Postmenopausal Osteoporosis
Conditions
Keywords
Postmenopausal osteoporosis, strategy, denosumab, zoledronate, rebound, withdrawal
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.
Interventions
DRUGa 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
DRUGa 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
Sponsors
University Hospital, Toulouse
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| Patients requiring a second ZOL | 1 year after inclusion, 2 year after inclusion | the proportion of patients requiring a second ZOL infusion across groups. |
Countries
France
Contacts
Primary ContactYannick DEGBOE, MD
Backup ContactCharline DAGUZAN
Outcome results
None listed