What are the risks and considerations when stopping Denosumab (Prolia) therapy?

From the Guidelines

Stopping Denosumab (Prolia) therapy requires careful management due to the risk of rebound bone loss and increased fracture risk, and patients should transition to an alternative antiresorptive medication, typically a bisphosphonate, to mitigate these risks. When Denosumab is discontinued, patients typically experience rapid bone mineral density loss and an increased risk of multiple vertebral fractures within a short period after the last dose, as noted in the study by 1. To mitigate these risks, patients should transition to an alternative antiresorptive medication, such as a bisphosphonate like zoledronate, which can be administered as a single 4- or 5-mg treatment, as suggested by 1.

The reason for this rebound effect is that Denosumab works by inhibiting RANK ligand, which temporarily suppresses bone resorption, but when discontinued, there's a rapid increase in bone turnover markers and accelerated bone loss, as explained in the study by 1. Patients with higher fracture risk, including those with previous fractures or very low bone density, require particularly careful management. Regular monitoring with bone density scans is recommended during this transition period, and patients should maintain adequate calcium and vitamin D intake throughout.

Some studies have also reported a risk of atypical femoral fractures (AFFs) in patients taking bisphosphonates or denosumab, as noted in the study by 1. However, the absolute risks of AFFs in patients on bisphosphonates/denosumab are low, and the risk may decline when treatment is stopped. Any decision to stop Denosumab should be made in consultation with a healthcare provider who can develop an individualized plan based on the patient's specific risk factors. Key considerations for stopping Denosumab include:

• Rapid bone mineral density loss and increased risk of multiple vertebral fractures
• Transition to an alternative antiresorptive medication, such as a bisphosphonate
• Regular monitoring with bone density scans
• Maintenance of adequate calcium and vitamin D intake
• Individualized plan based on the patient's specific risk factors, as recommended by 1 and 1.

From the FDA Drug Label

After your treatment with Prolia is stopped, or if you skip or delay taking a dose, your risk for breaking bones, including bones in your spine, is increased. Your risk for having more than 1 broken bone in your spine is increased if you have already had a broken bone in your spine. Do not stop, skip or delay taking Prolia without first talking with your doctor If your Prolia treatment is stopped, talk to your doctor about other medicine that you can take.

The main risks and considerations when stopping Denosumab (Prolia) therapy are:

• Increased risk of broken bones, including bones in the spine
• Increased risk of multiple broken bones in the spine if you have already had a broken bone in your spine It is recommended to not stop, skip, or delay taking Prolia without first talking with your doctor. If Prolia treatment is stopped, your doctor may prescribe other medicine that you can take 2.

From the Research

Risks of Stopping Denosumab

• Stopping Denosumab therapy can result in a rebound increase in bone turnover, loss of treatment-associated bone mineral density (BMD) gains, and an increased risk of spontaneous vertebral fractures (VFs) 3, 4, 5, 6, 7.
• The risk of multiple vertebral fractures is common or frequent (≥ 1/100 and < 1/10) after Denosumab discontinuation, with a median number of vertebral fractures of 5 within 7 to 20 months (median 11) after the last Denosumab injection 4.
• Patients at particular risk are those with prevalent VFs or greater on-treatment BMD gains 3.

Considerations for Stopping Denosumab

• Prescribing bisphosphonate before starting Denosumab and/or after stopping Denosumab may reduce the risk of multiple vertebral fractures 4, 5.
• However, the optimal sequential approach after longer-term Denosumab remains elusive, and the optimal bisphosphonate regimen post-Denosumab is currently unknown 3, 5.
• Clinicians and patients should be aware of the potential risk of multiple vertebral fractures after Denosumab discontinuation, and a re-evaluation should be performed after 5 years of Denosumab treatment 5.
• Patients considered at high fracture risk should either continue Denosumab therapy for up to 10 years or be switched to an alternative treatment 5.

Strategies to Prevent Bone Loss

• Subsequent antiresorptive treatment is mandatory after Denosumab discontinuation, although the optimal regimen is yet to be clarified 7.
• Bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover 5.
• Ongoing trials are needed to define the management of Denosumab discontinuation and to determine the optimal strategies to prevent bone loss and fractures 3, 4, 5, 6, 7.