What Happens When You Stop Denosumab
Stopping denosumab causes a dangerous rebound phenomenon characterized by rapid bone loss, markedly elevated bone turnover, and a substantially increased risk of multiple vertebral fractures—therefore, bisphosphonate therapy (typically zoledronic acid 4-5 mg as a single dose) should be initiated if denosumab is discontinued for more than 6 months. 1
The Rebound Phenomenon
When denosumab is discontinued, a predictable and clinically significant cascade occurs:
- Rapid increase in bone turnover markers beginning 3 months after the missed dose, reaching above-baseline levels by 6 months 1, 2
- Bone mineral density (BMD) declines to baseline levels within 12 months of stopping treatment 1, 2
- Steep increase in bone turnover markers and rapid BMD decrease occur because denosumab does not incorporate into bone matrix, unlike bisphosphonates 1
This rebound is fundamentally different from bisphosphonate discontinuation due to denosumab's unique pharmacokinetics—it is not stored in bone and its effects are rapidly reversible 1.
Vertebral Fracture Risk
The most concerning consequence of denosumab discontinuation is the dramatically elevated fracture risk:
- Vertebral fracture rate increases from 1.2 per 100 patient-years during treatment to 7.1 per 100 patient-years after stopping 2
- 60.7% of patients who experience a vertebral fracture after stopping denosumab develop multiple vertebral fractures (compared to 38.7% in placebo discontinuation) 2
- Multiple vertebral fractures have been reported in clinical case series and re-analyses of osteoporosis trials, presumably due to rebound increase in bone resorption 1
Highest Risk Patients
The odds of developing multiple vertebral fractures after stopping denosumab are:
- 3.9 times higher in patients with prior vertebral fractures (sustained before or during treatment) 2
- 1.6 times higher with each additional year of off-treatment follow-up 2
- 1.2 times higher per 1% annualized total hip BMD loss 2
Hypercalcemia Risk
Beyond fractures, denosumab discontinuation can trigger severe metabolic complications:
- Rebound hypercalcemia can occur, particularly in patients with giant cell tumor of bone and those with growing skeletons 3
- 0.7% of patients experienced serious adverse events of hypercalcemia more than 30 days following treatment discontinuation, which was recurrent in some patients 3
- The rebound effect is associated with marked increase in vertebral fracture risk in addition to hypercalcemia 4, 5
Recommended Transition Strategy
Bisphosphonate treatment (e.g., zoledronic acid) to suppress rebound osteolysis is recommended if denosumab is discontinued for more than 6 months 1:
- Many osteoporosis clinicians use a single 4- or 5-mg treatment of zoledronic acid as the optimal post-denosumab regimen, though the ideal protocol remains unknown 1
- Bisphosphonate therapy should be considered to reduce or prevent the rebound and potential excess risk for vertebral fractures 1
Critical Caveats About Bisphosphonate Transition
The evidence shows mixed success with bisphosphonate transition strategies:
- In eight patients aged 56-89 years, zoledronic acid after stopping denosumab resulted in bone turnover marker rises and BMD decline 6
- Two annual doses of zoledronic acid after three years of denosumab failed to suppress high bone turnover markers in one patient, with BMD dropping and necessitating denosumab restart 6
- Standard dose zoledronic acid does not prevent bone loss in a significant proportion of patients 6
- Bisphosphonates may preserve bone density following short-term denosumab but the optimal sequential approach after longer-term denosumab remains elusive 7
Alternative Strategies Under Investigation
- Gradual dose reduction (30 mg then 15 mg) partially maintains initial BMD gain at the spine (39% preserved) but does not prevent bone loss at the hip 8
- Prior bisphosphonate use before denosumab may mitigate rebound risk 6
- Bone turnover markers may help in monitoring treatment and determining need for further bisphosphonates 6
Clinical Implications for Practice
Patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment 2:
- Drug holidays are not an option with denosumab, with risk of bone loss even when transitioning to bisphosphonates 6
- Risk is greater with longer duration of denosumab treatment 6, 7
- Patients at particular risk are those with prevalent vertebral fractures or greater on-treatment BMD gains 7
- Clinicians and patients should be aware of this potential risk in cancer patients both with and without bone metastases 1
Special Population Considerations
In adolescents, the rebound effect carries additional concerns: