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.
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.
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.
Parallel
a second infusion of ZOL when crosslaps levels reach 300 pg/mL
Druga first infusion of ZOL 5 mg, 6 months after denosumab withdrawal (= study start) and a second infusion when crosslaps levels reach 300 pg/mL, no later than month-12
a rescue second infusion at month-12 (standard traitment)
Druga first infusion of ZOL 5 mg, 6 months after denosumab withdrawal (= study start), and potentially a rescue second infusion at month-12, in case unfavourable outcome (incident osteoporotic fractures) or high risk of unfavourable outcome
Maintain lumbar bone mineral density (BMD) after 1 year of ZOL
The proportion of patients who failed to maintain lumbar BMD after 1 year of ZOL according to the Least Significant Change (LSC) criterion
Maintain hip bone mineral density (BMD) after 1 year of ZOL
The proportion of patients who failed to maintain hip BMD after 1 year of ZOL according to the Least Significant Change (LSC) criterion
the changes in hip and lumbar BMD from baseline
the changes in hip and lumbar BMD from baseline to 1 year, and from year 1 to year 2 after ZOL, according to the Least Significant Change (LSC) criterion
the changes from baseline in bone turnover markers
Bone turnover markers is a composite measure derived from crosslaps, bone alkaline phosphatase, osteocalcin, amino-terminal propeptide of type 1 procollagen, TRAP5b, dickkopf 1, sclerostin
morphometric vertebral fractures
the number of morphometric vertebral fractures measured by vertebral fracture assessment (VFA) or X-rays, of clinical vertebral fractures and of clinical peripheral fractures
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