strategies for zoledronic acid post-denosumab discontinuation in postmenopausal osteoporosis

Conditions: Postmenopausal Osteoporosis

Summary: denosumab (dmab) is a treatment for postmenopausal osteoporosis. however, its withdrawal is associated with a rebound phenomenon associated with an unexpected increased risk of vertebral fractures. defining the optimal strategy for dmab withdrawal is critically needed. investigator propose an open-label randomized superiority strategy trial to compare the 1-year lumbar densitometric efficacy of biomarkers-driven zoledronate (zol) infusion vs standardized zol treatment to mitigate rebound phenomenon.

denosumab (dmab) is a potent and validated treatment for postmenopausal osteoporosis. however, its withdrawal, especially after reaching therapeutic target, is associated with a rebound phenomenon characterized by: (i) an increase in bone turnover markers levels usually within first 6 months off-treatment, (ii) a decrease in bmd, and (iii) an unexpected increased risk of (multiple) vertebral fractures. although current experts' recommendations propose a post-dmab bisphosphonates therapy (such as zol) to mitigate rebound phenomenon, the optimal strategy is still matter of debate. data suggesting a protective effect with bisphosphonates (1 infusion of zol or weekly alendronate) are scarce, with discrepancies, and highlight that a substantial proportion of patients experiences rebound-related bone loss despite bisphosphonate therapy. crosslaps, a bone turnover maker, are available for daily clinical practice and reflect the antiresorptive activity of anti-resorptive drugs such as bisphosphonates. investigator hypothesize that monitoring crosslaps levels, can help to identify patients requiring more intensive bisphosphonate (additional zol infusion) therapy to control the post-dmab rebound phenomenon. investigator propose to compare 2 strategies for dmab withdrawal in postmenopausal osteoporosis: a standard treatment control group treated with a single zol infusion versus a biomarker-guided zol group with an additional zol infusion in case of insufficient inhibition of bone resorption according to crosslaps.

Eligibility criteria:
inclusion criteria: * women with post-menopausal osteoporosis * and treated with denosumab for at least 2 years and reaching decision of denosumab withdrawal because of achieved therapeutic target defined as no fracture during treatment; no new risk factors; no bmd decrease \> 0.03 g/cm² at the spine or hip; * and with a history of severe fracture or a femoral or lumbar t-score ≤ -2.5 prior denosumab initiation. exclusion criteria: * dmab use for bone disease other than post-menopausal osteoporosis. * uncontrolled endocrine diseases. liver failure. * use of medication affecting bone metabolism during the last year, including bisphosphonates, teriparatide, romosozumab, selective estrogen receptor modulators, breast cancer hormonotherapy, glucocorticoids over 5 mg/day. * contra-indication to bisphosphonates according to license recommendation including chronic kidney disease with gfr stage \> or = g3b. prior intolerance to zoledronic acid. * subjects unable to give an informed consent or to fill the case report form. subjects under law protection. * foreseeable poor compliance with the strategy, alcoholism, toxicomania.

Keywords: postmenopausal osteoporosis strategy denosumab zoledronate rebound withdrawal