To investigate the role of osteoprotegerin (OPG) on alcohol (ethanol)-mediated osteoporosis, we measured a variety of bone remodeling parameters in mice that were either on a control diet, an ethanol (5%) diet, or an ethanol (5%) diet plus OPG administration. OPG diminished the ethanol-induced (1) decrease in bone mineral density (BMD) as determined by dual-energy densitometry, (2) decrease in cancellous bone volume and trabecular width and the increase of osteoclast surface as determined by histomorphometry of the femur, (3) increase in urinary deoxypyridinolines (Dpd's) as determined by ELISA, and (4) increase in colony-forming unit-granulocyte macrophage (CFU-GM) formation and osteoclastogenesis as determined by ex vivo bone marrow cell cultures. Additionally, OPG diminished the ethanol-induced decrease of several osteoblastic parameters including osteoblast formation and osteoblast culture calcium retention. These findings were supported by histomorphometric indices in the distal femur. Taken together, these data show that OPG diminishes ethanol-induced bone loss. Furthermore, they suggest that OPG achieves this through its ability to abrogate ethanol-induced promotion of osteoclastogenesis and promote osteoblast proliferation.