StrAtegies For Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal oSTeoporosis (SAFEST)

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Yannick DEGBOE, MD; Phone Number: +33 05 61 77 73 75; Email: degboe.y@chu-toulouse.fr
• Study Contact Backup: Name: Charline DAGUZAN; Phone Number: +33 05 61 77 84 90; Email: daguzan.c@chu-toulouse.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • Amiens Hospital
    • Contact: Vincent GOEB
  • Bordeaux, France
    • Recruiting
    • Bordeaux Hospital
    • Contact: Nadia MEHSEN
  • Cahors, France
    • Recruiting
    • Cahors Hospital
    • Contact: Slim LASSOUED
  • Dax, France
    • Recruiting
    • Dax Hospital
    • Contact: Emilie SHIPLEY
  • Le Mans, France
    • Recruiting
    • Le Mans Hospital
    • Contact: Guillaume DIREZ
  • Lille, France
    • Not yet recruiting
    • Lille Hospital
    • Contact: Bernard CORTET
  • Limoges, France
    • Recruiting
    • Limoges Hospital
    • Contact: Anna BILLO
  • Marseille, France
    • Recruiting
    • Marseille Hsopital
    • Contact: Sophie TRIJAU
  • Montpellier, France
    • Recruiting
    • Montpellier Hospital
    • Contact: Paulina SZAFORS
  • Nice, France
    • Recruiting
    • Nice Hospital
    • Contact: Veronique BREUIL
  • Orléans, France
    • Recruiting
    • Orléans Hospital
    • Contact: Eric LESPESSAILLES
  • Paris, France
    • Recruiting
    • Cochin Hospital
    • Contact: Karine BRIOT
  • Paris, France
    • Recruiting
    • Lariboisiere Hospital
    • Contact: Thomas FUNCK-BRENTANO
  • Poitiers, France
    • Recruiting
    • Poitiers Hospital
    • Contact: Guillaume LARID
  • Rennes, France
    • Recruiting
    • Rennes Hospital
    • Contact: François ROBIN
  • Saint-Etienne, France
    • Recruiting
    • Saint Etienne Hospital
    • Contact: Thierry THOMAS
  • Toulouse, France
    • Recruiting
    • Toulouse Hospital
    • Contact: Yannick DEGBOE
    • Sub-Investigator: Anna GOSSET

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive biomarkers-guided arm; A second infusion when crosslaps levels reach 300 pg/mL, no later than month-12	Drug: 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
Active Comparator: Standard treatment arm; Potentially a rescue second infusion at month-12, in case unfavourable outcome (incident osteoporotic fractures) or high risk of unfavourable outcome	Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1 year after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1 year after inclusion
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	Day 0, 1 year after inclusion, 2 year after inclusion
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	1 year after inclusion, 2 year after inclusion
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	1 year after inclusion, 2 year after inclusion
Patients requiring a second ZOL	the proportion of patients requiring a second ZOL infusion across groups.	1 year after inclusion, 2 year after inclusion
Relation between biomarker values and densitometry evolution	the relation is defined by biomarker values (cross laps) and densitometry evolution measured bu osteodensitometry	3, 6, 9, 12 months after inclusion
Relation between biomarker values and appearance of new vertebral fracture	the relation is defined by biomarker values (cross laps) and appearance of new vertebral fracture measured by VFA or X-rays	3, 6, 9, 12 months after inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2025
• Primary Completion (Estimated): October 1, 2030
• Study Completion (Estimated): October 1, 2030

Study Registration Dates

• First Submitted: January 6, 2025
• First Submitted That Met QC Criteria: January 6, 2025
• First Posted (Actual): January 9, 2025

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: withdrawal; Postmenopausal osteoporosis; rebound; strategy; denosumab; zoledronate
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Bone Diseases, Metabolic; Osteoporosis; Nutritional and Metabolic Diseases; Osteoporosis, Postmenopausal
• Other Study ID Numbers: RC31/23/0370

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No