{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:26:26Z","timestamp":1787613986950,"version":"build-2736575974"},"reference-count":216,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Bone metastases represent a major cause of morbidity in advanced cancers, yet the neural regulation of metastatic growth within bone remains largely unexplored. The skeletal system is richly innervated by sensory and sympathetic nerve fibers that influence bone remodeling, hematopoiesis, and immune surveillance. Emerging evidence suggests that disseminated tumor cells exploit these neural circuits to create a growth-permissive microenvironment. Tumor-secreted neurotrophic factors can induce nerve sprouting, while sympathetic activation via \u03b2-adrenergic receptors promotes osteoclastogenesis, immunosuppression, and tumor proliferation. Neuropeptides such as substance P and calcitonin gene-related peptide exert dual effects on bone cells and infiltrating immune populations, further shaping the metastatic niche. The interplay between neural signals, osteolytic activity, and immune modulation positions the neuro\u2013bone axis as a critical but underappreciated driver of metastatic progression. In this review, we synthesize current evidence on the anatomy and function of bone innervation, tumor-induced neural remodeling, and neuro\u2013immune\u2013osteoclast interactions. We highlight preclinical and clinical data supporting neuromodulatory strategies, including \u03b2-blockers, neurotrophin inhibitors, and targeted nerve ablation, as potential adjuncts to standard bone metastasis therapies. Finally, we identify key knowledge gaps, including the need for spatial and functional mapping of nerve\u2013tumor interfaces and for integrating neuroimaging into bone metastasis detection. By framing the neuro\u2013bone axis as a therapeutic target, we aim to catalyze interdisciplinary research that bridges oncology, neuroscience, and bone biology, with the goal of disrupting neural support for metastatic growth<\/jats:p>","DOI":"10.3390\/biology15040364","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:00:52Z","timestamp":1771840852000},"page":"364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Neuro\u2013Bone Axis in Metastatic Progression: Innervation, Neuro-Immune\u2013Osteoclast Crosstalk, and Therapeutic Opportunities"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8614-5718","authenticated-orcid":false,"given":"Mohamad","family":"Bakir","sequence":"first","affiliation":[{"name":"Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6963-2878","authenticated-orcid":false,"given":"Alhomam","family":"Dabaliz","sequence":"additional","affiliation":[{"name":"Department of Clinical Skills, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Raddaoui","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Fatash","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nourhan","family":"Elsaadany","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael","family":"AlKattan","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9708-2111","authenticated-orcid":false,"given":"Khalid Said","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.21037\/aoj-20-97","article-title":"Narrative review of the epidemiology, economic burden, and societal impact of metastatic bone disease","volume":"7","author":"DiCaprio","year":"2022","journal-title":"Ann. 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