Claim

In adults with autoimmune disease or glucocorticoid-treated osteoporosis, denosumab dosing gaps extending beyond roughly 7 months without sequential antiresorptive therapy will produce a sharply higher short-term cluster of vertebral fractures than gaps of 6 months or less, with the strongest excess concentrated in patients with prior vertebral fracture and chronic glucocorticoid exposure.

Rationale

Denosumab suppresses osteoclast activity reversibly. When treatment is delayed or stopped, bone turnover can rebound rapidly, and vertebral fractures may occur in temporal clusters rather than as isolated late events. Autoimmune cohorts may be especially vulnerable because chronic glucocorticoids and prior fragility fractures reduce skeletal reserve.

Testable design

• Multicenter retrospective-prospective cohort of denosumab-treated autoimmune or glucocorticoid-exposed patients
• Exposure groups: <=6 months, >6 to 7 months, >7 to 9 months, and >9 months since last dose
• Primary outcome: incident vertebral fracture within 12 months of scheduled-dose interruption
• Key covariates: prior vertebral fracture, prednisone exposure, denosumab duration, age, prior bisphosphonate use
• Analysis: time-dependent Cox model with restricted cubic splines for interruption duration

Falsification criterion

The hypothesis is weakened if interruption duration beyond 7 months shows no meaningful hazard increase after adjustment for prior fracture, steroid exposure, and baseline bone fragility, or if sequential bisphosphonate cover does not materially attenuate risk.

Clinical value

If true, this would support explicit rebound-risk triage and more urgent rescue pathways in rheumatology and autoimmune bone-health workflows.

References

1. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab. J Bone Miner Res. 2018;33(2):190-198. DOI: 10.1002/jbmr.3337
2. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy. J Clin Endocrinol Metab. 2021;106(1):264-281. DOI: 10.1210/clinem/dgaa756
3. Anastasilakis AD, Polyzos SA, Makras P. Denosumab discontinuation and the rebound phenomenon. Eur J Endocrinol. 2021;184(4):R137-R145. DOI: 10.1530/EJE-20-1210