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.
Definition
MRONJ has been defined by consensus of the American Association of Oral and Maxillofacial Surgeons (AAOMS). 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) alone or in combination with immune modulators or an angiogenic inhibitor
- the persistence of exposed bone in the oral cavity for more than 8 weeks
- no history of radiation therapy or metastatic disease to the jaws.r
MRONJ was first reported in 2002 and has become an increasingly recognised problem in patients receiving BMAs such as 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.
BMAs 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 (SREs) in malignancy, particularly multiple myeloma, breast and prostate cancer.r MRONJ secondary to BMA treatment is an uncommon but potentially serious complication.
Pathophysiology
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, 62 to 82% of cases had tooth extraction prior to developing MRONJ
- periodontal or periapical infection/inflammation
- innate or acquired immune dysfunction
- genetic factors.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.
Denosumab is a fully humanized monoclonal antibody directed against receptor activator of NFkB ligand (RANKL). 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
Incidence/prevalence
In a combined analysis of three phase III trials (n = 5723) in patients with metastatic bone disease receiving BMAs, 89 patients were determined to have MRONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab, and MRONJ 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 MRONJ, 61.8% had a history of tooth extraction.r
MRONJ is more common in patients receiving intravenous than oral bisphosphonates, and there appears to be a higher incidence in patients with myeloma, metastatic breast cancer and prostate cancer; with incidence rates of 8.5%, 3.1%, and 4.9%, respectively.rr
Results from a randomised clinical trial (CALGB) - looking at the optimal treatment duration of zoledronic acid in breast cancer, prostate cancer and myeloma patients - demonstrated that the incidence of MRONJ increases with cumulative drug exposure (incidence rate: 1.5% in patients treated for 4-12 months and 7.7% in patients treated for 37-48 months).r
The risk of MRONJ in patients taking oral bisphosphonates for postmenopausal osteoporosis is estimated to be approximately 1 in 10,000 to 1 in 100,000 patients per year.r
Risk factors
| Risk factors for developing MRONJ |
| Prolonged exposure to bisphosphonates |
There is increasing evidence to support that MRONJ 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 treatmentrr
|
| Type of bone-modifying agent |
- The potent nitrogen-containing bisphosphonates appear to be most associated with MRONJ
- Intravenous administration results in greater drug exposure than oral administration
- Several studies have suggested a higher incidence of MRONJ with zoledronic acid than with pamidronaterrr
- In clinical trials, the risk of MRONJ increased with longer exposure to denosumab, particularly when the duration of therapy exceeded four years with a number of studies showing the incidence increased over the first two to three years, and then appeared to plateaur
|
| Dental extraction/local trauma |
Approximately 61% of reported cases have had dental or oral surgical procedures prior to development of MRONJr
|
| Dental co-morbidities |
50% of cases have had pre-existing inflammatory dental disease such as periodontal disease or periapical pathologyr
|
| Concomitant drugs |
- MRONJ is a rare but serious adverse effect of certain drugs of which bisphosphonates are the most widely known. It is also associated with other medications such as denosumab, corticosteroids, and some antiangiogenics such as sunitinib, bevacizumab or aflibercept.rr Some tyrosine kinase inhibitors, such as lenvatinib, have been associated with MRONJr
- Thalidomide in combination with zoledronic acid or pamidronate has also been implicated with increased risk of MRONJ.r However other studies have failed to show this associationrr
- A correlation to chemotherapy with MRONJ is less substantiated in the literature r
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| Other concomitant risk factors |
- Poor oral hygiene
- Dentures
- Smoking
- Alcohol use
- Diabetes
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