Abstract <p>This work provides a comprehensive investigation of local(structural-functional) and systemic (metabolic) adaptive alterationsin bone tissue, induced by hindlimb unloading of different durationsin male Wistar rats. Hindlimb bone and blood samples were obtainedfrom animals following 7- and 21-day hindlimb unloading, as wellas from corresponding vivarium control groups. In the femur, themass fractions of Ca, Mg, P, and Zn were measured using inductivelycoupled plasma atomic emission spectrometry. The trabecular compartmentof the tibia was analyzed histomorphometrically. Serum concentrationsof bone metabolism regulators—1,25-dihydroxyvitamin D₃,parathyroid hormone (PTH), fibroblast growth factor-23 (FGF23),Dickkopf-related protein 1 (DKK1), sclerostin (SOST), osteoprotegerin(OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL)—weredetermined using ELISA and multiplexed fluorescent bead-based immunoassay.It was found that the bones of animals after hindlimb unloadingof both durations differed from the control groups by their lowermass and reduced Ca and Mg content. Low Zn values were noted after21 days of exposure. The proportion of trabecular bone substancein the tibia and the parameters of osteocyte viability in animalsafter both durations of hindlimb unloading were significantly lowerthan in the control groups. Differences in serum levels of RANKL(after 7-day exposure) and OPG, DKK1 (after 21-day exposure) were foundbetween the groups after hindlimb unloading and the correspondingcontrol groups. Thus, antiorthostatic suspension led to local demineralization andstructural alterations in rat bone tissue. Structural-functionalchanges were observed as early as 7 days of exposure, accompaniedby a decrease in serum RANKL levels. After 21 days, changes in trabecularwidth, a decrease in blood OPG levels, a decrease in osteocyte number,and an increase in the proportion of empty lacunae after hindlimbunloading were noted against the background of low blood DKK1 content.</p>