New therapeutic targets for osteoporosis: beyond denosumab.

Treatments for osteoporosis over the last few decades have largely focused on antiresorptive agents that effectively prevent bone loss. Beginning with hormone therapy, a variety of new potent antiresorptive agents were developed, including oral and intravenous bisphosphonates, raloxifene and other selective estrogen receptor modulators, nasal spray calcitonin, and denosumab. Teriparatide and PTH 1-84 are the only approved anabolic agents to date that primarily build new bone density. A variety of new biologic agents that focus on molecular targets important for the stimulation of new bone formation are being developed. Cathepsin K inhibitors appear to have mixed antiresorptive and anabolic actions because they inhibit one of the major osteoclast digestive enzymes without suppressing bone formation, thereby leading to anabolic effects on bone. New biologic agents in clinical trials include anti-sclerostin and anti-dickkopf antibodies that stimulate the Wnt/β-catenin pathway in osteoblasts, leading to new bone formation. These new agents will effectively stimulate new bone formation by different mechanisms, leading to improved bone mineral density and reduced fractures.