Never stop denosumab without deciding what follows it

Design

GRADE-assessed systematic review and meta-analysis of 6 studies, mostly observational

Population

683 adults with osteoporosis or low bone mass who discontinued denosumab

Primary outcome

incident vertebral fracture after discontinuation

Effect

RR 0.29 (95% CI 0.14 to 0.59) for incident vertebral fracture with sequential alendronate or zoledronic acid

A GRADE-assessed review pooled six studies and 683 patients with osteoporosis or low bone mass who stopped denosumab, comparing those who went on to a potent bisphosphonate - alendronate or zoledronic acid - with those who received no further antiresorptive therapy or a selective oestrogen receptor modulator.

Sequential bisphosphonate was associated with fewer incident vertebral fractures (RR 0.29, 95% CI 0.14 to 0.59), fewer multiple vertebral fractures (RR 0.08, 0.01 to 0.43) and fewer clinical vertebral fractures (RR 0.18, 0.07 to 0.49). There was no significant reduction in any fracture (RR 0.35, 0.10 to 1.24) or non-vertebral fracture (RR 0.43, 0.07 to 2.64). The protection came almost entirely from comparisons against no subsequent therapy; comparisons against a selective oestrogen receptor modulator were few and inconclusive. Certainty was low to very low, because most of the included studies were observational and several estimates were imprecise.

The finding is not new pharmacology - guidelines already recommend sequential therapy - but it is the pooled number to quote, and it aligns the evidence with the recommendation. For an orthopaedic surgeon the relevant version is narrower: patients arrive in fracture clinic having stopped denosumab without a follow-on, often for reasons nobody planned, and the vertebral fracture in front of you is the predictable result. Do not stop or pause denosumab without a written plan for what replaces it, and do not assume the plan exists because someone else prescribes it. A single zoledronic acid infusion, timed to when the next denosumab dose was due, is the pragmatic answer for patients who will not reliably return.

• Never discontinue denosumab without documenting the follow-on antiresorptive and its date
• Prefer zoledronic acid where return visits are unreliable; a single infusion covers the gap
• Time the follow-on to the date the next denosumab dose was due
• Ask about denosumab specifically in any new vertebral fracture - it changes the management
• Do not substitute a selective oestrogen receptor modulator on the strength of this evidence

Why it matters

The fracture risk after stopping denosumab is created by the gap, and the gap is usually administrative rather than clinical.

Don't overread it

Most included studies were observational with low to very low certainty, and the benefit was demonstrated for vertebral fractures only.

The statistics, in plain English

A relative risk of 0.29 means about a 71% lower rate of new vertebral fracture, but the 0.08 figure for multiple fractures rests on very few events - which is why its interval runs from 0.01 to 0.43. Where the interval crosses 1.0, as for non-vertebral fracture (0.07 to 2.64), no effect has been shown and the width tells you the analysis was underpowered rather than that the drug fails there. Low to very low GRADE certainty means the true effect may differ substantially; the direction is more trustworthy than the number.

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