Bone Radiopharmaceuticals: Evolution from Palliative Therapy to Targeted Precision Oncology and Theranostics

Bone radiopharmaceuticals have evolved from early palliative agents into integral components of targeted precision oncology and theranostics. This review comprehensively traces the historical trajectory, pathophysiological mechanisms, and clinical applications of bone-directed nuclear medicine. We contrast primary bone malignancies—which directly produce malignant osteoid matrix—with metastatic bone disease, which colonizes the endosteal niche via the RANK/RANKL/OPG axis and the metastatic vicious cycle. The molecular mechanisms governing skeletal radioisotope localization are systematically detailed, encompassing calcium mimetics (223Ra), inorganic phosphate integration (32P), hydroxyapatite chemisorption (99mTc-labeled diphosphonates), isomorphous surface exchange ([18F]NaF), and direct biomarker targeting. Furthermore, we highlight the therapeutic transition from medium-range beta-emitters to high-linear energy transfer (LET) targeted alpha therapy (225Ac), nanometer-scale Auger electron emitters, and cell-directed theranostic vectors. By unifying radiopharmaceutical chemistry, microdosimetry, and emerging artificial intelligence-driven personalized dosimetry, this review provides a strategic roadmap for advancing precision bone endoradiotherapy.