Osteoarthritis (OA) is affecting large proportions of the population worldwide. So far, no effective disease modifying drug has been developed for this disease, limiting the therapeutic options to pain medications, physiotherapy and ultimately surgical approaches, mainly joint implant surgery. In vitro and animal studies have demonstrated that bisphosphonates have the potential to become effective modalities for the treatment of OA. This group of pharmacological agents modulates crucial aspects of OA pathogenesis (subchondral bone turnover and loss, bone marrow edema formation, cartilage degeneration and synovitis), and have shown clear efficacy in animal models of OA. Human studies have, however, so far been disappointing with only one of six clinical studies showing clear short-term efficacy. Possible reasons for these discrepancies will be discussed.