Follow denosumab with a potent bisphosphonate - the vertebral fracture reduction is large

Design

Systematic review and random-effects meta-analysis, GRADE assessed, search to 1 May 2026

Population

Six studies; 683 adults with osteoporosis or low bone mass who discontinued denosumab

Primary outcome

Incident vertebral fracture after denosumab discontinuation

Effect

Incident vertebral fracture RR 0.29 (95 per cent CI 0.14 to 0.59); multiple vertebral RR 0.08 (0.01 to 0.43); clinical vertebral RR 0.18 (0.07 to 0.49); any fracture not significant

Stopping denosumab releases a rebound in bone turnover, rapid bone loss and a well-described spike in vertebral fractures, often multiple. Six studies with 683 participants contributing to the primary analysis were pooled to ask whether alendronate or zoledronic acid afterwards prevents them, against no subsequent antiresorptive or a selective oestrogen receptor modulator.

The effect sizes are large. Incident vertebral fracture risk ratio 0.29 (95 per cent CI 0.14 to 0.59), a 71 per cent relative reduction. Multiple vertebral fractures 0.08 (0.01 to 0.43). Clinical vertebral fractures 0.18 (0.07 to 0.49). What did not reach significance was any fracture (0.35, 0.10 to 1.24) and non-vertebral fracture (0.43, 0.07 to 2.64) - which is what you would expect if the mechanism is specifically the vertebral rebound rather than a general anti-fracture effect. Nearly all the signal came from comparisons against no subsequent therapy; the comparisons against a selective oestrogen receptor modulator were too few to conclude anything.

Certainty was graded low to very low, because most included studies were observational and several outcomes imprecise. That does not weaken the practical instruction, because it points the same way as existing guidelines and because the alternative - stopping denosumab with nothing to follow - has a known and serious harm. The orthopaedic relevance is direct: patients arrive in fracture clinic having quietly stopped denosumab, sometimes because an injection was missed rather than decided. Treat a missed or discontinued dose as an urgent prescribing event, not as a lapse to sort out at the next review.

• Ask every osteoporosis patient in fracture clinic whether they are still receiving denosumab and when the last dose was.
• Treat a missed injection as urgent; the rebound does not wait for the next appointment.
• Arrange alendronate or zoledronic acid to follow any planned discontinuation, before the last dose is given.
• Do not promise a reduction in hip or other non-vertebral fractures; only the vertebral outcomes reached significance.
• Record who is responsible for the follow-on prescription, since this is where the handover between specialties fails.

The statistics, in plain English

Risk ratios of 0.08 to 0.29 are very large effects, but the intervals are wide because the pooled samples are small - 0.01 to 0.43 for multiple fractures rests on few events. The non-significant results for any fracture and non-vertebral fracture have intervals reaching 1.24 and 2.64, so those are unanswered rather than negative. Low to very low certainty means the true effect may differ substantially from these numbers; the direction, which matches guideline advice and a well-understood mechanism, is the trustworthy part.

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