The Use of Steovess/Binosto After Denosumab Discontinuation to Prevent Increase in Bone Turnover

Study Overview
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Brief Summary
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It is hypothesized that effervescent alendronate will be able to maintain bone turnover markers within the pre-menopausal reference range and thereby reducing the likelihood of bone turnover associated changes (rebound effect), after discontinuation of denosumab treatment in a non-osteoporotic population.

Detailed Description
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Denosumab discontinuation is associated with a rebound effect in bone turnover and loss in bone mass density. These changes resulted in an increase of fracture incidence in patients with postmenopausal osteoporosis back to background levels. However, no excess in fracture incidence was observed. Amongst patients who presented with vertebral fractures after treatment discontinuation, there was a slightly higher incidence of multiple vertebral fractures in patients discontinuing Prolia versus those who discontinued the placebo treatment. A 2 year, randomized, crossover study demonstrated that alendronate intake after discontinuing denosumab treatment, lead to remaining stable bone mass densitometry (BMD) values in postmenopausal women. In a study within a non-osteoporotic study population, ongoing at our department, increases in bone turnover are to be expected as soon as patients end study participation (i.e. open label treatment with denosumab, Prolia, anti-RANK ligand inhibition). It is currently recommended that alternative anti-resorptive therapy may be warranted after Prolia discontinuation. One study describes the use of oral alendronate after denosumab therapy to maintain bone mineral density. However, gastro-intestinal upset and tolerability, as well as difficulty in swallowing pills may limit oral alendronate compliance. To attenuate this concern, buffered soluble (effervescent) alendronate 70 mg, developed with the aim to improve the gastrointestinal tolerability through full dissolution of alendronate in buffered palatable solution before ingestion, will be used. This study wants to provide a follow up and study wether the use of effervescent alendronate after previous denosumab treatment can prevent a rebound effect in bone turnover that is to be expected when denosumab is discontinued. Subjects that completed our erosive hand OA study and therefore discontinued denosumab 60 mg/every 3 months, will receive alendronate. Moreover, the study wants to asses if there is difference between using alendronate for six or twelve months, starting at the earliest three months but no later than four months after the last injection of denosumab.

Official Title
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The Use of Buffered Soluble Alendronate 70 mg (Steovess/Binosto) After Denosumab Discontinuation to Prevent Increase in Bone Turnover

Conditions
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Erosive Osteoarthritis

Intervention / Treatment
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* Drug: Alendronate Effervescent Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have completed the 48 weeks of the randomised placebo-controlled study phase followed by the 96 weeks open label denosumab 60 mg SC every 3 months phase. (EudraCT number: 2015-003223-53) Last denosumab injection minimal 3 months or maximum 4 months before baseline Able and willing to give written informed consent and to comply with the requirements of the study protocol Exclusion Criteria: Patients with clinically significant hypersensitivity to any of the components of effervescent alendronate. Patient who is pregnant or planning pregnancy Female subjects who are breast-feeding. History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction or other unhealed dental surgery; or planned invasive dental work during the study Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures Hypocalcaemia. Oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-intestinal bleeding, or surgery of the upper gastro-intestinal tract other than pyloroplasty. Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as stricture or achalasia. Inability to stand or sit upright for at least 30 minutes.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 40 subjects randomized in 2 groups (n=20). 1 group will receive effervescent alendronate treatment for 24 weeks, the other group will receive the same treatment for 48 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 24 weeks<br>Subject receiving alendronate treatment for 24 weeks (n = 20) | Drug: Alendronate Effervescent Oral Tablet<br>* At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks<br>|
| Experimental: 48 weeks<br>Subject receiving alendronate treatment for 48 weeks (n = 20) | Drug: Alendronate Effervescent Oral Tablet<br>* At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone turnover marker above the premenopausal reference range at week 48 | the number of patients that maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the premenopausal reference range at week 48 | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone turnover marker above the premenopausal reference range at week 12 and week 24 | The number of patients that maintain CTx-I levels within the premenopausal reference range at week 12 and 24 as well as the changes in CTx-I and N-terminal propeptide of type I procollagen (P1NP) levels from baseline until 12, 24 and 48 weeks | 12, 24 and 48 weeks |