StrAtegies For Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal oSTeoporosis

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат a second infusion of ZOL when crosslaps levels reach 300 pg/mL
  a 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
• Препарат a rescue second infusion at month-12 (standard traitment)
  a 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

Первичные конечные точки

• Maintain lumbar bone mineral density (BMD) after 1 year of ZOL [Срок оценки: 1 year after inclusion]

Вторичные конечные точки (7)

• Maintain hip bone mineral density (BMD) after 1 year of ZOL [Срок оценки: 1 year after inclusion]
• the changes in hip and lumbar BMD from baseline [Срок оценки: Day 0, 1 year after inclusion, 2 year after inclusion]
• the changes from baseline in bone turnover markers [Срок оценки: 1 year after inclusion, 2 year after inclusion]
• morphometric vertebral fractures [Срок оценки: 1 year after inclusion, 2 year after inclusion]
• Patients requiring a second ZOL [Срок оценки: 1 year after inclusion, 2 year after inclusion]
• Relation between biomarker values and densitometry evolution [Срок оценки: 3, 6, 9, 12 months after inclusion]
• Relation between biomarker values and appearance of new vertebral fracture [Срок оценки: 3, 6, 9, 12 months after inclusion]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 17 центров

• Amiens Hospital — Amiens
• Bordeaux Hospital — Bordeaux
• Cahors Hospital — Cahors
• Dax Hospital — Dax
• Le Mans Hospital — Le Mans
• Lille Hospital — Lille
• Limoges Hospital — Limoges
• Marseille Hsopital — Marseille
• … и ещё 9 центров

Идентификаторы

NCT: NCT06767150 · RC31/23/0370

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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