# The Neuro–Bone Axis in Metastatic Progression: Innervation, Neuro-Immune–Osteoclast Crosstalk, and Therapeutic Opportunities

## TL;DR

This review explores how the nervous system supports cancer growth in bones and suggests targeting nerves as a new treatment strategy.

## Contribution

The paper introduces the neuro–bone axis as a novel therapeutic target for bone metastases.

## Key findings

- Tumors manipulate nerves to promote bone destruction and immune suppression.
- Neuromodulatory strategies like beta-blockers show promise in preclinical and clinical studies.
- Neural signals and osteoclast activity create a supportive environment for metastatic growth.

## Abstract

Bone metastases are a frequent and debilitating complication of advanced cancers, particularly those of the breast, prostate, and lung, causing severe pain and fractures that drastically reduce a patient’s quality of life. While it is well understood that tumors invade the bone, the role of the body’s nervous system in facilitating this invasion has been largely overlooked. This review explores the “neuro–bone axis”, a network where nerves and tumor cells interact. Emerging evidence shows that tumors can manipulate nerves to grow into the cancer site and release stress signals that destroy bone tissue and suppress the immune system. The authors synthesize current research to demonstrate how this neural activity creates a fertile environment for cancer growth. The conclusion highlights that repurposing existing drugs, such as heart medications (beta-blockers) or pain relievers that block nerve signals, could interrupt this destructive cycle. By treating the nervous system as an active participant in cancer progression, new therapies can be developed to not only extend survival but also significantly reduce pain and skeletal complications for patients.

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 β-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–bone 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–immune–osteoclast interactions. We highlight preclinical and clinical data supporting neuromodulatory strategies, including β-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–tumor interfaces and for integrating neuroimaging into bone metastasis detection. By framing the neuro–bone 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