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Osteolytic diseases are characterized by an increase in the number and/or activity of bone‐resorbing osteoclasts. Identification of natural compounds that can suppress osteoclast formation and function is crucial for the prevention and treatment of osteolytic diseases. Vitexin, a naturally‐derived flavonoid extracted from various medicinal plant species, demonstrates a broad range of pharmacological properties including anticancer and anti‐inflammatory effects. Here in this study, we showed that vitexin exerts antiosteoclastogenic effects by directly inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast formation and bone resorption in vitro and protected against lipopolysaccharide (LPS)‐induced inflammatory osteolysis in vivo. Vitexin suppressed the early activation of ERK and p38 MAPK pathways in response to RANKL thereby attenuating the downstream induction of c‐Fos and NFATc1, and abrogating the expression of osteoclast marker genes. Collectively, these results provide evidence for the therapeutic application of vitexin in the treatment of osteoclast‐mediated bone lytic diseases. [ABSTRACT FROM AUTHOR]

• Hinokitiol lowered RANKL-induced osteoclast formation and bone resorption in vitro. • Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways. • Hinokitiol also suppressed the activity and expression of c‐Jun, c‐Fos, and NFATC1. • Hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. • Hinokitiol has potential as a novel treatment for osteoclast-induced osteoporosis. Osteoporosis is a metabolic bone-loss disease characterized by abnormally excessive osteoclast formation and bone resorption. Identification of natural medicines that can inhibit osteoclastogenesis, bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL)‐induced signaling is necessary for improved treatment of osteoporosis. In this study, hinokitiol, a tropolone-related compound extracted from the heart wood of several cupressaceous plants, was found to inhibit RANKL-induced osteoclast formation and bone resorption in vitro. Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways, thereby suppressing the activity and expression of downstream factors (c‐Jun, c‐Fos, and NFATC1). Consistent with the above in vitro findings, hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. Collectively, our results imply that hinokitiol can potentially serve as an effective agent for treating osteoclast-induced osteoporosis. [ABSTRACT FROM AUTHOR]