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Development of an adverse outcome pathway for deposition of energy leading to bone loss.
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  • Snehpal Sandhu,
  • Mitchell Keyworth,
  • Syna Karimi-Jashni,
  • Dalya Alomar,
  • Benjamin Smith,
  • Tatiana Kozbenko,
  • Stephen Doty,
  • Robyn Hocking,
  • Nobuyuki Hamada,
  • Robert Reynolds,
  • Ryan Scott,
  • Sylvain Costes,
  • Afshin Beheshti,
  • Carole Yauk,
  • Ruth Wilkins,
  • Vinita Chauhan
Snehpal Sandhu
Health Canada
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Mitchell Keyworth
Health Canada
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Syna Karimi-Jashni
Health Canada
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Dalya Alomar
Health Canada
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Benjamin Smith
Health Canada
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Tatiana Kozbenko
Health Canada
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Stephen Doty
Hospital for Special Surgery Healthcare Research Institute
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Robyn Hocking
Health Canada
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Nobuyuki Hamada
Central Research Institute of Electric Power Industry
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Robert Reynolds
Broad Institute Stanley Center for Psychiatric Research
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Ryan Scott
NASA Ames Research Center
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Sylvain Costes
NASA Ames Research Center
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Afshin Beheshti
NASA Ames Research Center
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Carole Yauk
University of Ottawa
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Ruth Wilkins
Health Canada
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Vinita Chauhan
Health Canada

Corresponding Author:[email protected]

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Abstract

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 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). A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 1865 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.
27 Aug 2024Submitted to Environmental and Molecular Mutagenesis
27 Aug 2024Submission Checks Completed
27 Aug 2024Assigned to Editor
27 Aug 2024Review(s) Completed, Editorial Evaluation Pending
27 Aug 2024Editorial Decision: Accept