PT  - JOURNAL ARTICLE
AU  - Maria Parlani
AU  - Francesco Boccalatte
AU  - Anna Yeaton
AU  - Feng Wang
AU  - Jianhua Zhang
AU  - Iannis Aifantis
AU  - Eleonora Dondossola
TI  - Radium 223 induces transient functional bone marrow toxicity
AID  - 10.2967/jnumed.121.263310
DP  - 2022 Feb 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.121.263310
4099  - http://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263310.short
4100  - http://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263310.full
AB  - Radium 223 (Ra223) is a bone-seeking, alpha-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra223 hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study we investigate the consequences of Ra223 treatment on bone marrow biology. Ra223 accumulated in bones and induced zonal radiation damage confined at the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by three-dimensional multiphoton microscopy, ex vivo. Flow cytometry and single cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, non-specific Ra223-mediated cytotoxicity on resident populations, including stem, progenitor and mature leukocytes. This was paralleled by a significant decrease of white blood cells and platelets in peripheral blood, which was overcome within 40 days post-treatment. Ra223 exposure did not impair full hematopoietic reconstitution, suggesting that the bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra223 reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting its safety for patients.