denosumab and osteonecrosis of the jaw (ONJ)

Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κ-Β ligand (RANKL), is a powerful antiresorptive agent (1):

• exists as a fully humanized antibody against RANK ligand and inhibits osteoclast function and associated bone resorption
• dose approved for osteoporosis is 60 mg administered subcutaneously every 6 months
• in the 10-year FREEDOM Extension study, treatment with denosumab resulted in a continuous increase in bone mineral density (BMD), associated with a low risk of vertebral and non-vertebral fractures (VFs)
• osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) are rare but serious side effects associated with anti-resorptive therapies
• based on the US FDA adverse event reporting system, the strongest significant signals showed that ONJ and atypical femur fracture could be more frequent with denosumab than with zoledronate

Osteonecrosis of the jaw (ONJ) is a well-known and common side effect in patients receiving denosumab 120 mg for cancer. Risk factors for ONJ include (2):

• smoking
• old age
• poor oral hygiene
• invasive dental procedures (eg, tooth extractions, dental implants, oral surgery)
• comorbidity (eg, dental disease, anaemia, coagulopathy, infection)
• advanced cancer
• previous treatment with bisphosphonates
• concomitant treatments (eg, chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck)

In clinical trials, ONJ incidence increased with duration of denosumab 120 mg exposure (2):

• patient-year adjusted incidence of confirmed ONJ was 1.1% in the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter
• patients with certain dental risk factors (eg, history of ONJ, unhealed oral surgery) were excluded from these trials.

There have been rare cases of ONJ in patients receiving denosumab 60 mg for osteoporosis in clinical practice (2)

• the most common risk factors were:
  • invasive dental procedures
  • history of bisphosphonate therapy,
  • being more than 65 years old

Advice for healthcare professionals (2)

Osteonecrosis of the jaw

The following precautions are now recommended to reduce the risk of ONJ:

Denosumab 120 mg (cancer indication)

• A dental examination and appropriate preventive dentistry before starting denosumab 120 mg are now recommended for all patients.
• Do not start denosumab 120 mg in patients with a dental or jaw condition requiring surgery, or in patients who have not recovered following oral surgery.

Denosumab 60 mg (osteoporosis indication)

• Check for ONJ risk factors before starting denosumab 60 mg. A dental examination and appropriate preventive dentistry are now recommended for patients with risk factors.

Tell all patients to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain, or swelling to a doctor and dentist.

Notes:

• risk for ONJ among patients treated with denosumab, has a large range—from 0.04 percent to 0.3 percent (3)

Reference:

1. Lamy O, Everts-Graber J, Rodriguez EG. Denosumab for osteoporosis treatment: when, how, for whom, and for how long. A pragmatical approach. Aging Clin Exp Res. 2025 Mar 8;37(1):70.
2. Drug Safety Update volume 8 issue 2, September 2014: A2.
3. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg. 2022 May;80(5):920-943.