AOP Report: Development of an adverse outcome pathway for deposition of energy leading to bone loss

Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy.