Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. This study investigates the physiological role of OPG by generating OPG-deficient mice. Adolescent and adult OPG-deficient mice exhibit reduced total bone density, characterized by severe trabecular and cortical bone porosity, thinning of the skull's parietal bones, and a high incidence of fractures. These findings indicate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also show medial calcification of the aorta and renal arteries, suggesting that OPG regulation may play a role in the association between osteoporosis and vascular calcification. OPG is a member of the tumor necrosis factor receptor gene superfamily. Transgenic mice overexpressing OPG in the liver have high levels of OPG protein in their systemic circulation and exhibit increased bone density. OPG is localized in cartilage rudiments of developing bones, the small intestine, and the muscular wall of major arteries. Targeted deletion of OPG in mice results in severe, early-onset osteoporosis and calcification of the aorta and renal arteries, indicating that OPG plays a role in regulating physiological bone formation and pathological calcification. OPG-deficient mice show decreased bone mineral density, with severe osteoporosis and increased bone resorption. Histologically, OPG-deficient mice exhibit profound osteoporosis in the lumbar vertebrae and metaphyseal regions of the humerus, femurs, and tibias. The cortical bone of long bones shows increased porosity, and the femoral growth plate is not visible. OPG-deficient mice also exhibit calcification of the aorta and renal arteries, suggesting that OPG may regulate vascular calcification. The study demonstrates that OPG is essential for maintaining postnatal bone mass and skeletal architecture. The loss of OPG leads to increased osteoclast activity and bone resorption, resulting in osteoporosis. The findings suggest that OPG may play a role in regulating both bone formation and vascular calcification. The study also highlights the importance of OPG in maintaining normal skeletal development and the potential therapeutic applications of OPG in treating osteoporosis and other bone-related diseases.Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. This study investigates the physiological role of OPG by generating OPG-deficient mice. Adolescent and adult OPG-deficient mice exhibit reduced total bone density, characterized by severe trabecular and cortical bone porosity, thinning of the skull's parietal bones, and a high incidence of fractures. These findings indicate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also show medial calcification of the aorta and renal arteries, suggesting that OPG regulation may play a role in the association between osteoporosis and vascular calcification. OPG is a member of the tumor necrosis factor receptor gene superfamily. Transgenic mice overexpressing OPG in the liver have high levels of OPG protein in their systemic circulation and exhibit increased bone density. OPG is localized in cartilage rudiments of developing bones, the small intestine, and the muscular wall of major arteries. Targeted deletion of OPG in mice results in severe, early-onset osteoporosis and calcification of the aorta and renal arteries, indicating that OPG plays a role in regulating physiological bone formation and pathological calcification. OPG-deficient mice show decreased bone mineral density, with severe osteoporosis and increased bone resorption. Histologically, OPG-deficient mice exhibit profound osteoporosis in the lumbar vertebrae and metaphyseal regions of the humerus, femurs, and tibias. The cortical bone of long bones shows increased porosity, and the femoral growth plate is not visible. OPG-deficient mice also exhibit calcification of the aorta and renal arteries, suggesting that OPG may regulate vascular calcification. The study demonstrates that OPG is essential for maintaining postnatal bone mass and skeletal architecture. The loss of OPG leads to increased osteoclast activity and bone resorption, resulting in osteoporosis. The findings suggest that OPG may play a role in regulating both bone formation and vascular calcification. The study also highlights the importance of OPG in maintaining normal skeletal development and the potential therapeutic applications of OPG in treating osteoporosis and other bone-related diseases.