StrAtegies for Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal OSTeoporosis (SAFEST)

Toulouse University Hospital

Status and phase: Not yet enrolling; Phase 4

Conditions: Postmenopausal Osteoporosis

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

Study type: Interventional

Funder types: Other

Identifiers

NCT06767150

RC31/23/0370

Details and patient eligibility

About

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.

Full 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.

Enrollment: 200 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 2 patient groups

Intensive biomarkers-guided arm

Experimental group

Description:

A second infusion when crosslaps levels reach 300 pg/mL, no later than month-12

Treatment:

Drug: a second infusion of ZOL when crosslaps levels reach 300 pg/mL

Standard treatment arm

Active Comparator group

Description:

Potentially a rescue second infusion at month-12, in case unfavourable outcome (incident osteoporotic fractures) or high risk of unfavourable outcome

Treatment:

Drug: a rescue second infusion at month-12 (standard traitment)