Radium-223(^(223)Ra)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 an...Radium-223(^(223)Ra)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.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm 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^(223)Ra,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^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra 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^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.展开更多
基金supported by Bayer HealthCare Pharmaceuticals Inc.(57440)Department of Defense,CDMRP-KCRP(KC210132P1,USA)+2 种基金University of Texas MD Anderson Cancer CenterCancer Prevention and Research Institute of Texas(RP230160,USA)National Institutes of Health(P41EB023833,P30CA016672,USA).
文摘Radium-223(^(223)Ra)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.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm 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^(223)Ra,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^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra 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^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.
