How to safely discontinue denosumab (Prolia/Xgeva) treatment?

From the Guidelines

Safely discontinuing denosumab requires transitioning to an alternative antiresorptive medication, such as a bisphosphonate, to prevent rebound bone loss and increased fracture risk. When stopping denosumab, patients should be switched to a bisphosphonate, typically zoledronic acid 5mg as a single intravenous infusion, as this regimen is supported by recent clinical guidelines 1. This transition should occur to reduce or prevent the rebound increase in bone turnover that occurs when denosumab is abruptly discontinued. Patients should continue calcium (1000-1200mg daily) and vitamin D (800-1000 IU daily) supplementation throughout this process.

Key Considerations

• The optimal bisphosphonate regimen post-denosumab is currently unknown, but many osteoporosis clinicians use a single 4- or 5-mg treatment of zoledronate 1.
• Denosumab's effects are quickly reversible, and without follow-up treatment, rapid bone loss occurs within 3-6 months of a missed dose, potentially leading to multiple vertebral fractures.
• Bisphosphonates provide sustained antiresorptive effects that help maintain the bone density gained during denosumab treatment and prevent the rebound increase in bone turnover.

Monitoring and Follow-up

• Monitoring bone mineral density 1-2 years after the transition is recommended to assess the effectiveness of the bisphosphonate therapy.
• Patients should be closely monitored for signs of rebound bone loss and increased fracture risk, and adjustments to their treatment plan should be made as needed.

Recent Guidelines

• Recent clinical guidelines support the use of bisphosphonates, such as zoledronic acid, as an alternative antiresorptive medication after denosumab discontinuation 1.
• The guidelines also recommend continued calcium and vitamin D supplementation to prevent hypocalcemia and support bone health.

From the FDA Drug Label

If Prolia treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy [see Adverse Reactions (6.1)]. Evaluate an individual's benefit-risk before initiating treatment with Prolia If Prolia treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy Multiple vertebral fractures have been reported following Prolia discontinuation. Patients should be transitioned to another antiresorptive agent if Prolia is discontinued.

To safely discontinue denosumab (Prolia/Xgeva) treatment, transition patients to an alternative antiresorptive therapy 2, 2. This is necessary because multiple vertebral fractures have been reported after discontinuation of Prolia treatment 2, 2, 2.

• Evaluate the individual's benefit-risk before discontinuing treatment with Prolia 2, 2.
• Monitor for consequences of bone over-suppression, such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing 2, 2, 2.

From the Research

Discontinuing Denosumab Treatment

To safely discontinue denosumab (Prolia/Xgeva) treatment, several factors need to be considered, including the patient's fracture risk, duration of treatment, and potential alternative therapies.

• Rebound Bone Loss and Fracture Risk: Discontinuation of denosumab can lead to rebound bone loss and an increased risk of vertebral fractures, as reported in studies 3, 4.
• Transitioning to Alternative Therapies: Transitioning to alternative therapies, such as bisphosphonates, may help mitigate bone loss, but the optimal regimen is currently unknown 3, 4.
• Monitoring Bone Turnover Markers: Monitoring bone turnover markers (BTMs) can help assess the need for further therapy after denosumab discontinuation 3.
• Risk of Rebound Hypercalcemia: Rarely, denosumab discontinuation can lead to rebound hypercalcemia, particularly in patients with a history of malignancy-related bony metastases 5.
• Guidelines for Discontinuation: The European Calcified Tissue Society (ECTS) recommends re-evaluating patients after 5 years of denosumab treatment and considering alternative therapies or continuation of denosumab for up to 10 years for patients at high fracture risk 4.

Considerations for Discontinuation

When considering discontinuation of denosumab, the following factors should be taken into account:

• Duration of Treatment: Longer duration of treatment may increase the risk of bone loss after discontinuation 3.
• Prior Bisphosphonate Use: Prior use of bisphosphonates may mitigate the risk of bone loss after denosumab discontinuation 3.
• Patient Fracture Risk: Patients at high fracture risk should be considered for continuation of denosumab or alternative therapies 4.

Alternative Therapies

Alternative therapies, such as bisphosphonates, may be considered after denosumab discontinuation to reduce the risk of bone loss and fractures. However, the optimal bisphosphonate regimen after denosumab is currently unknown, and further studies are needed to confirm safety and efficacy 6, 7.