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By Gary G. Goodell, D.D.S., M.S., M.A.

Introduction

The medical use of bisphosphate drugs, both I.V. and oral, along with other antiresorptive and antiangiogenic drugs for the treatment of cancer and osteoporosis, has increased rapidly over the past 20-plus years. There is increasing awareness of these drugs’ possible adverse side effect of Bisphosphate-associated Osteonecrosis of the Jaw (BONJ). This is a severe adverse drug reaction, consisting of progressive bone destruction in the maxillofacial region of the patient.

The first case reports describing a possible relationship between bisphosphonate therapy and osteonecrosis of the jaw in the Journal of Endodontics and the Journal of the American Dental Association termed the phenomenon as bisphosphonate-associated osteonecrosis of the jaw or BONJ. More recently, other dental specialty communities and authors have referred to the condition by various other names including Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ). With the advent of other antiresorptive and antiangiogenic agents implicated in this disease, in 2014 the American Association of Maxillofacial Surgeons (AAOMS) suggested the use of the term Medication-Related Osteonecrosis of the Jaw or MRONJ. In 2019, the ADA Council on Scientific Affairs, Department of Scientific Information, also proposed that the entity be termed MRONJ.  With this confluence, the AAE Special Committee on Bisphosphonates now recommends the use of the term Medication-Related Osteonecrosis of the Jaw (MRONJ).

Use of Antiresorptive and Antiangiogenic Agents

MRONJ is caused by two pharmacological agents: antiresorptive (including bisphosphonates (BPs) and receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitors) and antiangiogenic agents. BPs can be divided into aminobisphosphonate (NBPs) and non-NBPs.  Examples of NBPs are zoledronate (Zometa®, Reclast®), pamidronate (Aredia®), alendronate (Fosamx®), ibandronate (Boniva®), and risedronate (Actonel®). Examples of non-BNPs are tiludronate (Skelid®), clodronate (Bonefos®, Loron®, Ostac®), and etidronate (Didronel®).

RANK-L inhibitors are monoclonal antibodies such as denosumab (Prolia®) that inhibit osteoclast function and associated bone resorption. Antiangiogenic inhibitors such as sunitinib (Sutent®) and sorafenib (Nexavar®) interfere with new blood vessel formation by binding to various signaling molecules disrupting the angiogenesis-signaling cascade.

Intravenous (IV) bisphosphonates (BPs) are antiresorptive medications used to treat conditions associated with cancer as well as hypercalcemia of malignancy, skeletal-related events connected with bone metastases from solid tumors and the management of lytic lesions related to multiple myeloma. Subcutaneously injected RANK-L inhibitors are antiresorptives used for osteoporosis and some metastatic bone diseases. Oral BPs are used for osteoporosis, osteopenia, and less common conditions such as Paget’s disease and osteogenesis imperfecta. Antiangiogenic inhibitors are used for gastrointestinal, renal cell, and neuroendocrine tumors.

Case Definition of MRONJ

According to the American Association of Oral and Maxillofacial Surgeons, patients may be considered to have MRONJ if the following characteristics are present:

  • Current or previous treatment with antiresorptive or antiangiogenic agents.
  • Exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than eight weeks.
  • No history of radiation therapy to the jaws or obvious metastatic disease to the jaws.

In addition to these requirements, common features may also include pain, soft tissue swelling, ulceration, erythema, and suppuration.

Additional Issues Related to MRONJ Include:

  • The exact mechanism for MRONJ is not yet clearly understood. Several etiopathogenic mechanisms of this condition have been proposed, but no model can explain all morphological changes observed at the macroscopic and microscopic level. However, evidence does suggest bisphosphonates inhibit osteoclastic function, induce apoptosis of osteoclasts and inhibit osteoclast differentiation from precursors. Inhibition of angiogenesis has also been implicated.
  • The treatment for MRONJ is problematic. There is no evidence to suggest that interrupting bisphosphonate therapy prevents or lowers the risk of MRONJ. Case reports document no response or a limited response to local surgical wound debridement. There is no clear consensus on healing after marginal or segmental resection with or without antibiotics. However, case reports of recent studies using more aggressive surgery or treatment with a combination of teriparatide and amoxicillin have been promising. Surgical resection therapy remains controversial. Therefore, recognition of risk factors and application of preventive dental treatment procedures are important for patients taking I.V. and perhaps oral bisphosphonates.

Other Risk Factors Associated with MRONJ

  • The concurrent use of steroids has consistently not been found to be a risk factor.
  • Previous history of cancer (e.g., multiple myeloma or metastatic disease to bone), osteoporosis, Paget’s disease, chronic renal disease on dialysis or other indications for bisphosphonate treatment.
  • History of a traumatic dental procedure. However, spontaneous development of MRONJ without a prior traumatic dental procedure has occurred.

