Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it