Alendronate in an Weekly Effervescent Tablet Formulation Following Denosumab Discontinuation

Study Overview
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Brief Summary
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Discontinuation of denosumab results in a rebound response of bone turnover markers, which rise above baseline at 3 months and remain elevated until reaching again baseline levels approximately 30 months after the last dose. Bone mineral density (BMD) gains are also lost and BMD values reach original baseline values after 1-2 years off-treatment.For the above reasons, current literature recommends that patients who discontinue denosumab should continue to receive either intravenous (iv) or oral (peros) bisphosphonate therapy for some time. The study aims to investigate changes in the BMD of the lumbar spine 12 months after transitioning from denosumab to oral alendronate 70 mg in a weekly effervescent tablet formulation

Detailed Description
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Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κ-Β ligand (RANKL), is a potent antiresorptive agent commonly prescribed in patients with postmenopausal osteoporosis. Discontinuation of denosumab results in a rebound response of bone turnover markers, which rise above baseline at 3 months and remain elevated until reaching again baseline levels approximately 30 months after the last dose. Bone mineral density (BMD) gains are also lost and BMD values reach original baseline values after 1-2 years off-treatment, in contrast to bisphosphonates, which remain within the skeleton acting for several months or even years after discontinuation while preserving most of the BMD gains achieved despite the cessation of treatment. For the above reasons, current literature recommends that patients who discontinue denosumab should continue to receive either intravenous (iv) or oral (peros) bisphosphonate therapy for some time. Due to lack of specifically designed studies, the period of treatment with bisphosphonates after denosumab discontinuation has been arbitrarily proposed to be 1 to 2 years. Preservation of BMD gains after denosumab discontinuation has so far been demonstrated: (a) with one year of alendronate treatment, in a study designed to investigate patients' compliance to treatment, and b) with a single dose of zolendronate 5mg iv in a recent study specifically designed to address this question in which BMD levels remained stable for the next two years. Preventing bone loss, and the reported high risk of multiple vertebral fractures after discontinuation of denosumab treatment, is a clinical issue of critical importance raising serious concerns to the international scientific community and needs to be addressed. Clinical studies specifically designed to investigate both the efficacy of various bisphosphonates and the optimal duration of their administration in order to avoid the reported adverse effects of denosumab discontinuation are currently lacking. This study aims to investigate changes in the BMD of the lumbar spine (LS) and femoral neck (FN) 12 months after transitioning from denosumab to oral alendronate 70 mg in a weekly effervescent tablet formulation. Alendronate will be given either for 6 or 12 months following Denosumab discontinuation

Official Title
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Alendronate in an Weekly Effervescent Tablet Formulation for Preservation of Bone Mass After Denosumab Discontinuation in Postmenopausal Women With Low Bone Mass. An Observational Study (Binosto After Denosumab - The BAD Study)

Conditions
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Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: Binosto 70Mg Effervescent Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: i) osteopenic postmenopausal Caucasian women following Dmab treatment ii) assignment to treatment with alendronate in an effervescent tablet formulation following Dmab discontinuation Exclusion Criteria: i) secondary osteoporosis; ii) diseases that could affect bone metabolism iii) medications that could affect bone metabolism iv) chronic kidney disease (stage >3b) and/or liver failure v) neoplastic disease vi) hypersensitivity to alendronate or to any of the excipients vii) abnormalities of the esophagus and other factors which delay esophageal emptying such as stricture or achalasia viii) inability to stand or sit upright for at least 30 minutes ix) hypocalcaemia x) confirmed esophagitis

Ages Eligible for Study
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Maximum Age: 90 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group Alendronate 6m<br>Postmenopausal Caucasian women who were treated with denosumab and became osteopenic (BMD T-score of > -2.5 at the LS and the non-dominant FN) and were assigned from their treating physician to receive treatment with alendronate in an effervescent tablet formulation for 6 months and then followed for another 6 months without medication. In case serum P1NP levels are > 35μg/L and/or serum CTX levels are > 280 ng/L at 9 months (3 months following alendronate discontinuation) the patients would be strongly advised to restart alendronate treatment. | Drug: Binosto 70Mg Effervescent Tablet<br>* As discussed in group descriptions<br>* Other names: calcium carbonate 1000 mg/d and cholecalciferol 800 IU/d;|
| Group Alendronate 12m<br>Postmenopausal Caucasian women who were treated with denosumab and became osteopenic (BMD T-score of > -2.5 at the LS and the non-dominant FN) and were assigned from their treating physician to receive treatment with alendronate in an effervescent tablet formulation for 12 months. | Drug: Binosto 70Mg Effervescent Tablet<br>* As discussed in group descriptions<br>* Other names: calcium carbonate 1000 mg/d and cholecalciferol 800 IU/d;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Mineral Density LS | Changes in the BMD of the lumbar spine 12 months after transitioning from denosumab to oral alendronate 70 mg in a weekly effervescent tablet formulation. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Mineral Density FN | Changes in the BMD of the femoral neck (FN) of the non-dominant hip 12 months after transitioning from denosumab to oral alendronate 70 mg in a weekly effervescent tablet formulation | 12 months | 
| Serum levels of bone turnover markers (BTMs): P1NP, CTX and TRAP5b | Changes in BTMs 12 months after transitioning from denosumab to oral alendronate 70mg in a weekly effervescent tablet formulation. | 12 months | 
| Comparison of Bone Mineral Density LS | Comparison of changes in the BMD of the LS after transitioning from denosumab to 12 months versus 6 months of treatment with oral alendronate 70 mg in a weekly effervescent tablet formulation. | 12 months | 
| Comparison of Bone Mineral Density FN | Comparison of changes in the BMD of the FN of the non-dominant hip after transitioning from denosumab to 12 months versus 6 months of treatment with oral alendronate 70mg in a weekly effervescent tablet formulation. | 12 months | 
| Comparison of changes in: the serum levels of bone turnover markers (BTMs) P1NP, CTX and TRAP5b; the 24-hours urine levels of calcium | Comparison of changes in the levels of serum BTMs and 24hours urine calcium after 12 months versus 6 months treatment with oral alendronate 70mg in a weekly effervescent tablet formulation in patients previously treated with denosumab | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Denosumab, Alendronate, osteoporosis, discontinuation of treatment