Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in bone metabolism. Long-term treatment with corticosteroid drugs may lead to glucocorticoid-related osteoporosis, and previous studies have defined FGF21 as a factor may participate in bone metabolism and most studies showed that it negatively regulates bone metabolism. Herein we examine the interplay between these factors in bone metabolism. In our study, expressions of PPAR, ALP, and TRAP-5b were compared between WT mice and FGF21 inhibited mice (FGFi mice) and WT and FGFi mice treated with adrenocorticotropic hormone (ACTH). We found ACTH treatment significantly blocked ALP decreases in FGFi mice as compared to WT whereas TRAP-5b expression was significantly increased (p<0.01). Collectively, our findings suggest the following: FGF21 may serve as a negative regulator of bone metabolism, the negative regulation of bone metabolism via FGF21 may require the PPAR gamma pathway, and FGF21 may be involved in the ACTH-Cortisol axis-related bone mass loss.