Little is known about the regulation of cortical bone. This genetic study showed that suppression of Wnt-signaling pathways by secreted frizzled-related protein 4 was critical to cortical-bone formation and strength. Osteoporosis is a skeletal disease that is characterized by low bone mass, defective bone structure, and a high risk of fracture. Cortical-bone mass is a major determinant of bone strength and therefore of susceptibility to fractures. With aging, the mass of cortical bone may decrease more than the mass of trabecular bone, and fractures occurring in older persons result mostly from cortical-bone fragility. Although progress has been made in therapeutic approaches to reducing the risk of vertebral fracture (which occurs at sites rich in trabecular bone), currently available treatments do little to reduce the risk of nonvertebral fracture, which results . . .