INTRODUCTION: Prolonged exposure to microgravity is associated with a significant reduction in bone density, exposing astronauts to renal calculi in flight and osteoporotic fractures on return to Earth. While physical countermeasures and bisphosphonates may reduce demineralization, additional therapies are needed for future interplanetary missions. This literature review aims to understand the current background pertaining to denosumab (a monoclonal antibody therapy used in osteoporosis) and its potential use for long duration spaceflight.METHOD: A literature review was conducted using the following keywords: "osteoporosis"; "osteopaenia"; "microgravity"; "space flight"; "bed rest"; "denosumab"; "alendronate"; "bisphosphonates"; and "countermeasures". Additional articles were identified through references. Included for discussion were 48 articles, including systemic reviews, clinical trials, practice guidelines, and textbooks.RESULTS: No previous bed rest or in-flight studies regarding denosumab were identified. In osteoporosis, denosumab is superior to alendronate in maintaining bone density with a lower rate of side-effects. Emerging evidence in reduced biomechanical loading state suggests denosumab improves bone density and decreases fracture risk. Concerns exists over vertebral fracture risk following discontinuation. The dosing regimen of denosumab offers practical advantages over bisphosphonates. Existing spaceflight studies with alendronate serve as a template for a study with denosumab and allow for a direct comparison of efficacy and safety.DISCUSSION: Denosumab has numerous potential advantages as a countermeasure to microgravity-induced osteopenia when compared to alendronate, including: improved efficacy; fewer side-effects: better tolerability; and a convenient dosing regimen. Two further studies are proposed to determine in-flight efficacy and the suitability of monoclonal antibody therapy in the spaceflight environment.Rengel A, Tran V, Toh LS. Denosumab as a pharmacological countermeasure against osteopenia in long duration spaceflight. Aerosp Med Hum Perform. 2023; 94(5):389-395.