Suite 4200 MCE, South Tower, Nashville, TN 37232 USA.
3Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN 37232 USA.
4Vanderbilt University School of Medicine, 1161 21st Ave S, #D3300, Nashville, TN 37232 USA.
5Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Yushima Bunkyo Ward, Tokyo, 113-8519 Japan.
Masonic Research Institute, 2150 Bleecker St, Utica, NY 13501 USA.
7Department of Biomedical Engineering, Vanderbilt University, PMB 351631, 2301 Vanderbilt Place, Nashville, TN 37235 USA.
Department of Veterans Affairs, Tennessee Valley Health Care System, F-519 VA Acre Building, 1210 24th Ave. South, Nashville, TN 37232 USA.
9Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave, Robinson Research Building, Nashville, TN 37232 USA.
10Department of Pediatrics, Vanderbilt University Medical Center, 4202 Doctor's Office Tower, 2200 Children's Way, Nashville, TN 37232 USA.


Bone fractures create five problems that must be resolved: bleeding, risk of infection, hypoxia, disproportionate strain, and inability to bear weight. There have been enormous advancements in our understanding of the molecular mechanisms that resolve these problems after fractures, and in best clinical practices of repairing fractures. We put forth a modern, comprehensive model of fracture repair that synthesizes the literature on the biology and biomechanics of fracture repair to address the primary problems of fractures. This updated model is a framework for both fracture management and future studies aimed at understanding and treating this complex process. This model is based upon the fracture acute phase response (APR), which encompasses the molecular mechanisms that respond to injury. The APR is divided into sequential stages of "survival" and "repair." Early in convalescence, during "survival," bleeding and infection are resolved by collaborative efforts of the hemostatic and inflammatory pathways. Later, in "repair," avascular and biomechanically insufficient bone is replaced by a variable combination of intramembranous and endochondral ossification. Progression to repair cannot occur until survival has been ensured. A disproportionate APR-either insufficient or exuberant-leads to complications of survival (hemorrhage, thrombosis, systemic inflammatory response syndrome, infection, death) and/or repair (delayed- or non-union). The type of ossification utilized for fracture repair is dependent on the relative amounts of strain and vascularity in the fracture microenvironment, but any failure along this process can disrupt or delay fracture healing and result in a similar non-union. Therefore, incomplete understanding of the principles herein can result in mismanagement of fracture care or application of hardware that interferes with fracture repair. This unifying model of fracture repair not only informs clinicians how their interventions fit within the framework of normal biological healing but also instructs investigators about the critical variables and outputs to assess during a study of fracture repair.


Acute phase response; Endochondral ossification; Fracture repair; Fracture vascularity; Non-union; Strain

Conflict of interest statement

Compliance with Ethical StandardsFunding for this study was provided by the Vanderbilt Department of Orthopedics and Rehabilitation (J.G.S), the Caitlyn Lovejoy Foundation, and the National Institute of Health through RO1HL122238 (J.R.M) and RO1HL133153 (J.R.M). J.G.S. is a member of the education advisory board at Orthopediatrics, receives research funding from Orthopediatrics, and research support from IONIS Pharmaceuticals. J.G.S. and S.N.M.-L. receive research and training support from PXE International. All other authors have declared that no conflict of interest exists. In all studies where animals were involved, all applicable international, national, and institutional guidelines for the care and use of animals were followed.

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