Sebba AI. Clin Ther. 2008 Mar;30(3):443-52. Background: Oral bisphosphonates are routinely prescribed for the treatment of postmenopausal osteoporosis. In clinical trials, oral bisphosphonates have been found to increase bone mineral density (BMD) and decrease fracture risk in the majority of the treated population. However, in both clinical trials and clinical practice, not all patients experience significant increases in BMD. In clinical trials, nonresponse is often defined as a BMD change of =0%. In clinical practice, a decrease in BMD greater than the calculated least significant change (LSC) is considered nonresponse to therapy. It is important to discern whether patients with a decline in BMD may still benefit from oral bisphosphonate therapy, that is, have a reduced risk for fracture, despite having a suboptimal BMD response. Objectives: The objectives of this review were to determine whether meaningful BMD nonresponder rates exist with all oral bisphosphonates and to examine the relationship between BMD nonresponder status and fracture risk. Finally, we discuss the potential implications of BMD nonresponse for patients in clinical practice. Methods: Publications on BMD response and bone loss during treatment with bisphosphonates were identified by searches of MEDLINE (1990-October 2007) and ISI Web of Science (1997-October 2007). Search terms included nonresponse, responder, osteoporosis, bone mineral density, bisphosphonate, alendronate, risedronate, ibandronate, bone loss, and fracture. Results: In clinical trials of alendronate, risedronate, and ibandronate, the percentages of patients with a change in BMD =0% at the lumbar spine after 2 years of treatment ranged from 8% to 25%. Results from post hoc analyses of clinical trial data from studies of alendronate and risedronate that have examined fracture risk among BMD responders, BMD nonresponders, and patients receiving placebo suggest that patients who experienced an increase in BMD have reduced vertebral fracture risk relative to those with a decline in BMD (range, 38%-50%). Additional analyses suggest that patients who experience a decline in BMD while receiving oral bisphosphonate therapy still appear to receive some benefit (fracture risk reduction, 38%-60%) from treatment compared with patients receiving placebo. Conclusions: Results from post hoc analyses of clinical trial data suggest that patients receiving oral bisphosphonate therapy who experience a decline in BMD have a higher risk for fracture compared with patients whose BMD increases, but may have a reduced fracture risk compared with patients receiving placebo. Further investigation is needed to determine how these results impact patients in clinical practice whose BMD loss exceeds the LSC.