Purpose: Treatment with denosumab (DMAB) decreases bone resorption and fracture risk. Following discontinuation, bone resorption increases, bone mass is lost and fractures have been reported. The aim of the study was to investigate if an infusion of zoledronic acid (ZOL) can prevent increases in bone turnover and bone loss in patients previously treated with DMAB and if the timing of the ZOL infusion is important. Methods: The study was a 2-year randomized, open label, interventional study in patients with osteopenia after DMAB treatment for an average of 4.6 years. ZOL was administrated 6 months (6M group, n=20) or 9 months (9M group, n=20) after the last DMAB injection or when bone turnover was increased (OBS group, n=20). Patients in the OBS and the 9M groups were monitored closely and if p-carboxy-terminal collagen crosslinks (CTX) increased > 1.26 ug/l (50% above the range for postmenopausal women and elderly men), if BMD decreased > 5% at the lumbar spine or total hip, or if a patient suffered a low energy vertebral or hip fracture, ZOL was administered. In the OBS group, ZOL was administered no later than month 6. The patients were monitored with DXA 6, 12 and 24 months after treatment. ZOL was re-administered if BMD decreased > 5% at the lumbar spine or total hip or if CTX increased above 1.26 ug/l. We report the outcome 12 months after the initial ZOL infusion. The study is ongoing. Results: A total of 60 postmenopausal women and men with a mean age of 67.7 (range 51-85) years were enrolled in the study. In the OBS group 1, 2, 6, 1 and 0 patients fulfilled the CTX or BMD criteria for treatment 1, 2, 3, 4 and 5 months after baseline. The remaining 10 patients were treated at month 6. In the 9M group 2 patients fulfilled the CTX criteria for ZOL treatment at month 2. A total of 10, 5 and 5 patients in the 6M, 9M and OBS groups, respectively were re-retreated. In the 6M group CTX decreased initially, but increased rapidly thereafter, and 6 months after ZOL, CTX was 0.60±0.08 g/L (mean±SEM). CTX increased rapidly in the 9M and OBS Groups before ZOL, was suppressed by ZOL but increased again thereafter; CTX was 0.47±0.05 μg/L and 0.47±0.05 μg/L 6 months after ZOL in the 9M and the OBS groups, respectively. Mean CTX was within the premenopausal reference range 12 months after ZOL in all 3 groups. From study baseline to twelve months after ZOL BMD at the lumbar spine had decreased by 4.8±0.7%, 4.1±1.1%, and 4.7±1.2% in the 6M, 9M and OBS groups, respectively (p≤0.002 for all without differences between groups) and at the total hip by 2.6±0.5%, 3.2±0.8%, and 3.6±0.8% in the 6M, 9M and OBS groups, respectively (p≤0.001 for all without differences between groups). The decline in BMD was more pronounced in the months before ZOL in the 9M and OBS groups whereas the decline was steadier in the 6M group. Conclusion: Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients with osteopenia.