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

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

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.

Study Overview

• Status: Completed
• Conditions: Erosive Osteoarthritis
• Intervention / Treatment: Drug: Alendronate Effervescent Oral Tablet

Detailed Description

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 osteoarthritis (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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 24 weeks; Subject receiving alendronate treatment for 24 weeks (n = 20)	Drug: Alendronate Effervescent Oral Tablet; 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
Experimental: 48 weeks; Subject receiving alendronate treatment for 48 weeks (n = 20)	Drug: Alendronate Effervescent Oral Tablet; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels	Difference in bone turnover marker C-terminal telopeptide of type I collagen (CTX-I) after 48 weeks. Comparisons made within and between both treatment arms	48 weeks
PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels	Difference in Bone Turnover Marker N-terminal propeptide of type I procollagen (PINP) After 48 Weeks. Comparisons are made both within and between both treatment arms.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With CTX-I (C-terminal Telopeptide of Type I Collagen )Levels Above the Reference Range at Week 48	The number of patients that do not maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the bone turnover marker reference range at week 48.	48 weeks
The Number of Patients PINP (N-terminal Propeptide of Type I Procollagen) Above Reference Range at Week 48	The number of patients that do not maintain N-terminal propeptide of type I procollagen (PINP) levels within the bone turnover marker reference range at week 48	48 weeks
Bone Mass Density at the Spine After 48 Weeks	Difference in bone mass density at the spine after 48 Weeks. Comparisons are made both within and between both treatment arms	48 weeks
Bone Mass Density at the Hip After 48 Weeks	Difference in Bone Mass Density at the hip After 48 Weeks. Comparisons are made both within and between both treatment arms.	48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
BMD changes	Other outcomes are changes in T-score at lumbar spine and hip at BMD from baseline to week 24 and week 48.	24 and 48 weeks
Hand radiographic changes	The radiographic changes at the finger joints in terms of new erosive joints and changes according to the Ghent University scoring system (GUSS) between W24 and W48 and baseline.	24 and 48 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Collaborators: Amgen; EffRx Pharmaceuticals SA
• Investigators: Principal Investigator: Ruth Wittoek, Prof. dr., Ghent Universitary Hospital

Publications and helpful links

General Publications

• Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist N, Recknor C, Austin M, Wang A, Grauer A, Wagman RB. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013 Apr;28(4):746-52. doi: 10.1002/jbmr.1808.
• Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.
• Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
• Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012 Jan;23(1):317-26. doi: 10.1007/s00198-011-1780-1. Epub 2011 Sep 17.
• Hodges LA, Connolly SM, Winter J, Schmidt T, Stevens HN, Hayward M, Wilson CG. Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate. Int J Pharm. 2012 Aug 1;432(1-2):57-62. doi: 10.1016/j.ijpharm.2012.04.073. Epub 2012 May 4.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2019
• Primary Completion (Actual): March 9, 2022
• Study Completion (Actual): March 9, 2022

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: May 25, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): December 13, 2024
• Last Update Submitted That Met QC Criteria: December 11, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Physiological Effects of Drugs; Bone Density Conservation Agents; Alendronate
• Other Study ID Numbers: BC-6072

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD that underlie results in a publication will be shared
• IPD Sharing Time Frame: 6 months after publication. Data will stay available for 3 years after publication
• IPD Sharing Access Criteria: acces will be provided upon reasonable request from researchers with a sound clinical research question
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No