The purpose of this document is to provide information to health professionals regarding medication related osteonecrosis of the jaw (MRONJ). It should be noted that MRONJ is a novel term, used to broaden the definition of what was previously called bisphosphonate related osteonecrosis of the jaw (BRONJ).r Several other medications, most notably denosumab, are associated with this uncommon complication of antiresorptive therapy in the treatment of skeletal related events in malignancy.
Medication related osteonecrosis of the jaw has been defined by consensus of the American Association of Oral and Maxillofacial Surgeons. Patients may be considered to have MRONJ if all of the three following characteristics are present:
- current or previous treatment with a bone modifying agent (BMA) or an angiogenic inhibitor
- the persistence of exposed bone in the oral cavity for more than 8 weeks
- no history of radiation therapy or obvious metastatic disease to the jaws.rr
Medication related osteonecrosis of the jaw (MRONJ) was first reported in 2002 and has become an increasingly recognised problem in patients receiving bisphosphonates and denosumab for bony malignancies.r Bone destruction is associated with osteoporosis, lytic bone disease and skeletal fractures, frequently affecting the vertebrae, calvarium (vault of the skull), sternum, ribs, proximal humeri and femurs.
Bisphosphonates and denosumab (BMA's) are used in a number of settings including the treatment of osteoporosis, the management of tumour-induced hypercalcaemia and in the reduction of skeletal related events (SRE) in malignancy, particularly multiple myeloma, breast and prostate cancer.r Osteonecrosis of the jaw secondary to bisphosphonate or denosumab treatment is an uncommon but potentially serious complication.
The pathogenesis of MRONJ is not well understood, but important contributing factors include:
- inhibition of osteoclast activity and reduced bone turnover and remodelling
- prevention of release of bone specific factors that promote bone formation
- antiangiogenic effects of some bisphosphonates (zoledronic acid) which may result in impaired blood supply to bone
- local trauma - up to 65 to 70% of cases had an invasive dental procedure to the affected site prior to developing MRONJ
- periodontal or periapical infection/inflammation.r
Bisphosphonates are a class of drug that act by inhibiting bone turnover and preventing bone resorption. Two classes of bisphosphonates are in clinical use:
- potent nitrogen-containing agents including zoledronic acid, pamidronate, alendronate, risedronate and ibandronate
- a less potent class of non-nitrogen-containing bisphosphonates including etidronate, tiludronate and clodronate.r
Denosumab is a fully humanized monoclonal antibody directed against RANKL (receptor activator of NFkB ligand). RANKL is secreted by activated osteoblasts and upon binding to its receptor, RANK, results in osteoclast maturation and proliferation, thus playing a critical role in regulating bone resorption. Denosumab binds with high affinity and specificity to RANKL thus exerting a potent antiresorptive effect.r
In a combined analysis of three phase III trials (n = 5723) in patients with metastatic bone disease receiving BMA's, 89 patients were determined to have osteonecrosis of the jaw (ONJ): 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab, and ONJ treatment was deemed to be conservative in 95% of the patients. The difference in these figures was not considered statistically significant. Of the total number of patients who developed ONJ, 61.8% had had a tooth extractionr.
The Saad et alr paper also stated that ONJ is more common in patients receiving IV than PO bisphosphonates, and there appears to be a higher incidence in patients with metastatic breast cancer or myeloma.
A CALGB randomized clinical trial looking at the optimal treatment duration of zoledronic acid in breast cancer, prostate cancer and myeloma patients,r stated the incidence of ONJ increases with cumulative drug exposure, from 1.5% of patients treated for 4 to 12 months, to 7.7% of patients treated for 37 months to 48 months.
The risk of ONJ in patients taking oral bisphosphonates for postmenopausal osteoporosis is estimated to be approximately 1 in 10,000 to 1 in 100,000 patient-years.r
|Risk factors for developing MRONJ
|Prolonged exposure to bisphosphonates
Increasing evidence that ONJ is related to duration of treatment and total cumulative bisphosphonate exposure. Current treatment guidelines from the Mayo clinic and ASCO recommend a limit of 2 years duration for bisphosphonate treatment.rr
|Type of bone-modifying agent
- The potent nitrogen-containing bisphosphonates appear to be most associated with ONJ
- Intravenous administration results in greater drug exposure than oral administration
- Several studies have suggested a higher incidence of ONJ with zoledronic acid than with pamidronaterrr
- In clinical trials, the risk of ONJ increased with longer exposure to denosumab, with a number of studies showing the incidence increased over the first three years, and then appeared to plateau.r
|Dental extraction/local trauma
Approximately 61% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
Up to 30% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
- Both steroids and chemotherapy have been implicated in the development of ONJ in some studies, however most patients with multiple myeloma or bony malignancies have received one or both of these and hence the relative contribution of either of these is difficult to accurately determine
- Thalidomide in combination with zoledronic acid or pamidronate has also been implicated with increased risk of ONJ,r other studies however have failed to show this associationrr
- Bevacizumab and sunitinib have been implicated in increased risk of ONJ through retrospective analysis of large phase III trials of these drugs as well as several case reports.r The strength of evidence is greater for bevacizumab and the mechanism is thought to be via inhibition of VEGF-mediated angiogenesis. Other tyrosine kinase inhibitors have not been associated with MRONJ.
|Other concomitant risk factors
- Poor oral hygiene
- Alcohol use