Recently, accumulating evidence has indicated that glucocorticoid-induced osteoporosis (GIOP) is closely related to oxidative stress and apoptosis. Alpha-lipoic acid (LA), a naturally endogenous anti-oxidant, possesses anti-oxidative and anti-apoptosis activities, implicating LA as a therapeutic agent for the treatment of GIOP. In this study, the osteogenesis-promoting effects of LA against GIOP were investigated and the mechanisms were further probed. Here, the results showed that LA inhibited oxidative stress, suppressed apoptosis and improved osteopenia by promoting the expression of osteogenesis markers, including ALP, COL-I, OCN, BMP-2, RUNX2 and OSX. Further study revealed that the osteogenesis-promoting effects of LA likely occur via the regulation of the NOX4, NF-kappaB, JNK and PI3K/AKT pathways. The present study indicated that LA may prevent GIOP and promote osteogenesis and might be a candidate for the treatment of GIOP.