Osteoporosis is a major health care problem, and whereas efficacious treatments for vertebral fracture reduction are available for osteoporosis patients, these therapies are still limited with respect to capacity for restoration of bone loss, as well as efficacy on non-vertebral fractures, such as hip fractures, which are the source of morbidity and mortality. Areas covered: Studies of rare bone diseases in humans, such as osteopetrosis, sclerosteosis, pycnodysostosis and more, have shed light on a series of drug targets in bone that have the potential to result in therapies for osteoporosis with novel mechanisms of action, and the potential to improve the standard of care substantially. We focus on how they are separated from classic treatments for osteoporosis, in terms of novel modes of action, additional beneficial effects on bone turnover and importantly also safety. We focus on the status of anti-sclerostin antibodies, novel parathyroid hormone-related protein analogs, inhibitors of cathepsin K and ClC-7 in osteoclasts, all of which are currently in development. Expert opinion: There is a good possibility that the treatment of osteoporosis will be greatly improved within the coming years; however, with numerous effective and safe drugs already available careful attention to the safety of these novel candidates is crucial.