Radiation-Induced Remodeling of Bone Metastases and the Bone Marrow Microenvironment: From External-Beam Radiotherapy to Radiopharmaceutical Therapy

Background/Objectives: Bone metastases arise within a specialized microenvironment in which tumor cells interact with skeletal, stromal, vascular, immune, and hematopoietic compartments. Radiotherapy therefore affects not only metastatic tumor cells but also the surrounding bone and marrow niches. This review examines radiation-induced remodeling of the bone metastatic and bone marrow microenvironments across external-beam radiotherapy (EBRT) and radiopharmaceutical therapy (RPT). Methods: We performed a narrative synthesis of experimental and clinical studies addressing cellular radiosensitivity, skeletal and stromal remodeling, hematopoietic injury, vascular and immune responses, oxidative and metabolic stress, and spatial and temporal patterns of radiation delivery. Emerging transcriptomic, proteomic, metabolomic, lipidomic, single-cell, and spatial approaches were also considered. Results: EBRT and RPT produce overlapping but biologically distinct perturbations because of differences in dose rate, exposure duration, particle range, target localization, microscopic energy deposition, and spatial dose heterogeneity. These differences can influence tumor control, resistance, bone remodeling, and marrow toxicity through effects on osteoblasts, osteoclasts, stromal and vascular cells, immune populations, and HSPCs. These issues are particularly relevant to metastatic castration-resistant prostate cancers, in which bone seeking and tumor targeting radiopharmaceuticals differentially irradiate cellular compartments within the same skeletal environment. Conclusions: Bone metastases should be viewed as part of a dynamic bone–tumor–marrow microenvironment. Integrating radiation biology, spatial dosimetry, and multi-omics may support more individualized treatment strategies that maximize tumor control while limiting skeletal and hematologic injury.