The study investigates the physiological role of osteoprotegerin (OPG) by generating OPG-deficient mice. Adolescent and adult OPG−/− mice exhibit severe osteoporosis characterized by decreased total bone density, trabecular and cortical bone porosity, and increased fracture incidence. Notably, these mice also show medial calcification of the aorta and renal arteries, suggesting a role for OPG in regulating vascular calcification. The findings demonstrate that OPG is a critical regulator of postnatal bone mass and suggest that OPG may play a role in the association between osteoporosis and vascular calcification.The study investigates the physiological role of osteoprotegerin (OPG) by generating OPG-deficient mice. Adolescent and adult OPG−/− mice exhibit severe osteoporosis characterized by decreased total bone density, trabecular and cortical bone porosity, and increased fracture incidence. Notably, these mice also show medial calcification of the aorta and renal arteries, suggesting a role for OPG in regulating vascular calcification. The findings demonstrate that OPG is a critical regulator of postnatal bone mass and suggest that OPG may play a role in the association between osteoporosis and vascular calcification.