ESA VIVALDI (1 & 2) campaigns: sex-specific bone responses to dry immersion-induced unloading.

Skeletal unloading during microgravity rapidly disrupts bone and metabolic homeostasis, yet sex-specific physiological responses remain poorly characterized. Dry immersion (DI), a ground-based analogue of microgravity, provides a model to investigate early determinants of unloading-induced bone deconditioning. We assessed sex differences in serum biochemical markers of bone and energy metabolism during two 5-day European Space Agency DI campaigns (VIVALDI 1 and 2) involving healthy males (n = 19) and females (n = 18). DI induced rapid alterations in bone remodeling in both sexes, characterized by increased bone resorption. Tartrate-resistant acid phosphatase isoform 5b (TRAP5b) increased more in females than in males (+22% vs. +11%; P = 0.02), whereas crosslinked C-terminal telopeptide of type I collagen (CTX) rose (+10%; P < 0.05) only in females at DI completion. Bone formation markers declined similarly in both sexes, including procollagen type I N-terminal propeptide (PINP) (-22% males, -19% females; P < 0.001), osteocalcin, and carboxylated osteocalcin, whereas bone alkaline phosphatase increased, indicating dissociation between new matrix formation and mineralization. Periostin decreased in both sexes but more markedly in females (-29%; P < 0.001) and did not recover post-DI. Calcium increased transiently at DI-48 h (P < 0.001), whereas parathyroid hormone (PTH) declined throughout immersion and recovery (P < 0.001). IGF-1 (+8%; P < 0.001) and visfatin (+63% males, +78% females; P < 0.001) increased, with visfatin normalizing post-DI only in females. Overall, although both sexes exhibited early bone deconditioning, females showed greater and more persistent resorption and periostin reduction, suggesting a faster progression toward bone loss. These early sex-specific responses identify potential biomarker that may enhance mechanistic understanding and guide the development of targeted countermeasures for spaceflight- and immobilization-related bone loss.NEW & NOTEWORTHY Dry immersion induces rapid bone deconditioning in both sexes, but females show greater skeletal sensitivity to unloading, with stronger resorptive increases [tartrate-resistant acid phosphatase isoform 5b (TRAP5b), crosslinked C-terminal telopeptide of type I collagen (CTX)] and a more pronounced periosteal decline (periostin) that does not recover after immersion. Concurrent rises in IGF-1 and visfatin are suggestive of coordinated metabolic-skeletal responses. These sex-specific biomarker patterns highlight early physiological differences and may help guide the development of targeted countermeasures for spaceflight and immobilization.