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The present study aimed to investigate the impact of 20(s)-ginsenoside Rg1 (20(S)-Rg1) on glucocorticoid (GC)-induced osteoporosis. Calvarial osteoblasts (COB) were treated with 10 nM dexamethasone (Dex) and 10 nM 20(S)-Rg1. TRAP staining showed that Dex induced significantly increased osteoclast (OCL) formation and 20(S)-Rg1 obviously reduced the ability of Dex-induced OCL formation. The inhibitory effect of 20(S)-Rg1 on OCL formation was consistent with the decreased mRNA and protein levels of tumor necrosis factor (TNF)-α and receptor activator of nuclear factor-kappa B ligand (RANKL). 20(S)-Rg1 also significantly attenuated the degradation of the protein and mRNA levels of osteoprotegerin (OPG), and increased the protein level of RANK. 20(S)-Rg1 markedly decreased the protein level of AMP-activated protein kinase (AMPK) phosphorylation, and the activity of AMPK. 20(S)-Rg1 also significantly increased the protein levels of peroxisome proliferator-activated receptor (PPAR)-γ and peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)1/PGC-1β. The expression of Sirtuin1 0b46394aab