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

  • 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: registration number NCT00523341; registered August 30, 2007
Author: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
Pubmed Id:
Parent Title (English):BMC musculoskeletal disorders
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/04/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/03/13
Tag:Denosumab; Extension study; FREEDOM; Osteoporosis; Selection bias
Issue:1, Art. 174
Page Number:8
First Page:1
Last Page:8
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Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0