Combined Electromagnetic Fields Mitigate Unloading-Induced Bone Loss by Enhancing Osteogenic Responses via Multiphysics-Induced Mechanotransduction

Unloading-induced bone loss is a major medical challenge during long-duration human spaceflight, largely driven by suppressed osteoblast-mediated bone formation, and practical countermeasures are needed. Electromagnetic stimulation has shown benefits for bone repair, and its non-invasiveness supports potential space use; however, its single-modality efficacy remains limited. Here, we investigated a combined electromagnetic field (CEMF) integrating a static magnetic field (SMF, 0.4–0.6 T) and a pulsed electromagnetic field (PEMF, 0.38 ± 0.19 mT) to attenuate unloading-related bone loss and examine field-induced mechanical stimulation. Finite-element simulations mapped magnetic flux density, field gradient, induced current density, and Lorentz force density in bone tissue. CEMF was evaluated in vivo in hindlimb unloading (HLU) mice and in vitro in MC3T3-E1 osteoblasts. CEMF improved bone mineral density, trabecular and cortical microarchitecture, and mechanical properties in HLU mice, with increased osteoblast number and mineral apposition rate. In vitro, CEMF promoted osteogenic differentiation and upregulated COL1A1 and RUNX2. Transcriptome analysis suggested activation of ECM–integrin mechanical signaling and the PI3K–AKT pathway. These findings indicate that CEMF-induced multiphysics stimulation enhances osteogenic responses and may serve as a complementary, non-invasive countermeasure for spaceflight-associated bone loss.