Adverse Outcome Pathway on Deposition of Energy Leading to Occurrence of Bone Loss

The present Adverse Outcome Pathway (AOP) describes the linkage between bone loss and the deposition of energy by radiation, a prototypic stressor relevant to spaceflight and radiotherapy. The initial ionization events cause oxidative stress, defined as an imbalance between oxidants and antioxidants, leading to oxidation of signaling proteins involved in bone-regulating pathways such as Wnt/β-catenin and RANK-L. Oxidative damage also induces cell death, including apoptosis and autophagy in osteocytes and osteoblasts, reducing bone-forming capacity. Additionally, this cell death triggers the release of signals that promote osteoclast activation, disrupting bone cell homeostasis. The result is a shift in bone remodeling dynamics, where bone resorption exceeds formation. These changes lead to decreased bone density and quality, culminating in bone loss. Although the biological plausibility of this AOP is well supported and essentiality of most key events is high to moderate, the overall weight of evidence is considered moderate. Quantitative understanding of dose-response relationships remains limited. Modulating factors such as age and genetic background add further complexity. his AOP provides a valuable framework for assessing skeletal risks associated with radiation exposure and informing protective strategies in clinical and spaceflight settings.