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 <i>ex vivo</i> 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.