Discontinuing denosumab is associated with bone loss and possibly increased fracture risk. We investigated if treatment with zoledronate (ZOL) could prevent bone loss and if the timing of the ZOL infusion influenced the outcome. We report on a 2‐year randomized, open label, interventional study including 61 patients with osteopenia, discontinuing denosumab after 4.6 ± 1.6 years. We administrated ZOL 6 months (6M group, n = 20) or 9 months (9M group, n = 20) after the last denosumab injection or when bone turnover had increased (OBS group, n = 21). We monitored the patients with DXA and bone turnover markers. Our primary endpoints were change in lumbar spine BMD (LSBMD) 6 months after ZOL and the proportion of patients who failed to maintain BMD. The study is ongoing (clinicaltrials.gov;​ NCT03087851). We included 61 participants and 59 patients completed follow‐up 12 months after ZOL. Six months after ZOL, LSBMD had decreased significantly by (mean ± SE) 2.1% ± 0.9%, 4.3% ± 1.1%, and 3.0% ± 1.1% in the 6M, 9M, and OBS groups, respectively, and by 4.8% ± 0.7%, 4.1% ± 1.1%, and 4.7% ± 1.2% 12 months after ZOL in the 6M, 9M, and OBS groups, respectively (p < .02, no between‐group differences). BMD loss above the least significant change was seen in all groups;​ at the spine:​ 6M, n = 6 (30%);​ 9M, n = 9 (45%);​ and OBS, n = 9 (47%);​ and at the total hip:​ 6M, n = 1 (5%);​ 9M, n = 5 (25%);​ and OBS, n = 2 (11%). In the 6M group p‐crosslinked C‐terminal telopeptide (p‐CTX) decreased initially, but increased rapidly thereafter, and 6 months after ZOL, p‐CTX was 0.60 ± 0.08 g/L. p‐CTX increased rapidly in the 9M and OBS groups, was suppressed by ZOL but increased again thereafter;​ p‐CTX was 0.47 ± 0.05 μg/L and 0.47 ± 0.05 μg/L in the 9M and OBS groups 6 months after ZOL, respectively. Incident vertebral fractures were seen in two women in the 9M group. Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients discontinuing denosumab.