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Fracture healing under healthy and inflammatory conditions

Abstract

Optimal fracture treatment requires knowledge of the complex physiological process of bone healing. The course of bone healing is mainly influenced by fracture fixation stability (biomechanics) and the blood supply to the healing site (revascularization after trauma). The repair process proceeds via a characteristic sequence of events, described as the inflammatory, repair and remodeling phases. An inflammatory reaction involving immune cells and molecular factors is activated immediately in response to tissue damage and is thought to initiate the repair cascade. Immune cells also have a major role in the repair phase, exhibiting important crosstalk with bone cells. After bony bridging of the fragments, a slow remodeling process eventually leads to the reconstitution of the original bone structure. Systemic inflammation, as observed in patients with rheumatoid arthritis, diabetes mellitus, multiple trauma or sepsis, can increase fracture healing time and the rate of complications, including non-unions. In addition, evidence suggests that insufficient biomechanical conditions within the fracture zone can influence early local inflammation and impair bone healing. In this Review, we discuss the main factors that influence fracture healing, with particular emphasis on the role of inflammation.

Key Points

  • Fracture healing is a complex, highly regulated process with consecutive and closely linked phases of inflammation, repair and remodeling

  • Optimal fracture healing requires suitable biological as well as biomechanical conditions

  • The mechanical environment considerably influences tissue differentiation during bone healing: stable fracture fixation induces direct bone formation, moderate stability provokes endochondral ossification, whereas unstable fixation inhibits bone healing

  • The immune system is intimately involved in the fracture healing process, especially during the early inflammatory healing phase

  • Disorders associated with systemic inflammation, such as diabetes mellitus, trauma, sepsis and rheumatoid arthritis, can prolong or disturb fracture healing and increase the risk of non-unions by incompletely understood mechanisms

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Figure 1: Main factors affecting the fracture healing process.
Figure 2: Secondary diaphyseal bone healing in a sheep tibia osteotomy model.
Figure 3: Images demonstrating the metaphyseal bone healing process.
Figure 4: Primary diaphyseal bone healing in a sheep metatarsal osteotomy model.
Figure 5: Time course of fracture healing events in rats.
Figure 6: Schematic representation of inflammation and repair during fracture healing.

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Correspondence to Lutz Claes.

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Claes, L., Recknagel, S. & Ignatius, A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8, 133–143 (2012). https://doi.org/10.1038/nrrheum.2012.1

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