Vitamin K2 is a cofactor of gamma-carboxylase, which converts the glutamic acid (Glu) residue in osteocalcin molecules to gamma-carboxyglutamic acid (Gla), and is, therefore, essential for gamma-carboxylation of osteocalcin. Available evidence suggests that vitamin K2 also enhances osteocalcin accumulation in the extracellular matrix of osteoblasts in vitro. Osteocalcin-knockout mice develop hyperostosis, suggesting that the Gla-containing osteocalcin promotes normal bone mineralization. Although the precise role of osteocalcin in bone mineralization remains obscure, it probably regulates the growth of hydroxyapatite crystals. Furthermore, vitamin K2 also inhibits the expression of the osteoclast differentiation factor (ODF)/RANK ligand, tartrate-resistant acid phosphatase activity, and mononuclear cell formation, and induces osteoclast apoptosis in vitro. There is some evidence indicating that vitamin K2 prevents bone resorption in ovariectomized rats, retards the increase in bone turnover in orchidectomized rats, ameliorates the increase in bone resorption and decrease in bone formation in sciatic neurectomized rats, and prevents the decrease in bone formation in glucocorticoid-treated rats. These findings suggest that vitamin K2 may not only stimulate bone formation but also suppress bone resorption in vivo. Clinically, vitamin K2 sustains the lumbar bone mineral density (BMD) and prevents osteoporotic fractures in patients with age-related osteoporosis, prevents vertebral fractures in patients with glucocorticoid-induced osteoporosis, increases the metacarpal BMD in the paralytic upper extremities of patients with cerebrovascular disease, and sustains the lumbar BMD in patients with liver-dysfunction-induced osteoporosis. Vitamin K deficiency, as indicated by an increased circulating level of undercarboxylated osteocalcin, may contribute to osteoporotic fractures. Even though the effect of vitamin K2 on the BMD is quite modest, this vitamin may have the potential to regulate bone metabolism and play a role in reducing the risk of osteoporotic fractures. No randomized well-controlled prospective studies conducted on a sufficiently large number of patients have been reported yet, therefore, further studies are needed to confirm the efficacy of vitamin K2 in the treatment of osteoporosis.