SKELETAL BIOLOGY AND REGULATION (MR FORWOOD AND A ROBLING, SECTION EDITORS) When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification Kylie A. Alexander 1 & Hsu-Wen Tseng 1 & Marjorie Salga 2,3 & François Genêt 2,3 & Jean-Pierre Levesque 1 Accepted: 9 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophys- iology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. Recent Findings Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-β1-mediated pathways. Summary This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients. Keywords Neurogenic heterotopic ossification . Inflammation . Cytokines . Macrophages . Central nervous system Introduction Neurogenic heterotopic ossifications (NHOs) are abnormal extra-skeletal bone formations mostly in periarticular muscles [1] after severe damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia [2] and hence their name “neuro- genic.” NHOs were first identified in spine-injured soldiers during World War I with the first use of radiography in bat- tlefield injuries [3–5] and are still very prevalent in defense personnel with battlefield injuries, with up to 60% of blast and gunshot victims developing NHO when there is concomitant spinal damage [6–8]. NHO also occurs in up to 25% of civil- ians with severe SCI and 5–20% with TBI [9–12]. NHOs develop within a few months after CNS injury in periarticular muscles, with decreasing frequencies in the hip, elbow, knee, and shoulder (Fig. 1). NHO can be very incapacitating, mainly due to their large size (up to 2 kg), often causing significant pain and gradual reduction in the range of motion of affected limbs which often progresses to complete joint ankylosis. This exacerbates functional disabilities by increasing difficulty in sitting, eating, and dressing [13]. NHO growth can also cause nerve and blood vessel compression, further increasing patient morbidity [14, 15]. This article is part of the Topical Collection on Skeletal Biology and Regulation * Jean-Pierre Levesque jean-pierre.levesque@mater.uq.edu.au 1 Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland 4102, Australia 2 Department of Physical Medicine and Rehabilitation, CIC 1429, Raymond Poincaré Hospital, APHP, Garches, France 3 END:ICAP U1179 INSERM, University of Versailles Saint Quentin en Yvelines, UFR Simone Veil-Santé, Montigny le Bretonneux, France Current Osteoporosis Reports https://doi.org/10.1007/s11914-020-00636-w