TY  - JOUR
A1  - Adachi, Jonathan D.
A1  - Bone, Henry G.
A1  - Daizadeh, Nadia S.
A1  - Dakin, Paula
A1  - Papapoulos, Socrates
A1  - Hadji, Peyman
A1  - Recknor, Chris
A1  - Bolognese, Michael A.
A1  - Wang, Andrea
A1  - Lin, Celia J. F.
A1  - Wagman, Rachel B.
A1  - Ferrari, Serge
T1  - Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study
T2  - BMC musculoskeletal disorders
N2  - 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
KW  - Denosumab
KW  - Osteoporosis
KW  - Selection bias
KW  - Extension study
KW  - FREEDOM
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45829
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-458299
SN  - 1471-2474
N1  - Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
VL  - 18
IS  - 1, Art. 174
SP  - 1
EP  - 8
PB  - BioMed Central
CY  - London
ER  -