Long Bones Exhibit Adaptive Responses to Chronic Low‐Dose‐Rate Ionizing Radiation despite its Lifespan‐Shortening and Carcinogenic Effects on C57BL/6 Mice

ABSTRACT Ionizing radiation (IR) is a well‐known carcinogen. High‐dose‐rate (HDR) IR is known to damage long bones (in terms of mass and structure), but the relationships among dose rates (particularly low‐dose‐rate [LDR] IR), long‐bone condition, cancer incidence, and lifespan shortening remain elusive. The aim of this study was to elucidate the effects of LDR‐IR on long‐bone condition by comparing the long‐term consequences of HDR‐ and LDR‐IR exposure in mice. We utilized micro–computed tomography (μCT) scans of the long bones at similar ages (mean 77–96 weeks) to compare mice receiving approximately equivalent total doses of internal LDR‐IR or external HDR‐IR starting at 4 weeks of age, and their respective control groups. The lifespan‐shortening effects of LDR‐IR and HDR‐IR were similar in these mixed‐sex cohorts. Notably, compared to HDR‐IR mice, mice internally exposed to chronic LDR‐IR with continuous hypohematopoiesis showed a significantly higher trabecular bone connective density [femur: 247% (p = 0.0042), tibia: 169% (p = 0.0005)] and midshaft cortical bone thickness/area (femur: 130% [p = 0.0079]/120% [p = 0.021], tibia: 148% [p = 0.0004]/129% [p = 0.002]). Consistent with this result, when comparing 26–32 weeks post‐IR with 2–8 weeks post‐IR, compared to HDR‐IR‐treated mice, LDR‐IR‐treated mice exhibited higher levels of an osteoblast marker (OPG; p = 0.67 for HDR‐IR, p = 0.068 for LDR‐IR) and lower levels of an osteoclast marker (CTX‐I; p = 0.0079 for HDR‐IR, p = 0.72 for LDR‐IR) despite significantly higher levels of inflammatory markers (CCL2 and CXCL1; p = 0.36–0.8 for HDR‐IR, p = 0.013–0.041 for LDR‐IR). These results suggest that long bones under chronic LDR‐IR stress may exhibit an adaptive response to stresses such as chronic inflammation associated with IR‐induced lifespan shortening. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.