Glucocorticoid use is the most common cause of osteoporosis in young individuals. In the current study, we investigated the effects of glucocorticoid treatment on circulating sclerostin concentrations and serum bone turnover markers in healthy young men. We performed additional measurements in two combined randomized, placebo-controlled, double-blind, dose–response intervention studies: 64 healthy men (age: 22 ± 2 years; BMI: 22.1 ± 1.7 kg/m2) were allocated to receive placebo (n = 16), prednisolone 7.5 mg once daily (n = 24), or prednisolone 30 mg once daily (n = 24) for 2 weeks using block randomization. Primary outcome variables were serum sclerostin and serum bone turnover markers (CTx and P1NP), before and after the intervention. Baseline characteristics and variables did not differ between intervention groups. Compared with placebo, prednisolone high-dose decreased serum sclerostin concentrations (−8.5 [−28.0 to 7.3] versus 1.5 [−6.5 to 20.0] pg/mL, p = 0.048), decreased P1NP concentrations (−28.0 [−39.3 to −18.3] versus –1.5 [−15.3 to 11.3] μg/L, p < 0.001) and increased CTx concentrations (108.0 [55.0 to 177.0] versus 64.0 [−24.3 to 120.0] ng/L, p = 0.038). Compared with placebo, prednisolone low-dose did not alter sclerostin concentrations (p = 0.5) or CTx concentrations (p = 0.7), but tended to decrease P1NP concentrations (−9.0 [−24.0 to −1.3] versus –1.5 [−15.3 to 11.3] μg/L, p = 0.095). At baseline concentrations of sclerostin were positively correlated with concentrations of CTx (Spearman's rank correlation coefficient ρ = +0.409, p = 0.001), but not with P1NP. No significant correlations were observed between changes in outcome variables during the interventions. Short-term high-dose, but not low-dose, prednisolone treatment reduces serum sclerostin concentrations in healthy young men. Whether this reflects a counter regulatory mechanism to compensate glucocorticoid-induced negative effects through other mechanisms remains to be elucidated.