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      Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair

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          Abstract

          Purpose of Review

          The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system’s critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling.

          Recent Findings

          Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation.

          Summary

          The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

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          Most cited references137

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          Epidemiology of adult fractures: A review.

          The epidemiology of adult fractures is changing quickly. An analysis of 5953 fractures reviewed in a single orthopaedic trauma unit in 2000 showed that there are eight different fracture distribution curves into which all fractures can be placed. Only two fracture curves involve predominantly young patients; the other six show an increased incidence of fractures in older patients. It is popularly assumed that osteoporotic fractures are mainly seen in the thoracolumbar spine, proximal femur, proximal humerus and distal radius, but analysis of the data indicates that 14 different fractures should now be considered to be potentially osteoporotic. About 30% of fractures in men, 66% of fractures in women and 70% of inpatient fractures are potentially osteoporotic.
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            Fracture healing: mechanisms and interventions.

            Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed.
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              Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry.

              The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.
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                Author and article information

                Journal
                Current Osteoporosis Reports
                Curr Osteoporos Rep
                Springer Science and Business Media LLC
                1544-1873
                1544-2241
                January 18 2024
                Article
                10.1007/s11914-023-00846-y
                38294715
                6b782c28-f3ee-4abf-b9ef-8653fa6f3d9b
                © 2024

                https://creativecommons.org/licenses/by/4.0

                https://creativecommons.org/licenses/by/4.0

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