The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 ± 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established.