Combination therapy for osteoporosis has been tested in small trials of short duration with various combinations. Pertinent human and animal randomized clinical trial data were identified through Medline and reviewed with a focus on the risks and benefits of different types of combination therapies. Improvements in bone density were found in some, but not all, combinations. There are no large trials of adequate length or numbers to determine fracture efficacy. Consider combination therapy if monotherapy is unsuccessful, if there is an added nonskeletal benefit to the proposed combination or as sequential treatment with an anabolic agent followed by an antiresorptive agent. Although combination therapy, in general, has limitations based on cost, concern about potential oversuppression of bone, and lack of long-term safety and fracture efficacy, selected patients may benefit.