MRONJ: Bisphosphonates aren’t the only drugs causing osteonecrosis of the jaw

Major drug groups — other than bisphosphonates — have been implicated in the risk of medication-related osteonecrosis of the jaw (MRONJ)

Two recent reports show that the list of drug classes associated with MRONJ is growing. The first report describes, in addition to bisphosphonates, other drugs including denosumab, some antiangiogenic drugs, and m-TOR inhibitors implicated in the pathogenesis of ONJ.

The second report describes medications other than antiresorptive and antiangiogenic drugs and their association with MRONJ.

FDA-reported MRONJ study

The authors of the first report are from Colleges of Pharmacy, Dentistry, and Medicine at the University of Florida, Gainesville. It can be accessed at:

Zhang X, et al. “Osteonecrosis of the jaw in the United States Food and Drug Administration’s adverse event reporting system (FAERS).” J Bone Mineral Res 2016; 31(2): 336-340.

The objectives of this study were to describe the number of MRONJ cases reported in the FDA’s adverse event reporting system (FAERS) and to estimate the reporting odds ratios for MRONJ owing to the medications known to be associated with MRONJ. Those included: bisphosphonates, RANKL inhibitors, antiangiogenic drugs, and m-TOR inhibitors. FAERS is a database that contains information on adverse event reports submitted to the FDA.

Methods

The FAERS database was accessed and searched with parameters from first quarter of 2010 through the first quarter of 2014. “Osteonecrosis of the jaw” was the search term, and the drugs queried included the four drug classes associated with MRONJ: bisphosphonates, antiangiogenic drugs, RANKL inhibitors, and m-TOR inhibitors. Demographic variables such as age, sex, region, and the indications for drug treatment (i.e., cancer or osteoporosis) were also collected.

Results

1. There were 17,119 MRONJ cases reported in the system. More than 1,000 MRONJ cases were reported for each quarter between Q2 2010 and Q2 2012. Afterwards the number of MRONJ cases reported dropped dramatically.
2. Of the 17,119 cases reported, 69.7% were female and 30.3% were male. Average age was 62 years.
3. Around 70% of reported cases were from the United States. The remainder of reported cases were from Japan (6.8%), Germany (5.6%), Italy (3.6%), France (1.5%). United Kingdom (1.5%), and some remaining countries not listed in the report.
4. For the 11,690 patients whose reported cases included indications, 59% of MRONJ cases were taking the medications to prevent skeletal-related events, and 41% of the MRONJ cases were taking the medications for the treatment or prevention of osteoporosis. Of the patients taking the drugs for skeletal-related events, 24% had breast cancer, 20% had multiple myeloma, 9% had prostate cancer, and the reminder had renal cancer, lung cancer, or metastases to bone owing to other cancer types.

The following is a breakdown of number of cases linked to various medications from the total of 17,119 ONJ cases:

• Bisphosphonates:
  • Zoledronate: 11,490 (67.1%)
  • Alendronate : 7,307 (42.7%)
  • Pamidronate: 5,251 (30.7%)
  • Risedronate: 827 (4.8%)
  • Ibandronate: 786 (4.6%)
  • Clodronate: 33 (0.2%)
  • Etidronate: 28 (0.2%)
• RANKL inhibitor:
  • Denosumab: 1,184 (6.9%)
• Antiangiogenic agents:
  • Bevacizumab: 703 (4.1%)
  • Sunitinib: 418 (2.4%)
  • Sorafenib: 90 (0.5%)
  • Pazopanib: 10 (0.1%)
  • Axitinib: 9 (0.1%)
• m-TOR inhibitors:
  • Everolimus: 84 (0.5%)
  • Temsirolimus: 28 (0.2%)

Drugs with the highest risk of causing MRONJ were the bisphosphonates, particularly pamidronate (approximately 500 times greater risk compared to no exposure) and zoledronate (approximately 170 times greater risk). The RANKL inhibitor denosumab showed a 14% greater risk. The antiangiogenic agents and the m-TOR inhibitors had modest risk of less than 5%.

Discussion and conclusion

This study identified four drug classes associated with MRONJ. Most MRONJ cases reported in the setting of skeletal-related event prevention occurred with the intravenous bisphosphonates pamidronate and zoledronate. MRONJ cases in the osteoporosis setting were mostly associated with alendronate.

This was the first study to show that m-TOR inhibitors such as temsirolimus and everolimus were associated with the risk of MRONJ.

The study revealed a decrease in the number of MRONJ cases in year 2012. According to the authors, this decline may have been attributed to the following factors:

• The publication of several case reports worldwide that brought this drug-induced adverse effect into the spotlight
• The presence of standard criteria defining and diagnosing MRONJ
• The increasing awareness of the risk for MRONJ among healthcare providers brought about by the development and release of consensus guidelines and position papers advocating dental screening
• The institution of appropriate measures before the initiation of antiresorptive drugs in patients at risk for developing MRONJ

NIH study: 6 case studies

The second study was funded by the NIH and was authored by oral and maxillofacial surgery specialists at the UCLA School of Dentistry. It can be accessed at:

Aghaloo TL, Tetradis S. “Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of cases.” J Oral Maxillofac Surg 2017; 75:129-142.

The report examines six cases of osteonecrosis of the jaw occurring between 2012 and 2015, out of approximately 100 patients with MRONJ associated with antiresorptive medications.

The six cases included:

1. Case 1: 83-year-old female taking methotrexate to treat rheumatoid arthritis. Inciting event: periodontal disease, location at right posterior maxilla.
2. Case 2: 42-year-old female taking prednisone and etanercept to treat rheumatoid arthritis. Inciting event: extraction, location at right maxilla site of upper right second premolar.
3. Case 3: 52-year-old female taking prednisone and rituximab to treat lymphoma. Inciting event: periodontal disease, location at left posterior maxilla.
4. Case 4: 70-year-old female receiving hip steroid injections to treat arthritis. Unknown inciting event: location left posterior maxillary alveolar ridge.
5. Case 5: 66-year-old female taking etanercept and adalimumab to treat rheumatoid arthritis. Inciting event: extraction, location anterior, posterior mandible.
6. Case 6: 41-year-old female with fibromyalgia, not receiving any drugs. Inciting event: periapical and periodontal disease, location left buccal maxilla

MRONJ has been reported in patients not receiving bisphosphonates, denosumab, or antiangiogenics, and in these six cases, there were no antiresorptive or antiangiogenic drugs. These cases are rare and associated with corticosteroids, infection, trauma, chemotherapy, and coagulation disorders.

Rheumatoid arthritis (RA) was present in three of the cases. Medications used to treat RA, such as prednisone, methotrexate, etanercept, adalimumab, and rituximab, can present a risk for impaired healing and can potentially present lesions identical to osteonecrosis of the jaw.

According to the authors, this is the first report of osteonecrosis of the jaw associated with etanercept, adalimumab, and rituximab. These three drugs are known as anti-tumor necrosis factor (anti-TNF) agents, which have been developed to treat RA. Methotrexate is a commonly used antimetabolite and antifolate drug in the treatment of cancer and RA.

The authors concluded with the following: “These 6 case reports add to a growing body of literature on emerging classes of drugs that have been linked to increased risk of MRONJ. The magnitude of risk for MRONJ in patients taking these new classes of drugs is uncertain and warrants awareness and monitoring.”