ABSTRACTStopping treatment for osteoporosis with denosumab (Dmab) leads to a major and rapid loss in bone mineral density (BMD) and a risk of vertebral fracture. Subsequent treatment with bisphosphonate (Bp) does not completely prevent this bone loss. We carried out a prospective pilot study to find out whether the gradual dose reduction with denosumab could prevent this bone loss. We proposed a therapeutic protocol consisting in reducing the doses of Dmab to women treated with Dmab for postmenopausal osteoporosis. Six months after the last dose of Dmab 60 mg, the subsequent injection was performed with a reduced dose of 30 mg, and the month‐12 injection was a 15‐mg injection. BMD and serum C‐terminal telopeptide of type I collagen (CTX) were measured at the start of treatment with Dmab (T0), at the last dose with 60 mg (T1), and at 6 months (T2) and 12 months (T3) after the last 15 mg Dmab injection. We included 13 patients aged 68.7 ± 3 years, and treated with Dmab for 45.2 ± 5 months. At the lumbar spine, 39% of the initial gain in BMD was preserved 1 year after the last dose (15 mg). Conversely, at the hip, the bone loss at the end of the treatment reduction protocol was equivalent to the initial gain. The mean CTX level was 166 ± 152 pg/mL 6 months after the last dose (T2; 15 mg), and 549 ± 425 pg/mL 12 months after the last dose (T3; 15 mg). One patient presented two vertebral fractures, 8 months after the last dose of Dmab (15 mg). Gradual dose reduction of denosumab (30 mg then 15 mg) does not prevent bone loss in the hip and partially maintains the initial gain at the spine. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.