Bone metastases remain a leading cause of morbidity and mortality in patients with advanced breast, prostate, and lung cancers. A striking clinical feature of bone metastasis is the ability of disseminated tumor cells (DTCs) to persist in a dormant state for years or even decades before reawakening to drive overt disease. While the molecular and microenvironmental cues that induce and maintain dormancy have been increasingly studied, the mechanisms governing dormancy escape remain poorly defined yet are critical for preventing relapse. In this review, we synthesize emerging evidence on how the bone microenvironment orchestrates the transition of dormant tumor cells into proliferative lesions. We discuss how osteoclast-mediated bone resorption liberates growth factors such as TGF-β and IGF-1, fueling reactivation; how loss of osteoblast-mediated quiescence signals disrupts the endosteal niche; and how bone marrow adipocytes provide metabolic support through lipid transfer and adipokine secretion. We highlight the role of immune surveillance in maintaining dormancy and how immunosuppressive myeloid populations, regulatory T cells, and inflammatory triggers, such as neutrophil extracellular traps, promote escape. Additional emphasis is placed on extracellular matrix remodeling, mechanotransduction, angiogenic switching, and systemic factors, including aging, hormonal changes, and sympathetic nervous system activation. We also review epigenetic and metabolic reprogramming events within dormant cells that enable reactivation. Finally, we evaluate therapeutic strategies to sustain dormancy or prevent reawakening, including osteoclast-targeted therapies, immune-modulating approaches, and epigenetic or metabolic interventions. By integrating these insights, we identify key knowledge gaps and propose future directions to intercept dormancy escape and delay or prevent metastatic relapse in bone.

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases.

Bone is a preferred site for disseminated tumor cells, yet the molecular mechanisms that prepare the skeletal microenvironment for metastatic colonization are only beginning to be understood. At the heart of this process are extracellular vesicles (EVs), nano-sized, lipid-encapsulated particles secreted by cancer cells and stromal components. This review consolidates current findings that position EVs as key architects of the bone-metastatic niche. We detail the biogenesis of EVs and their organotropic distribution, focusing on how integrin patterns and bone-specific ligands guide vesicle homing to mineralized tissues. We then outline the sequential establishment of the pre-metastatic niche, driven by EV-mediated processes including fibronectin deposition, stromal cell reprogramming, angiogenesis, neurogenesis, metabolic reconfiguration, and immune modulation, specifically, the expansion of myeloid-derived suppressor cells and impaired lymphocyte function. Within the bone microenvironment, tumor-derived EVs carrying microRNAs and proteins shift the balance toward osteoclastogenesis, inhibit osteoblast differentiation, and disrupt osteocyte signaling. These alterations promote osteolytic destruction or aberrant bone formation depending on tumor type. We also highlight cutting-edge imaging modalities and single-EV omics technologies that resolve EV heterogeneity and identify potential biomarkers detectable in plasma and urine. Finally, we explore therapeutic approaches targeting EVs, such as inhibition of nSMase2 or Rab27A, extracorporeal EV clearance, and delivery of engineered, bone-targeted vesicles, while addressing translational challenges and regulatory considerations. This review offers a roadmap for leveraging EV biology in predicting, preventing, and treating skeletal metastases by integrating advances across basic biology, bioengineering, and translational science.

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

Osteocytes, once viewed mainly as passive bone-embedded cells, are now recognized as active regulators of the metastatic bone niche. Emerging evidence indicates that these cells integrate mechanical, inflammatory, and tumor-derived cues to influence metastatic seeding, dormancy, reactivation, and lesion progression in bone. This review synthesizes current understanding of osteocyte contributions to skeletal metastasis. We discuss core signaling axes, including osteocyte-derived RANKL/OPG balance, Wnt antagonists (sclerostin/DKK1), mechanotransduction pathways (Piezo1 signaling and connexin-43 hemichannels), and osteocyte paracrine mediators (extracellular vesicles and senescence-associated factors), and examine how each axis modulates tumor cell dormancy, osteolysis, or osteoblastic progression. We then review translational strategies targeting osteocytes, recent preclinical and clinical insights. Emerging biomarkers (e.g., serum sclerostin, DKK1, bone turnover markers) and immune–skeletal imaging approaches are also considered. Controversies, including the paradoxical effects of sclerostin blockade and the identity of in vivo RANKL sources, are discussed. Finally, we outline key knowledge gaps and propose endpoints for future trials. In summary, an osteocyte-centric perspective reveals novel targets and strategies for managing bone metastases, guiding future translational research.

Background: Heparin-induced thrombocytopenia (HIT) is a rapid, life-threatening adverse drug reaction, with the widely used 4T score being the critical clinical tool guiding the need for serological confirmation. This study aimed to validate the diagnostic utility of the 4T score and evaluate its application in a tertiary hospital in Saudi Arabia. Methods: In this retrospective cohort study, we analyzed 449 patients with suspected HIT, comparing their initially recorded clinical 4T scores with those recalculated by trained specialists, using the anti-PF4/heparin IgG ELISA as the reference standard for HIT confirmation. Results: Of the 292 patients who underwent laboratory testing, the HIT positivity rate was 6.5% (n = 19). The primary finding was a markedly low agreement (15.4%) between the system-recorded and the standardized physician-calculated 4T scores, indicating significant inter-observer variability. Despite this, higher calculated 4T scores remained significantly associated with positive HIT test results, and the anti-PF4/heparin IgG ELISA demonstrated 100% sensitivity and 100% negative predictive value (NPV). Conclusions: While the 4T score is indispensable for guiding the diagnostic pathway, the observed profound inter-observer variability highlights an urgent need for standardized scoring training and protocol refinement to enhance diagnostic accuracy and reduce inappropriate therapeutic interventions.