Vitamin E, an essential nutrient with powerful antioxidant activity, is the mixture of two classes of compounds, tocopherols (TPs) and tocotrienols (TTs). Although Us exhibit better bone protective activity than alpha-TP, the underlying mechanism is poorly understood. In this study, we investigated whether alpha-TT and alpha-TP can modulate osteoclastic bone resorption. We found that alpha-TT but not alpha-TP inhibits osteoclastogenesis in coculture of osteoblasts and bone marrow cells induced by either IL-1 or combined treatment with 1 alpha,25(OH)(2) vitamin D-3 and prostaglandin E-2. In accordance with this, only alpha-TT inhibited receptor activator of NF-kappa B ligand (RANKL) expression in osteoblasts. In addition, alpha-TT but not alpha-TP inhibited RANKL-induced osteoclast differentiation from precursors by suppression of c-Fos expression, possibly through inhibiting ERK and NF-kappa B activation. This anti-osteoclastogenic effect was reversed when c-Fos or an active form of NFATc1, a critical downstream of c-Fos during osteoclastogenesis, was overexpressed. Furthermore, only alpha-TT reduced bone resorbing activity of mature osteoclasts without affecting their survival. Overall, our results demonstrate that alpha-TT but not alpha-TP has anti-bone resorptive properties by inhibiting osteoclast differentiation and activation, suggesting that alpha-TT may have therapeutic value for treating and preventing bone diseases characterized by excessive bone destruction. (C) 2011 Elsevier Inc. All rights reserved.