Postmenopausal OsteoporosisPhase 4SAFESTNCT06767150
StrAtegies For Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal oSTeoporosis
A Phase 4 study testing a second infusion of ZOL when crosslaps levels reach 300 pg/mL and a rescue second infusion at month-12 (standard traitment) in people with Postmenopausal Osteoporosis, run by University Hospital, Toulouse at 17 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Postmenopausal Osteoporosis
- What is being tested?
- a second infusion of ZOL when crosslaps levels reach 300 pg/mL and a rescue second infusion at month-12 (standard traitment)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 17 sitesFrance
- Study dates
- 2 Oct 2025to Oct 2030
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
17 sites in 1 country. Contact the study team or a site near you to ask about taking part.
17 sites in 1 country
France17 sites, 17 recruiting
- Recruiting
Amiens Hospital
Amiens
Vincent GOEB
- Recruiting
Bordeaux Hospital
Bordeaux
Nadia MEHSEN
- Recruiting
Cahors Hospital
Cahors
Slim LASSOUED
- Recruiting
Dax Hospital
Dax
Emilie SHIPLEY
- Recruiting
Le Mans Hospital
Le Mans
Guillaume DIREZ
- Not yet recruiting
Lille Hospital
Lille
Bernard CORTET
- Recruiting
Limoges Hospital
Limoges
Anna BILLO
- Recruiting
Marseille Hsopital
Marseille
Sophie TRIJAU
- Recruiting
Montpellier Hospital
Montpellier
Paulina SZAFORS
- Recruiting
Nice Hospital
Nice
Veronique BREUIL
- Recruiting
Orléans Hospital
Orléans
Eric LESPESSAILLES
- Recruiting
Cochin Hospital
Paris
Karine BRIOT
- Recruiting
Lariboisiere Hospital
Paris
Thomas FUNCK-BRENTANO
- Recruiting
Poitiers Hospital
Poitiers
Guillaume LARID
- Recruiting
Rennes Hospital
Rennes
François ROBIN
- Recruiting
Saint Etienne Hospital
Saint-Etienne
Thierry THOMAS
- Recruiting
Toulouse Hospital
Toulouse
Yannick DEGBOE
Anna GOSSET
About this study
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.
Read the 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.
- Conditions
- Postmenopausal Osteoporosis
- Being tested
- a second infusion of ZOL when crosslaps levels reach 300 pg/mL, a rescue second infusion at month-12 (standard traitment)
- Keywords
- Postmenopausal osteoporosis, strategy, denosumab, zoledronate, rebound, withdrawal
- Medical subject headings
- Osteoporosis, Postmenopausal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
a second infusion of ZOL when crosslaps levels reach 300 pg/mLDrug
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
a rescue second infusion at month-12 (standard traitment)Drug
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
| Study group | Role | What they receive |
|---|---|---|
| Intensive biomarkers-guided arm | Experimental | A second infusion when crosslaps levels reach 300 pg/mL, no later than month-12 Receives: Drug: a second infusion of ZOL when crosslaps levels reach 300 pg/mL |
| Standard treatment arm | Active comparator | Potentially a rescue second infusion at month-12, in case unfavourable outcome (incident osteoporotic fractures) or high risk of unfavourable outcome Receives: Drug: a rescue second infusion at month-12 (standard traitment) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 1 year after inclusion
Secondary outcomes (7)
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
Measured: 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
Measured: 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
Measured: 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
Measured: 1 year after inclusion, 2 year after inclusion
Patients requiring a second ZOL
the proportion of patients requiring a second ZOL infusion across groups.
Measured: 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
Measured: 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
Measured: 3, 6, 9, 12 months after inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2025
- Study start2 Oct 2025
- Primary completionOct 2030 (estimated)
- Study completionOct 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Postmenopausal OsteoporosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Toulouse
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06767150
- Sponsor's protocol ID
- RC31/23/0370
- Acronym
- SAFEST
- Status last verified
- Dec 2025
- First submitted
- 6 Jan 2025
- Last updated
- 31 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No