Gastrectomy/gastric bypass has been used for patients with gastric cancer, and its application is now expanding to treating patients with morbid obesity, the prevalence of which is increasing worldwide. It is well known that gastrectomy leads to osteopenia, but the underlying pathophysiology and optimum treatments for this disorder have not been delineated. We followed 13 patients who showed progressive osteopenia (bone mineral density T-score<-2.4 SD) after gastrectomy/gastric bypass due to gastric cancer and who were resistant to long-term treatment (mean, 6 years) of active vitamin D3 and prospectively studied the effects of alendronate, a bisphosphonate, on osteopenia-related parameters for 2 years. Oral administration of alendronate in addition to vitamin D3 led to remarkable improvement within 2 years, not only in clinical symptoms, such as radial bone fractures and lumbar pain, but also in parameters for osteopenia, including decreased bone mineral density of the lumbar spine (P<0.01), decreased concentrations of calcium (P<0.05), increased urine levels of deoxypyridinoline (P<0.01), increased serum levels of bone-specific alkaline phosphatase (P<0.01), increased serum levels of osteocalcin (P<0.01), and increased serum levels of intact parathyroid hormone (P<0.05), although body weight did not alter. These results suggest that bisphosphonate may improve osteopenia after gastrectomy/gastric bypass.