Intermittent artificial gravity training in 60-days HDT bed rest attenuates bone density loss at the proximal femur - Results of the AGBRESA RCT

As spaceflight-induced bone deterioration at weight-bearing sites poses a serious health risk, astronauts are routinely monitored using dual-energy X-ray absorptiometry (DXA). To prevent compromised long-term skeletal integrity, both a timely and precise detection of alterations, and the implementation of effective countermeasures are required. Artificial gravity (AG) has emerged as a promising multi-system approach to mitigate microgravity-related deconditioning. The Artificial Gravity Bed Rest Study with the European Space Agency (AGBRESA) is a clinical prospective trial in which 24 healthy participants (average age 33 ± 9 years, average weight 74 ± 10 kg) were exposed to a 60-day 6° head down tilt bed rest (HDT) as a ground-based analogue. Stratified randomization allocated participants to a control (Ctrl) group without AG exposure, a continuous AG (cAG) group exposed to AG 30 min/d, and an intermittent AG (iAG) group receiving AG 6 × 5 min/day with 3 min rest intervals between runs. This study differentially assessed whether exposure to cAG or iAG via short-arm centrifugation can mitigate deterioration at the right proximal femur during HDT, and whether quantitative computed tomography (QCT) improves the detection of disuse-induced bone alterations compared to DXA. Here we show that QCT indeed provided valuable insights into adaptations at the proximal femur to unloading with and without exposure to AG. With its limited spatial resolution, DXA detected a significant areal bone mineral density decline at the total hip region solely in Ctrl (–2.2 %, p < 0.001), while no significant changes were detected in either AG group. In contrast, QCT revealed region-specific bone loss across all groups, with trabecular volumetric bone mineral density declining at the femoral head, neck, and trochanter, alongside cortical thinning at the femoral neck and proximal shaft. Exploratory analyses suggest that each AG protocol shaped distinct predominant local mechanoadaptive responses. While iAG was associated with a more physiologically coherent attenuation of bone loss, cAG responses were characterized by a prominent axial redistribution of bone mass. Our results demonstrate that passive AG exposure provides limited mitigation to disuse-induced deterioration at the proximal femur. The approach of combining AG with active exercise is expected to enhance skeletal protection and is being explored in follow-up trials such as BRACE and BRAVE. Lastly, our findings challenge the status of DXA as the gold standard for bone monitoring in spaceflight analogues and highlight the importance of volumetric bone imaging for guiding personalized countermeasure strategies and optimizing skeletal protection in future long-duration missions.