Exposure to microgravity induces a rapid and profound loss of bone mass, particularly in weight-bearing skeletal regions, closely resembling accelerated osteoporosis on Earth. Traditionally attributed to mechanical unloading, bone loss in space is now recognized as being strongly regulated by oxidative stress. Excessive production of reactive oxygen species (ROS)-driven by mitochondrial dysfunction, cosmic radiation, altered circadian rhythms, and fluid shifts-disrupts osteoblast differentiation, enhances osteoclastogenesis, and compromises osteocyte viability. These effects are mediated through redox-sensitive signaling pathways, including RANK/RANKL/OPG, Wnt/β-catenin, and MAPK, as well as transcriptional regulators such as NF-κB, ERK, and FoxO. Moreover, oxidative stress modulates epigenetic regulators, notably microRNAs and long non-coding RNAs, tipping gene networks toward apoptosis, autophagy dysregulation, and cellular senescence in bone cells. Beyond mechanistic insights, recent studies highlight the long-term persistence of skeletal deficits after spaceflight and reveal sex- and age-related vulnerabilities, particularly in postmenopausal women due to estrogen deficiency. These findings position oxidative stress as a central driver of skeletal deterioration with clear translational relevance to age-related osteoporosis. Current and emerging countermeasures target both the mechanical and redox dimensions of bone loss. Pharmacological strategies include antioxidants, bisphosphonates, NADPH oxidase inhibitors, mitochondrial stabilizers, and autophagy modulators. Nutritional interventions emphasize antioxidant-rich diets, vitamin D and calcium supplementation, and omega-3 fatty acids. Mechanical and biophysical countermeasures-resistance training, vibration therapy, and artificial gravity-remain essential, while innovative approaches such as redox-sensitive gene therapy, siRNA-based modulation, and mitochondria-targeted antioxidants offer new therapeutic avenues. By integrating mechanistic, epigenetic, and translational perspectives, this review underscores the centrality of redox imbalance in spaceflight-induced bone loss and identifies actionable targets for prevention. Ultimately, dissecting ROS-mitochondria-cell fate signaling provides a unifying framework for protecting astronaut skeletal health and advancing therapies for terrestrial osteoporosis.
