FOSAMAX HEALTH WARNING

Biophosphonates and osteonecrosis of the jaw
Over the last two years, cases of ONJ have been reported in patients treated with bisphosphonates, many of whom were cancer patients receiving chemotherapy and corticosteroids. In the majority of the cases, ONJ developed after tooth extraction although some developed the condition spontaneously. Many had signs of local infection including osteomyelitis.

One of the earliest reports described osteonecrosis of the alveolar bone in three female patients undergoing chemotherapy for metastatic breast cancer. All three patients received pamidronate. Two of these patients developed bone necrosis after tooth extractions, but the third patient developed the condition spontaneously, resulting in an oroantral fistula. In all cases, histological examination of the lesions showed necrotic bone with no evidence of metastatic disease. There are other reports of patients receiving pamidronate or zoledronic acid and developed necrosis of the bone after dental extractions.

Data from the UK showed that cancer patients have an estimated four times higher risk at any site than the general population. Treatment with bisphosphonates is a standard of care in many types of bone complications of cancer. Therefore, it is not possible to determine if osteonecrosis of the jaw is related to bisphosphonates, concomitant drugs/other therapies, patient’s underlying disease, or other comorbid risk factors.

Local case report
The bisphosphonates registered locally include alendronate, clodronate, etidronate, ibandronic acid, pamidronate, risedronate and zoledronic acid. Bisphosphonates are commonly used for the treatment of postmenopausal and corticosteroid induced osteoporosis, Paget’s disease, hypercalaemia associated with malignancy and osteolysis and bone pain associated with metastatic bone disease.

To-date, the Pharmacovigilance Unit has received one local report of a patient with jaw osteolysis and suspected osteomyelitis while he was on zoledronic acid (Zometa®) 4 mg injection. There is another report of exostosis and aseptic bone necrosis after a dental extraction during alendronate (Fosamax®) therapy.

Recommendation
The following recommendations have been made in the updated prescribing information of the pamidronate and zoledronic acid in the US:

• A dental examination with appropriate preventive dentistry should be considered prior to treatment with bsiphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).
• Whilst on treatment, these patients should avoid invasive dental procedures, if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment.

It has been highlighted that cases of avascular bone necrosis were reported with high doses potent nitrogen-containing bisphosphonates e.g. pamidronate and zoledronic acid. There is limited data to suggest that the other bisphosphonates may have similar, albeit less, effects on jaw bones as well5. Healthcare professionals are encouraged to report all serious adverse reactions suspected to be associated with the use of bisphosphonates to the Pharmacovigilance Unit of the HSA.

References
1. Wang J et al. Osteonecrosis of the jaws associated with chemotherapy. J Oral Maxillofac Surg 2003; 61:1104-7.

2. Marx RE. Pamidronate (Aredia®) and zoledronate (Zometa®) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61:1115-7.

3. Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21:4253-4.

4. The General Practice Research Database, compiled by a dedicated multi-disciplinary team based at the Medicines and Healthcare products Regulatory Agency (MHRA) in London, UK

5. Robinson NA, Yeo JF. Bisphosphonates – A word of caution. Ann Acad Med Singapore 2004; 33(suppl):48S-49S

Source
Health Sciences Authority
December 17, 2004