Medicinal products containing everolimus and osteonecrosis of the jaw – Uppsala Monitoring Centre signal

(under investigation)

General information

Osteonecrosis of the jaw is a rare but potentially serious condition that was initially associated with the use of bisphosphonates. In recent years, osteonecrosis of the jaw has been associated with several other drugs, including everolimus, a selective inhibitor of mTOR (mammalian target of rapamycin) used to treat advanced malignant neoplasms and to prevent transplant rejection. During a review of the WHO VigiBase database to detect signals in December 2018, the term "osteonecrosis of the jaw" was identified for the drug everolimus. As of February 3, 2020, VigiBase had received 117 reports of this drug–adverse reaction combination.

Osteonecrosis of the jaw is not listed in the instruction for everolimus, but there are related terms such as stomatitis, jaw pain, oral pain, impaired wound healing and mucositis. Among the cases in VigiBase and the scientific literature, the vast majority concern patients who used concomitant drugs or had previous treatment with drugs known (or suspected) to cause osteonecrosis of the jaw, which complicates identification of the drug that caused this adverse reaction. However, there are several cases in which neither other drugs nor risk factors associated with osteonecrosis of the jaw had any effect, which identifies everolimus as an independent cause of osteonecrosis. In 15 VigiBase cases, the reaction decreased when the drug was discontinued.

The exact pathophysiology of osteonecrosis of the jaw remains unclear, but several theories have been proposed, and the mechanism of development is probably multifactorial. Factors that may cause osteonecrosis of the jaw include inhibition of bone remodeling (osteoclast), bone infection/inflammation, inhibition of angiogenesis, soft tissue toxicity, and impaired immunity. Considering the mechanism of action of everolimus, it is reasonable to assume that it may be involved in the development of osteonecrosis of the jaw.

Based on current data, the risk of developing osteonecrosis of the jaw due to treatment with products containing everolimus appears to be very low. However, in combination with other medicinal products that can cause osteonecrosis and with risk factors (diabetes or dental surgery), everolimus may act as a trigger. Further research in this area is needed, taking into account the growing population of patients at risk of osteonecrosis and the adverse impact on the quality of life of those affected.

Administration

The antitumor agent everolimus is indicated for the treatment of various oncological diseases (breast, pancreas, gastrointestinal tract, lung and kidney), and is also used as an immunosuppressant to prevent transplant rejection. Everolimus is a derivative of sirolimus.

Osteonecrosis of the jaw is characterized as an oral lesion of exposed necrotic bone that persists for at least 8 weeks without a prior history of radiation exposure or metastasis to the area. This oral condition is rare but potentially serious and very painful. Some medicinal products are known to cause osteonecrosis of the jaw, but the condition can also occur spontaneously. This adverse reaction was first described in 2003, in a report describing 36 patients who received two different bisphosphonate drugs. Osteonecrosis of the jaw was later identified as a class effect of these drugs. In subsequent years, other drugs, such as the monoclonal antibodies denosumab and bevacizumab and the tyrosine kinase inhibitor sunitinib, were also associated with the development of osteonecrosis of the jaw. More recently, the mTOR inhibitor everolimus has also been implicated as a risk factor for osteonecrosis of the jaw. Other risk factors include dental surgery (for example, tooth extraction), poor oral condition, diabetes, smoking and concomitant use of steroids.

Reports in the VigiBase database

As of February 3, 2020, VigiBase had received 117 reports of this drug–adverse reaction combination. The expected value for the adverse reaction of osteonecrosis of the jaw associated with the use of medicinal products containing everolimus was 35.

Reports were received from 15 countries worldwide. In 75% of cases the adverse reaction was recorded in women, since the most common indication for the use of everolimus in a number of cases was breast cancer, and the age range was 29-82 years, with a median of 64 years. More than 90% of cases were serious, including 6 reports of fatal outcomes (5%), but none of them were caused by osteonecrosis of the jaw.

In 18 cases, everolimus was the only registered drug, and in 26 cases it was the only suspected drug. The most frequently reported concomitant drugs were exemestane (54 reports), zoledronic acid (54 reports), denosumab (38 reports), capecitabine (11 reports) and fulvestrant (11 reports). The most frequent concomitant reactions reported were malignant neoplasm progression (13 cases), stomatitis (12 cases), fatigue (11 cases), pain (10) and bone metastases (9 cases). Stomatitis and bone metastases (if located in the jaw) may have contributed to the development of osteonecrosis.

The vast majority of patients were given everolimus for the treatment of breast cancer (73 cases) or kidney cancer (28 cases), and the dose ranged between 5 and 20 mg per day, with 10 mg being the most common daily dose. Most cases had a plausible time to onset of the adverse reaction, with a median of 31 week. In 15 cases the clinical manifestations of the adverse reaction decreased when the drug was discontinued.

Discussion and conclusions

Among the reports in VigiBase, the vast majority concerned patients who were concurrently receiving, or had previously received, therapy with medicinal products known (or suspected) to cause the adverse reaction of osteonecrosis of the jaw. This fact complicates the identification of the drug that caused the reaction. In addition, exemestane and fulvestrant (often used together with everolimus) may also play a role in the development of osteonecrosis of the jaw, given their mechanism of action. Some patients had potential risk factors – diabetes and tooth extraction. There were also a few cases of osteonecrosis of the jaw among patients who did not use other suspected drugs or had no known risk factors. Based on current data, the risk of developing osteonecrosis of the jaw due to treatment with everolimus appears to be very low. However, in combination with other medicinal products that can cause osteonecrosis of the jaw and with risk factors (diabetes or dental surgery), everolimus may act as a trigger. Although it is impossible to conclude what role everolimus played in each reported case, the VigiBase data and published data still point to a potential causal relationship, in which the drug may, at the very least, contribute to the development of osteonecrosis of the jaw. Further research in this area is needed given the increasing number of patients at risk of developing osteonecrosis of the jaw, the seriousness of this condition and its negative impact on patients' quality of life. Close cooperation between physicians and dentists, as well as information for patients at risk, are important aspects of the prevention, prompt recognition and treatment of osteonecrosis of the jaw.