DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Denosumab is a high-affinity IgG2 monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa-B ligand (RANKL).¹ By inhibiting the binding of RANKL to its receptor, RANK, denosumab effectively suppresses the formation, function, and survival of osteoclasts (cells that break down bone).^1,2 This targeted inhibition leads to a significant reduction in bone resorption, ultimately enhancing bone mass and strength.

In Malaysia, the registered innovator products for denosumab are Prolia^® and Xgeva^®.³ Prolia^® is indicated for postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, and bone loss in patients undergoing hormone ablation for cancer.¹ On the other hand, Xgeva^® is indicated for skeletal-related events (pathological fracture, radiation to bone, spinal cord compression, or surgery to bone) in patients with multiple myeloma or bone metastases from solid tumours.⁴ Xgeva^® is also indicated for adults and skeletally mature adolescents with giant cell tumour of bone that is either unresectable or where surgical resection is likely to result in severe morbidity.

To date, six products containing denosumab are registered with the Drug Control Authority (DCA), all in injectable form.³

 

Overview of Safety Concern

Vertebral fractures are defined as a reduction in vertebral height of 20% or greater, visualised via X-ray.⁵ Multiple vertebral fractures (MVF) following the discontinuation or delay of treatment with denosumab are a recognised safety risk and have been documented in the Product Information (PI) for all denosumab products, including Prolia^® and Xgeva^®, as well as their biosimilars.⁶

 

Source of Safety Concern

Prolia^® is administered as a six-monthly injection for the treatment of osteoporosis.^1,6 The National Pharmaceutical Regulatory Agency (NPRA) has received information from the Australian Therapeutic Goods Administration (TGA) that new vertebral fractures have emerged as early as 7 months following the final administration of Prolia^®.⁶ Approximately 70 cases have been identified as rebound fractures associated with the cessation or delayed dosing of the therapy. While pharmacovigilance data show a declining trend in reported cases since 2019, the underlying factors contributing to this decrease remain unspecified.

In response, strengthened warnings have been introduced for Prolia^® to emphasise the importance of treatment continuity and to underscore the necessity of a structured transition plan during any interruption of therapy.

 

Background of the Safety Issue

In 2022, the French National Agency for Medicines and Health Products Safety (ANSM) conducted an evaluation of available data, which did not establish a definitive increased risk of MVF specifically following denosumab discontinuation.⁷ Nonetheless, the implementation of alternative antiresorptive therapy upon cessation of denosumab remains recommended to mitigate potential clinical risks.

The occurrence of MVF following discontinuation of denosumab is thought to be related to rebound bone resorption, especially in patients with previous vertebral fractures.^2,5 Consequently, a decrease in bone mineral density (BMD) is expected, and monitoring of BMD is recommended.⁸

 

Local Adverse Drug Reaction Reports⁹

To date, the NPRA has received a total of 92 adverse drug reaction reports comprising 165 adverse events associated with denosumab use in Malaysia. The most frequently reported adverse events were hypocalcaemia (8), osteonecrosis of jaw (5), fatigue (4), no therapeutic response (4), and drug ineffective (4).

No reports of MVF after discontinuation of denosumab were identified. However, related events were reported, including thoracic spine compression fracture (1), thoracic vertebral fracture (1), and multiple fractures (1). These reports lacked substantial information, including whether the reported events occurred following discontinuation of denosumab.

 

Advice for Healthcare Professionals

• Be aware that MVF adverse events have been associated with discontinuation or delay of treatment for denosumab products, particularly in patients with a history of vertebral fracture.
• New vertebral fractures have been reported as early as 7 months after the last dose of Prolia^®.
• Before starting Prolia^® treatment, advise patients not to interrupt treatment without prior consultation with their treating physician.
• Counsel patients on the importance of adherence and the risks of MVF if denosumab treatment is discontinued or delayed.
• If Prolia^® treatment is discontinued, consider transitioning patients to an alternative antiresorptive therapy.
• Report all suspected adverse events associated with denosumab-containing products to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Prolia^® Solution for Injection 60mg/ml Pre-filled Syringe local package insert [Internet]. 2024 Aug [cited 2026 Jan 20]. Available from: http://www.npra.gov.my
2. Malaysian Clinical Practice Guidelines. Management of Osteoporosis 3rd Edition [Internet]. 2022 [cited 2026 Jan 21]. Available from: https://www.acadmed.org.my/CPGdl/CPG%20Management%20of%20Osteoporosis%203rd%20Edition%20v20221115.pdf
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2026 [cited 2026 Jan 20]. Available from: https://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Xgeva^® 120mg/1.7ml solution for injection local package insert [Internet]. 2024 Aug [cited 2026 Jan 20]. Available from: http://www.npra.gov.my
5. Royal Australian College of General Practitioners (RACGP). Osteoporosis management and fracture prevention in postmenopausal women and men over 50 years of age. [Internet]. 2024 Mar [cited 2026 Jan 20]. Available from: https://www.racgp.org.au/getattachment/487c5b92-7bd0-4b1c-86f5-2d86c649f92f/Osteoporosis-management-and-fracture-prevention-in-post-menopausal-women-and-men-50-years-of-age.aspx
6. Therapeutic Goods Administration (TGA) Australia. Medicine Safety Update. Strengthened warnings for fracture risk after discontinuation of denosumab (Prolia^® and biosimilars). [Internet]. 2025 Nov 21 [cited 2026 Jan 20]. Available from: https://www.tga.gov.au/news/safety-updates/strengthened-warnings-fracture-risk-after-discontinuation-denosumab-prolia-and-biosimilars
7. French National Agency for Medicines and Health Products Safety. Prolia^® (denosumab) and the potential risk of multiple vertebral fractures upon discontinuation of treatment. [Internet]. 2022 Nov 15 [cited 2026 Jan 20]. Available from: https://ansm.sante.fr/actualites/prolia-denosumab-et-risque-potentiel-de-fractures-vertebrales-multiples-a-larret-du-traitement
8. European Medicines Agency (EMA). EPAR – Product information. Prolia^® 60mg solution for injection in pre-filled syringe package insert [Internet]. 2025 Oct 22 [cited 2026 Jan 20]. Available from: https://www.ema.europa.eu/en/documents/product-information/prolia-epar-product-information_en.pdf
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Dec 5]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wang Khee Ing    

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali