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Strengthened warnings for fracture risk after discontinuation of denosumab (Prolia and biosimilars)

Medicine Safety Update
Published

Summary

The Product Information (PI) for denosumab products indicated for the treatment of osteoporosis have been updated to strengthen the existing warning for multiple vertebral fractures (MVF) following discontinuation or delay of treatment.

Denosumab is used for treatment:

  • of osteoporosis in postmenopausal women
  • to increase bone mass in men with osteopenia receiving androgen deprivation therapy for non-metastatic prostate cancer
  • to increase bone mass in men with osteoporosis at increased risk of fracture
  • to increase bone mass in women and men at increased risk of fracture due to long-term systemic glucocorticoid therapy.

Denosumab is PBS subsidised for treatment of osteoporosis.

What health professionals should do

Denosumab is administered as a six-monthly injection. New vertebral fractures have occurred as early as 7 months after the last dose of denosumab and consideration should be given to switching patients to an alternative antiresorptive therapy if treatment is discontinued.

Before starting treatment with denosumab, patients should be counselled on the importance of adherence and the risks of MVF if treatment is discontinued or delayed.

Be alert to the need for clear communication between patients and health professionals (including between specialists, general practitioners, dental practitioners and pharmacists) regarding denosumab treatment, including information around treatment interruption or cessation.

Be alert to recent updates to clinical guidance from Healthy Bones Australia (HBA) and the Royal Australian College of General Practitioners (RACGP): Position Statement on the Management of Osteoporosis (November 2025) and Osteoporosis management and fracture prevention in postmenopausal women and men over 50 years of age (March 2024).

These complement the PI changes by reinforcing continuity of denosumab treatment and the need for careful transition planning if denosumab therapy is delayed or discontinued. The revised guidance supports prescribers in minimising the risk of MVF through consistent patient review and adherence to safe management practices.

Background

MVF following discontinuation or delay of treatment with denosumab is a known safety signal which was first included in the PI for the innovator product, Prolia, in 2016.

We conducted a comprehensive investigation following recent reports raising concerns about the level of awareness and clarity regarding management of MVF following discontinuation or delay. The investigation involved seeking independent advice from the Advisory Committee on Medicines (ACM) at their August 2025 meeting. ACM noted that the signal was already known among clinicians, but agreed that further action was required to better mitigate the risk and to ensure ongoing patient confidence and safety. In line with the ACM advice, the PI and Consumer Medicine Information (CMI) have been strengthened regarding the risk of MVF following discontinuation or delay of denosumab treatment.

Adverse events reported to us

A search of the TGA’s Database of Adverse Event Notification (DAEN) on 9 October 2025 for denosumab products indicated for the treatment of osteoporosis retrieved:

  • 152 reports of spinal fracture
  • 28 reports multiple fractures
  • 24 reports of compression fracture
  • 22 reports lumbar vertebral fracture
  • 19 reports of rebound effect
  • 18 reports thoracic vertebral fracture
  • 4 reports of osteoporotic fracture.

Of these reports, about 70 cases appear to be associated with rebound fractures following discontinuation or delay in treatment with denosumab.

The case reporting pattern indicates there has been a downward trend in the number of cases reported since 2019.

Changes to the PI

Wording added to the PI for Prolia is bolded and underlined. Equivalent changes have been made to the CMI and biosimilar brands are required to align with these changes.

4.2 DOSE AND METHOD OF ADMINISTRATION

Dosage (dose and interval)

The recommended dose of Prolia is a single subcutaneous (SC) injection of 60 mg, once every 6 months. If Prolia treatment is discontinued, consideration should be given to transitioning to an alternative antiresorptive therapy.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE:

Multiple vertebral fractures (MVF) following discontinuation of Prolia treatment

Multiple vertebral fractures (MVF) may occur following discontinuation of treatment with Prolia, particularly in patients with a history of vertebral fracture. New vertebral fractures occurred as early as 7 months after the last dose of Prolia.

Patients being treated with Prolia, should be advised not to interrupt Prolia therapy without prior consultation with their treating physician. The individual benefit/risk should be evaluated before discontinuing treatment with Prolia. If Prolia treatment is discontinued, consideration should be given to transitioning to an alternative antiresorptive therapy.

Further reading

Disclaimer

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