StrAtegies for Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal OSTeoporosis

Phase 4

Not yet recruiting

• Conditions: Postmenopausal Osteoporosis
• Interventions: Drug: a second infusion of ZOL when crosslaps levels reach 300 pg/mL; Drug: a rescue second infusion at month-12 (standard traitment)

• Registration Number: NCT06767150
• Lead Sponsor: University Hospital, Toulouse

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.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-06
• Study First Submitted QC: 2025-01-06
• Last Update Submitted: 2025-01-06
• Study First Posted: 2025-01-09
• Last Update Posted: 2025-01-09
• Study Start: 2025-03
• Primary Completion: 2030-03
• Study Completion: 2030-03

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 200

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intensive biomarkers-guided arm	a second infusion of ZOL when crosslaps levels reach 300 pg/mL	A second infusion when crosslaps levels reach 300 pg/mL, no later than month-12
Standard treatment arm	a rescue second infusion at month-12 (standard traitment)	Potentially a rescue second infusion at month-12, in case unfavourable outcome (incident osteoporotic fractures) or high risk of unfavourable outcome

Primary Outcome Measures

Name	Time	Method
Maintain lumbar bone mineral density (BMD) after 1 year of ZOL	1 year after inclusion	The proportion of patients who failed to maintain lumbar BMD after 1 year of ZOL according to the Least Significant Change (LSC) criterion

Secondary Outcome Measures

Name	Time	Method
the changes from baseline in bone turnover markers	1 year after inclusion, 2 year after inclusion	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	1 year after inclusion, 2 year after inclusion	the number of morphometric vertebral fractures measured by vertebral fracture assessment (VFA) or X-rays, of clinical vertebral fractures and of clinical peripheral fractures
Patients requiring a second ZOL	1 year after inclusion, 2 year after inclusion	the proportion of patients requiring a second ZOL infusion across groups.
Maintain hip bone mineral density (BMD) after 1 year of ZOL	1 year after inclusion	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	Day 0, 1 year after inclusion, 2 year after inclusion	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
Relation between biomarker values and densitometry evolution	3, 6, 9, 12 months after inclusion	the relation is defined by biomarker values (cross laps) and densitometry evolution measured bu osteodensitometry
Relation between biomarker values and appearance of new vertebral fracture	3, 6, 9, 12 months after inclusion	the relation is defined by biomarker values (cross laps) and appearance of new vertebral fracture measured by VFA or X-rays

Trial Locations

Locations (17)

Amiens Hospital; 🇫🇷 Amiens, France

Bordeaux Hospital; 🇫🇷 Bordeaux, France

Cahors Hospital; 🇫🇷 Cahors, France

Dax Hospital; 🇫🇷 Dax, France

Le Mans Hospital; 🇫🇷 Le Mans, France

Lille Hospital; 🇫🇷 Lille, France

Limoges Hospital; 🇫🇷 Limoges, France

Marseille Hsopital; 🇫🇷 Marseille, France

Montpellier Hospital; 🇫🇷 Montpellier, France

Nice Hospital; 🇫🇷 Nice, France

Orléans Hospital; 🇫🇷 Orléans, France

Cochin Hospital; 🇫🇷 Paris, France

Lariboisiere Hospital; 🇫🇷 Paris, France

Poitiers Hospital; 🇫🇷 Poitiers, France

Rennes Hospital; 🇫🇷 Rennes, France

Saint Etienne Hospital; 🇫🇷 Saint-Étienne, France

Toulouse Hospital; 🇫🇷 Toulouse, France