Clinical trial NCT06767150: StrAtegies for Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal OSTeoporosis
Official title: StrAtegies for Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal OSTeoporosis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Postmenopausal Osteoporosis
Keywords: Postmenopausal osteoporosis
strategy
denosumab
zoledronate
rebound
withdrawal
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2025-01-09
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Primary outcomes:
measure: Maintain lumbar bone mineral density (BMD) after 1 year of ZOL
timeFrame: 1 year after inclusion
Secondary outcomes:
measure: Maintain hip bone mineral density (BMD) after 1 year of ZOL
timeFrame: 1 year after inclusion
measure: the changes in hip and lumbar BMD from baseline
timeFrame: Day 0, 1 year after inclusion, 2 year after inclusion
measure: the changes from baseline in bone turnover markers
timeFrame: 1 year after inclusion, 2 year after inclusion
measure: morphometric vertebral fractures
timeFrame: 1 year after inclusion, 2 year after inclusion
measure: Patients requiring a second ZOL
timeFrame: 1 year after inclusion, 2 year after inclusion
measure: Relation between biomarker values and densitometry evolution
timeFrame: 3, 6, 9, 12 months after inclusion
measure: Relation between biomarker values and appearance of new vertebral fracture
timeFrame: 3, 6, 9, 12 months after inclusion
Other outcomes:
Locations:
city: Amiens
country: France
facility: Amiens Hospital
city: Bordeaux
country: France
facility: Bordeaux Hospital
city: Cahors
country: France
facility: Cahors Hospital
city: Dax
country: France
facility: Dax Hospital
city: Le Mans
country: France
facility: Le Mans Hospital
city: Lille
country: France
facility: Lille Hospital
city: Limoges
country: France
facility: Limoges Hospital
city: Marseille
country: France
facility: Marseille Hsopital
city: Montpellier
country: France
facility: Montpellier Hospital
city: Nice
country: France
facility: Nice Hospital
city: Orléans
country: France
facility: Orléans Hospital
city: Paris
country: France
facility: Cochin Hospital
city: Paris
country: France
facility: Lariboisiere Hospital
city: Poitiers
country: France
facility: Poitiers Hospital
city: Rennes
country: France
facility: Rennes Hospital
city: Saint-Étienne
country: France
facility: Saint Etienne Hospital
city: Toulouse
country: France
facility: Toulouse Hospital
Study officials:
References: