Alendronate has been shown to reduce bone turnover and increase bone mass. However, little is known about the duration of the effect on bone after treatment withdrawal. The aim of this study was to investigate the long-term effects on bone mineral density (BMD) and bone turnover of various alendronate regimens after treatment withdrawal. In this study, we followed 203 postmenopausal women who previously participated in two alendronate randomized placebo-controlled trials. Daily oral treatment with various doses of alendronate (2.5-20 mg) were given for 2, 4, or 6 yr followed by no treatment for 7, 5, or 3 yr, respectively. Bone mineral density of the lumbar spine, hip, and forearm was measured by dual-energy x-ray absorptiometry. Biochemical markers of bone turnover were induced serum C-terminal telopeptides of type I collagen (CTX) and osteocalcin. Women who received alendronate (2.5-10 mg per day) for 2 yr had a 3.8% higher BMD compared to those receiving placebo when assessed 7 yr after withdrawal. The residual effect was proportionally larger in women who had received treatment for 4 (5.9%, P=0.02) or 6 yr (8.6%, P=0.002), respectively. However, the largest residual effect was found in women treated with alendronate 20 mg per day for 2 yr (9.7%, P=0.01 vs. placebo). The rate of bone loss after alendronate withdrawal was comparable to the bone loss observed in the placebo group. Bone markers tended to reverse back to normal levels, but were still affected even several years after withdrawal of treatment. This study has demonstrated that the efficacy of alendronate in preventing bone loss was proportional to the duration of treatment. The rate of bone loss after withdrawal of alendronate corresponded to the normal postmenopausal rate of bone loss. A residual effect on BMD was found up to 7 yr after treatment withdrawal.