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). 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
Bisphosphonates and denosumab (antiresorptive agents) 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 Several trials have demonstrated the superior efficacy of denosumab to zolendronic acid in reducing SREs in the setting of metastatic breast and castration-resistant prostate cancer, for which it is currently PBS approved.rrr Osteonecrosis of the jaw secondary to bisphosphonate or denosumab treatment is an uncommon but potentially serious complication.
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:r
- ​current or previous treatment with antiresorptive or antiangiogenic agents
- 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.
Pathophysiology
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
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 MRONJr
- periodontal or periapical infection/inflammation.r
Incidence/prevalence
Bone destruction affects 70% of patients with multiple myeloma and is a significant cause of morbidity.r It 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.
Medication related osteonecrosis of the jaw (MRONJ) was first reported in 2002 and has become an increasingly recognised problem in patients receiving bisphosphonates and more recently denosumab for bony malignancies.rr With regards to bisphosphonates, less than 10% of reported cases have been in patients receiving oral bisphosphonates for osteoporosis. Approximately 92% of reported cases received either zoledronic acid or pamidronate, both potent nitrogen containing bisphosphonates. It should be noted however, that these agents form the mainstay of treatment for bone disease in malignancy.r
The true incidence of bisphosphonate related osteonecrosis of the jaw is largely unknown. The majority of the data has been derived from case series and retrospective reviews each with statistical limitations. The current estimations put the overall incidence at between 1 and 11%. Multiple myeloma patients treated with bisphosphonates have a higher reported incidence at 2.3 to 11%, while bisphosphonate treated breast and prostate cancer patients have a reported incidence of 1.2 to 6.5%.r
Available evidence estimating the prevalence of ONJ in different types
| Study |
nONJ cases/total population |
Overall prevalence |
Stratified by tumour type |
| MM |
BC |
PC |
| Bamias et al. (80) |
17/227 |
6.9% |
9.9% |
2.9% |
6.5% |
| Zervas et al. (82) |
28/254 |
11.0% |
11.0% |
- |
- |
| Badros et al. (109) |
11/340 |
3.2% |
3.2% |
- |
- |
Ortega et al.
(110) |
5/178 |
2.8% |
- |
1.6% |
1.9% |
| Dimopoulos et al. (81) |
15/202 |
7.4% |
7.4% |
- |
- |
| Wang et al. (111) |
15/442 |
3.4% |
3.8% |
2.5% |
2.9% |
| Jadu et al. (112) |
21/655 |
3.2% |
3.2% |
- |
- |
| Hoff et al. (83) |
29/1,886 |
1.5% |
2.4% |
1.2% |
- |
| Estilo et al. (9) |
35/4,835 |
0.7% |
- |
- |
- |
Abbreviations: BC, breast cancer: MM, multiple myeloma; ONJ, osteonecrosis of the jaw; PC, prostate cancer
©The Oncologist 2009
There is limited evidence evaluating the incidence of ONJ associated with denosumab. In the large randomised control trials there appears to be a similar risk to bisphosphonates, with an incidence of approximately 1-2%.rrr One meta-analysis suggests that the risk is higher with denosumab particularly in the setting of metastatic prostate cancer.r It should be note that approximately two thirds of cases of ONJ occurred following tooth extraction.r
Risk factors
| 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 bisphosphonate |
- 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
|
| Dental extraction/local trauma |
Approximately 65 to 70% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
|
| Dental co-morbidities |
Up to 30% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
|
| Concomitant drugs |
- 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 restrospective 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
- Smoking
- Alcohol use
- Diabetes
|