In this study, through screening of natural compounds that exhibit inhibitory effects on osteoclastogenesis and RANKL signalling, we found that berberine sulfate is capable of inhibiting osteoclast formation, osteoclast marker genes expression, and RANKL-induced NF-κB and NFAT activities, suggesting that berberine sulfate is a potential anti-catabolic agent for the treatment of osteoporosis. The gene discussed is TNFSF11; the disease is osteoporosis.