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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2017

Open Access 01-12-2017 | Research article

Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study

Authors: Jonathan D. Adachi, Henry G. Bone, Nadia S. Daizadeh, Paula Dakin, Socrates Papapoulos, Peyman Hadji, Chris Recknor, Michael A. Bolognese, Andrea Wang, Celia J. F. Lin, Rachel B. Wagman, Serge Ferrari

Published in: BMC Musculoskeletal Disorders | Issue 1/2017

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Abstract

Background

Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.

Methods

To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.

Results

Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).

Conclusion

The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.

Trial registration

ClincalTrials.gov registration number NCT00523341; registered August 30, 2007
Appendix
Available only for authorised users
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Metadata
Title
Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study
Authors
Jonathan D. Adachi
Henry G. Bone
Nadia S. Daizadeh
Paula Dakin
Socrates Papapoulos
Peyman Hadji
Chris Recknor
Michael A. Bolognese
Andrea Wang
Celia J. F. Lin
Rachel B. Wagman
Serge Ferrari
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2017
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-017-1520-6

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