Fracture and Skeletal-Related Event Rates During Antiresorptive Drug Holidays

confidence: high · 2 sources

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Working research — not a recommendation.

This page records what the evidence says a policy does, not what anyone should do about it. It has been synthesized from the cited sources but has not been independently reviewed.

What the evidence says

The sources on this page are thin. They contain no measured fracture or skeletal-related event (SRE) rates for bisphosphonate drug holidays, and no numeric effect sizes for any outcome. The one drug with direct evidence is denosumab.

For denosumab, a review in the Cleveland Clinic Journal of Medicine reports that fracture risk did not increase in patients randomized to stop treatment. The same source reports that bone mineral density increased further when treatment was restarted. The review gives no effect size or confidence interval. Its authors state that a drug holiday cannot presently be recommended for patients receiving denosumab because supportive data are lacking. This is a finding of no measured effect, and the authors themselves say the data are too sparse to rest a conclusion on.

The same review reports a change in surrogate markers. A phase 2 extension study suggests that bone mineral density starts to decline and bone turnover markers start to rise within 12 months of stopping denosumab. The source gives no size for the decline. Its wording is tentative ("suggest"), but the 12-month timing is stated. The evidence on this page therefore has two parts: bone density falls and turnover rises after stopping, but fracture risk was not measured as higher.

For skeletal-related events, the only claim is speculation. A 2020 systematic review in Heliyon says an antiresorptive drug holiday "may also increase the risk of SREs", including recurrence of bone pain and possibly progression of bone metastases. That review did not measure SRE rates during drug holidays. The statement is a hypothesis about pharmacokinetics, not a finding from its included studies. No source on this page measures SRE rates during a holiday, so the direction and size of that effect are unknown.

Where the evidence splits

No contradictions in the current sources.

Thresholds and dose-response

No threshold established in the current sources.

Open empirical questions

Findings

Stopping denosumab shows no measured effect on fracture risk

confidence — direction: highconfidence — magnitude: lowconsensus: thin — a single review reports it, and the authors themselves say the data are insufficient
mechanism
not established in the source; the source reports the outcome only
effect
no measured effect; fracture risk did not increase in patients randomized to stop treatment, with no effect size or confidence interval given
conditions / moderators
denosumab only; the authors state that a drug holiday cannot presently be recommended because supportive data are lacking; not established beyond that

Stopping denosumab decreases bone mineral density and increases bone turnover markers within 12 months

confidence — direction: highconfidence — magnitude: mediumconsensus: thin — one source reports it, and no source disputes it
mechanism
not established in the source; the source reports the surrogate-marker change only
effect
decreases bone mineral density and increases bone turnover markers, starting within 12 months of discontinuation; no magnitude given
conditions / moderators
reported from a phase 2 extension study; the source uses tentative "suggest" language; not established beyond that

Antiresorptive drug holidays may increase skeletal-related events (hypothesis, not measured)

confidence — direction: mediumconfidence — magnitude: lowconsensus: thin — a single hedged statement in a literature discussion
mechanism
the authors hypothesize a pharmacokinetic route; the claim does not describe it in detail
effect
direction unquantified; the authors write "may increase" the risk of SREs, including recurrence of bone pain and possibly progression of bone metastases
conditions / moderators
patients with bone metastases are implied; the review did not measure SRE rates during drug holidays, so the statement is not an empirical finding