Denosumab, a fully human monoclonal antibody against the key osteoclastogenic factor RANK ligand, is currently approved for the treatment of postmenopausal osteoporosis. Denosumab differs from bisphosphonates in many aspects, for example, its ability to act in the extracellular compartment and its likelihood to be distributed throughout the skeleton. In contrast, bisphosphonates have to be internalized by osteoclasts and are mainly located across bone surfaces. This could explain why patients with osteoporosis, who are already treated with bisphosphonates, might experience further benefit when switching to denosumab. Head-to-head studies revealed that transition to denosumab resulted in a greater increase of bone mineral density (BMD) and a greater reduction of bone turnover than did continued alendronate. Additional analyses of the phase 3 FREEDOM trial demonstrated that fracture reduction was particularly high in cortical bone, such as the wrist. In addition, denosumab treatment for a 5- and 8-year period showed sustained reduction in fracture risk, increase in BMD and continued to be well tolerated. The 7-year extension study of FREEDOM and a phase 3 trial evaluating denosumab for the treatment of male osteoporosis are still ongoing and will provide supportive data in the near future.