Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | BMC Musculoskeletal Disorders |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12891-017-1520-6 |
| _version_ | 1819130080589250560 |
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| 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 |
| author_facet | 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 |
| author_sort | Jonathan D. Adachi |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-22T08:53:56Z |
| format | Article |
| id | doaj.art-82d84359d66240d5b137491968ed5b27 |
| institution | Directory Open Access Journal |
| issn | 1471-2474 |
| language | English |
| last_indexed | 2024-12-22T08:53:56Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Musculoskeletal Disorders |
| spelling | doaj.art-82d84359d66240d5b137491968ed5b272022-12-21T18:31:53ZengBMCBMC Musculoskeletal Disorders1471-24742017-04-011811810.1186/s12891-017-1520-6Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension studyJonathan D. Adachi0Henry G. Bone1Nadia S. Daizadeh2Paula Dakin3Socrates Papapoulos4Peyman Hadji5Chris Recknor6Michael A. Bolognese7Andrea Wang8Celia J. F. Lin9Rachel B. Wagman10Serge Ferrari11McMaster UniversityMichigan Bone and Mineral ClinicAmgen Inc., One Amgen Ctr Dr.Amgen Inc., One Amgen Ctr Dr.Leiden University Medical CenterKrankenhaus NordwestUnited Osteoporosis CentersBethesda Health Research CenterAmgen Inc., One Amgen Ctr Dr.Amgen Inc., One Amgen Ctr Dr.Amgen Inc., One Amgen Ctr Dr.Geneva University HospitalAbstract 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, 2007http://link.springer.com/article/10.1186/s12891-017-1520-6DenosumabOsteoporosisSelection biasExtension studyFREEDOM |
| spellingShingle | 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 Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study BMC Musculoskeletal Disorders Denosumab Osteoporosis Selection bias Extension study FREEDOM |
| title | Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study |
| title_full | Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study |
| title_fullStr | Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study |
| title_full_unstemmed | Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study |
| title_short | Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study |
| title_sort | influence of subject discontinuation on long term nonvertebral fracture rate in the denosumab freedom extension study |
| topic | Denosumab Osteoporosis Selection bias Extension study FREEDOM |
| url | http://link.springer.com/article/10.1186/s12891-017-1520-6 |
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