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Fracture healing physiology and the quest for therapies for delayed healing and nonunion.

ABSTRACT: Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/?-catenin signaling, and recombinant FGF-2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:213-223, 2017.

SUBMITTER: Kostenuik P

PROVIDER: S-EPMC6120140 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Fracture healing physiology and the quest for therapies for delayed healing and nonunion.

Kostenuik Paul P Mirza Faisal M FM

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20161219 2

Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad sp ...[more]

PMID: 27743449

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Project description:BACKGROUND:Although most humeral nonunions are successfully treated with a single procedure, some humeral nonunions are more difficult to heal and require multiple procedures. Current literature does not provide evidence describing how the prognosis for surgical repair in patients who develop humeral diaphyseal nonunions may be affected by initial operative versus nonoperative treatment. QUESTIONS/PURPOSES:The purpose of this study was to assess whether operative versus nonoperative treatment of acute humeral shaft fractures impacts outcome of subsequent repairs of humeral nonunions (NU) including the need for additional surgery and a comparison of pain relief (Visual Analogue Scale for pain) and functional outcome (Short Musculoskeletal Functional Assessment). METHODS:Thirty-four patients with humeral shaft nonunion were evaluated of which 15 patients had been treated operatively (OF), and 19 patients had been treated nonoperatively (NO) for their initial humerus shaft fracture. All patients underwent plating with autogenous bone graft or allograft ± bone morphogenic protein (BMP) 2 or 7 as their final NU repair surgery prior to healing. We compared functional outcome and pain for both cohorts and determined risk factors for requiring more than 1 nonunion repair surgery. RESULTS:The mean time of final follow-up was 14.7?±?10.4 months. Thirty-three of 34 NUs (97.1%) healed. Patients who underwent OF of their original fracture were more likely to require more than 1 NU repair surgery (66.7 vs. 0%, p?<?0.01). Of the 15 patients who underwent initial OF, 33.0% required 1 NU surgery, 33.0% required 2 NU surgeries, and 33.0% required 3 NU surgeries. Patients who underwent initial OF were more likely to require >6 months to achieve union (40.0 vs. 10.5%, p?=?0.04). At final follow-up, there was no difference in functional outcome or pain scores. Initial OF was the only independent predictor of needing more than 1 NU repair surgery (OR 70.1 CI 2.8-1762.3) to achieve healing. CONCLUSION:Humeral shaft nonunions following initial operative fixation of the index fracture is more resistant to achieving union when compared to nonunions forming after initial nonoperative treatment. When final healing is achieved, there is no difference in function or pain.

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Fracture healing physiology and the quest for therapies for delayed healing and nonunion.

Publications

Fracture healing physiology and the quest for therapies for delayed healing and nonunion.

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