Denosumab: updated recommendations

Minimising the risk of osteonecrosis of the jaw; monitoring for hypocalcaemia.

Article date: September 2014

Denosumab 120 mg solution for injection (Xgeva▼) is given once every 4 weeks to prevent skeletal related events (pathological fracture, radiation to bone, spinal cord compression, or surgery to bone) in adults with bone metastases from solid tumours.

Denosumab 60 mg solution for injection (Prolia) is given once every 6 months to treat osteoporosis in postmenopausal women at increased risk of fractures. It is also indicated for treatment of bone loss associated with hormone ablation in men with prostate cancer who are at high risk of fractures.

Osteonecrosis of the jaw

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:

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

To date, we have received 9 Yellow Card reports[1][1] of ONJ in patients receiving denosumab 120 mg, 12 reports in patients receiving denosumab 60 mg, and 5 reports in patients receiving an unspecified dose of denosumab.

Based on this evidence, the recommendations regarding the need for a dental examination and appropriate preventive dentistry before treatment have been updated as described below.

Hypocalcaemia

Denosumab is also associated with a risk of hypocalcaemia. This risk increases with the degree of renal impairment (see Drug Safety Update article from October 2012). Hypocalcaemia usually occurs in the first weeks of denosumab treatment, but it can also occur later. Therefore the recommendations for calcium monitoring have been updated as described below.

To date, we have received 23 Yellow Card reports1 of hypocalcaemia in patients receiving denosumab 120 mg, 37 reports in patients receiving denosumab 60 mg, and 6 reports in patients receiving an unspecified dose of denosumab.

Advice for healthcare professionals

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.

Hypocalcaemia

Calcium levels should now be monitored as follows:

Denosumab 120 mg (cancer indication)

  • Check calcium levels:
    • before the first dose
    • within two weeks after the initial dose
    • if suspected symptoms of hypocalcaemia occur.

Consider monitoring calcium levels more frequently in patients with risk factors for hypocalcaemia (eg, severe renal impairment, creatinine clearance <30 ml/min).

Denosumab 60 mg (osteoporosis indication)

  • Check calcium levels:
    • before each dose
    • within two weeks after the initial dose in patients with risk factors for hypocalcaemia (eg, severe renal impairment, creatinine clearance <30 ml/min)
    • if suspected symptoms of hypocalcaemia occur.

Tell all patients to report symptoms of hypocalcaemia to their doctor (eg, muscle spasms, twitches, or cramps; numbness or tingling in the fingers, toes, or around the mouth).

Further information:

Letters to healthcare professionals sent in August 2014 – includes advice on ONJ and hypocalcaemia that was previously in the summary of product characteristics and has not been changed, as well as the new advice above

Denosumab 60 mg

Denosumab 120 mg

Article citation: Drug Safety Update volume 8 issue 2, September 2014: A2


[1]Yellow Card reports are reports of suspected adverse drug reactions (ADRs) submitted voluntarily by healthcare professionals and members of the public in the UK. The number of reports received should not be used to determine the incidence of an ADR. This is because neither the total number of ADRs occurring, nor the number of patients using the drug is known. ADR reporting rates are influenced by the seriousness of ADRs, their ease of recognition, and the extent of use of a particular drug, and may be stimulated by publicity about a drug.

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