Cummings, S.R., Ferrari, S., Eastell, R., Gilchrist, N., Jensen, J.‐E.B., McClung, M., Roux, C., Törring, O., Valter, I., Wang, A.T. and Brown, J.P. (2018), Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo‐Controlled FREEDOM Trial and Its Extension. J Bone Miner Res, 33: 190-198.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/29105841
Full text article: https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.3337
| Methods | Study design: Post hoc analysis of participants from a randomised placebo-controlled trial and extension
Number of groups: 3 |
| Participants | Number of participants: 1475
Active group 1 (denosumab discontinued): 327 Active group 2 (denosumab continued): 678 Control group (placebo): 470 Age: Mean 72 Sex: 1475 female (100%) Participants with dementia: Unclear Inclusion criteria: · 60-90 years old · Post-menopausal women BMD T-score <-2.5 at lumbar spine or total hip, or >-4 at both If previously treated for >3 months and <3 years with a bisphosphonate, a 1- year washout was required to participate Exclusion criteria: Previous oral bisphosphonate ≥3 years cumulatively IV bisphosphonate, fluoride, or strontium within last 5 years Parathyroid hormone/derivatives, corticosteroids, systemic HRT, SERM, tibolone, calcitonin, calcitriol, within 6 weeks prior to enrolment Serum 25-hydroxyvitamin D level <12ng/mL Concomitant medicines: 1000mg calcium, ≥400IU cholecalciferol daily Country: USA, UK, Switzerland, New Zealand, Denmark, France, Sweden, Estonia, Canada Setting: Hospital and university outpatient clinics |
| Interventions | Medicine: Denosumab
Intervention: In the FREEDOM trial, active group 1 had denosumab replaced by placebo Withdrawal schedule: Abrupt discontinuation Comparator: Patients who never received denosumab, and patients continuing denosumab |
| Outcomes | Rate of vertebral fractures
Number of new and sustained vertebral fractures Rate of multiple fractures Number and rate of non-vertebral fractures |
| Dates | Dates: Aug 2004-Aug 2008
Follow-up duration: 120 months |
| Funding sources | Amgen Inc funded the initial FREEDOM trial and this post-hoc analysis |
| Notes | Subsequent analysis of the FREEDOM trial |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | Unclear | FREEDOM trial: 1:1 randomisation stratified according to 5-year age group; no further information |
| Allocation concealment (selection bias) | Unclear | Not described |
| Blinding of participants and personnel (performance bias) | Low | Placebo-controlled; does not describe blinding of physicians |
| Blinding of outcome assessment (detection bias) | Low | Data collection and analysis blinded |
| Incomplete outcome data (attrition bias) | Low | Discontinued participants remained in analysis with some adjustments |
| Selective reporting (reporting bias) | High | Post-hoc analysis |
| Other bias | High | Industry sponsored, sponsor had heavy involvement in data management, analysis and presentation |
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