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

BMC Musculoskeletal Disorders

Research Article

Andrea Wang¹  Celia J. F. Lin¹  Rachel B. Wagman¹  Paula Dakin¹  Nadia S. Daizadeh¹  Michael A. Bolognese²  Serge Ferrari³  Peyman Hadji⁴  Socrates Papapoulos⁵  Jonathan D. Adachi⁶  Henry G. Bone⁷  Chris Recknor⁸ 

[1] Amgen Inc., One Amgen Ctr Dr., 91320, Thousand Oaks, CA, USA;Bethesda Health Research Center, 10215 Fernwood Rd Ste 40, 20817, Bethesda, MD, USA;Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Genève, Switzerland;Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany;Leiden University Medical Center, Albinusdreef 2, 2333, Leiden, ZA, Netherlands;McMaster University, 501-25 Charlton Ave E., L8N 1Y2, Hamilton, ON, Canada;Michigan Bone and Mineral Clinic, 22201 Moross Rd, 48236, Detroit, MI, USA;United Osteoporosis Centers, 2350 Limestone Pkwy, 30501, Gainesville, GA, USA;

关键词: Denosumab;    Osteoporosis;    Selection bias;    Extension study;    FREEDOM;   

DOI  :  10.1186/s12891-017-1520-6

 received in 2016-11-30, accepted in 2017-04-06,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDenosumab 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.MethodsTo 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.ResultsExtension 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).ConclusionThe 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 registrationClincalTrials.gov registration number NCT00523341; registered August 30, 2007

【 授权许可】

CC BY   
© The Author(s). 2017