Bisphosphonates are effective agents for postmenopausal osteoporosis, but their efficacy in patients with type 2 diabetes mellitus (DM) is not known. The investigators evaluated bone mineral density (BMD) response to alendronate in women with concurrent late postmenopausal osteoporosis and type 2 DM. In a retrospective, matched case-control study, 26 late postmenopausal osteoporotic women with type 2 DM (age, 67.6+/-7.3 y; type 2 DM duration, 12.8+/-6.8 y; duration of menopause, 10.9+/-7.4 y; time on alendronate: 4.8+/-2.3 y; body mass index [BMI], 31.4+/-6.3 kg/m2) were matched with 26 controls according to age, BMI, duration of menopause, and alendronate treatment received. All subjects were given alendronate 10 mg/d or 70 mg/wk, along with sufficient vitamin D (>or=400 IU) and calcium (>or=1 g/d) intake, for 4.8 y. Response to alendronate therapy was determined by assessment of mean percent change in BMD of total hip, femoral neck, forearm, and lateral spine. The presence of type 2 DM resulted in no difference in spinal BMD response to alendronate therapy. In contrast, BMD in the total hip (mean percent change in BMD, -5.6% vs +1.4%; P=.096), femoral neck (-8.1% vs +1.1%; P=.015), and forearm (-3.6% vs +12.7%; P=.013) fell progressively from baseline in subjects with type 2 DM who were taking alendronate for 4.8 y, compared with controls. Elderly, postmenopausal, osteoporotic obese women with type 2 DM are resistant to long-term bisphosphonates, especially in regions of the hip, femoral neck, and forearm compared with the spine. The efficacy of bone resorption inhibitors in patients with type 2 DM, especially in comparison with anabolic agents, should be considered in additional studies.