Neurogenic heterotopic ossification: from molecular mechanisms to clinical treatment

Neurogenic heterotopic ossification (NHO), a disabling complication of severe central nervous system injuries, involves ectopic periarticular bone formation that causes profound functional impairments and reduced quality of life. This review highlights recent advances in NHO, especially focusing on the neuro-immune-osteogenic axis. Rather than a merely local disorder, NHO is a systemic response driven by neural, inflammatory, and interorgan signals, notably involving BMP/Smad, macrophage activation, and neuropeptide pathways. While combined-injury animal models advance mechanistic insights, they incompletely replicate human disease heterogeneity. Clinically, early diagnosis is hindered by nonspecific symptoms and insensitive radiography. Current treatments are mainly preventive or symptomatic, lacking efficacy for mature lesions. We highlight that addressing controversies in prophylaxis, surgical timing, and biomarker utility is essential. Future progress relies on validated early biomarkers, standardized imaging, mechanism-based therapeutics, and multidisciplinary precision management. The Translational Potential of this Article. This review highlights clinical mechanisms and emerging targets for NHO, which may enable earlier diagnosis, individualized prevention, and targeted treatment for patients with central nervous system injury.