Dissecting the effects of 223Radium on the bone microenvironment.

Radium-223 (223Ra) is a bone-seeking, alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone. 223Ra accumulates in mineralized bone areas with high bone turnover, where its effects are confined within 100 μm of the bone-marrow interface due to the short tissue penetrance of the alpha particles. A recent clinical study has shown a significantly increased fracture rate associated with the administration of 223Ra, mostly in tumor-free bones. Importantly, the biological mechanisms underlying this bone fragility remain unclear. In this work, we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of 223Ra on bone and key bone stromal cell components. We found that 223Ra caused major trabecular bone loss with no detectable impact on cortical bone. In addition, 223Ra impaired osteoblast bone-forming activity, which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation. Overall, these results suggest that the impact of 223Ra on bone health is orchestrated by multiple bone stromal cell components. 223Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid, which should always be combined with 223Ra.