Incidence of MRONJ

To measure the risk for ONJ among patients exposed to a medication, we must know the risk of MRONJ in patients not exposed to antiresorptive or antiangiogenic medications. Control subjects with cancer given placebo had a risk of developing MRONJ between 0% and 0.019%. Depending on the agent used, target tissue or tumor, length and timing of treatment, and existing drugs and diseases, the literature suggests that patients receiving IV bisphosphonates generally have a risk of developing MRONJ of between 0% and 18%. However, one study analyzing the incidence of ONJ after treatment with zoledronate reported a low single digit incidence 0.7% to 6.7%. Another study had an incidence of 27.5% with long term use of zoledronate. A final study showed patients receiving long term oral bisphosphonate therapy < 4 years only had a MRONJ risk of 0.1% and over 4 years a MRONJ risk of 0.21%. RANK-L inhibitors injected subcutaneously, for cancer therapy or osteoporosis, showed a risk of developing MRONJ of between 0.7% and 1.9%. The magnitude of risk for MRONJ likely varies with the agent taken, duration of usage, patient factors (e.g. concurrent drugs, diseases, etc.) and dental treatment. The existing knowledge currently strongly suggests that patients on I.V. or subcutaneously injected antiresorptives (BPs or RANK-L inhibitors) have a higher risk for developing MRONJ, while patients taking oral bisphosphonates have a significantly lower risk.  Despite these studies, it is impossible to accurately predict a specific patient’s risk. To date, there are no case reports that directly or indirectly implicate non-surgical endodontic treatment in the development of  treating patients taking bisphosphonates:

I.V. Antiresorptive Guidelines

  • Patients taking I.V. antiresorptives are at higher risk for developing MRONJ.
  • Preventive procedures are very important to reduce the risk of developing MRONJ because treatment of MRONJ is not predictable. Preventive care might include caries control, conservative periodontal and restorative treatments, and, if necessary, appropriate endodontic treatment. This might include nonsurgical endodontic treatment of teeth that otherwise would be extracted. Nonrestorable teeth may be treated by removal of the crown, endodontic treatment of remaining roots and restoration like preparing an overdenture abutment.
  • Surgical procedures such as tooth extractions, endodontic surgical procedures or placement of dental implants appear to pose an increased risk for developing osteonecrosis of the jaws and should be avoided if possible.

Oral Bisphosphonate Guidelines

Patients taking oral bisphosphonates are at lower risk for developing MRONJ. Appropriate clinical procedures might include intraoral examination, indicated dental procedures (e.g., regular checkups, caries control, indicated periodontal and restorative treatments), and patient education about the symptoms of MRONJ and their relatively low risk of developing ONJ from surgery or soft tissue procedures.

General Guidelines and Recommendations

  • Recognize the risk factors of MRONJ.
  • Informed consent for endodontic procedures should involve a discussion of risks, benefits and alternative treatments.
  • Consider MRONJ when developing a differential diagnosis of nonodontogenic pain.
  • Use the entire health care team, including the patient’s general dentist, oncologist and oral surgeon, when developing treatment plans for these patients.

These recommendations do not represent any standard of care. The individual practitioner ultimately decides what the best course of action for their patient and is encouraged to continually review publications for new developments and treatments in antiresorptive and antiangiogenic therapy.

References

  1. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. Ruggiero S, Gralow J, Marx RE, et al. J Oncol Pract 2006;2:7-14
  2. Medication-related osteonecrosis of the jaw: clinical and practical guidelines. Rosella D, Papi P, Cicauli L, et al. J Int Soc Prevent Communit Dent 2016;6:97-114.
  3. American Association of Endodontists: Colleagues for Excellence. Bisphosphonate-Associated Osteonecrosis of the Jaw – Fall 2012
  4. Treatment of osteonecrosis of the jaw. Yamachika E, Matsubara M, Ikeda A, et al. J Craniofac Surg 2015;26:e575-7.
  5. Treatment with teriparatide for advanced bisphosphonate-related osteonecrosis of the jaw around dental implants: a case report. Zushi Y, Takaoka K, Ueta M, et al. Int J Implant Dent 2017;3:11
  6. American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw – 2014 Update
  7. Surgical management of bisphosphonate-related osteonecrosis of the jaw stages II and III. Bodem JP, Schaal C, Kargus S, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2016;121:367-72.
  8. Extensive surgical procedures result in better treatment outcomes for bisphosphonate-related osteonecrosis of the jaw in patients with osteoporosis. Kim HY, Lee SJ, Myoung H, et al. J Oral Maxillofac Surg 2017;7:1401-13.
  9. Bisphosphonate-related osteonecrosis of the jaws: cohort study of surgical treatment results in seventy-four stage II/III patients. Pichardo SE, Kuijpers SC, van Merkesteyn JP, et al. J Craniomaxillofac Surg 2016;9:1216-20.
  10. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis. Recommendations from the American Dental Association Council on Scientific Affairs. November 2011
  11. Bisphosphonate-related osteonecrosis of the jaw: specificities. Paulo S, Abrantes AM, Laranjo M, Carvalho L, et al. Oncol Rev 2014;8:254.
  12. Osteonecrosis of the jaw in oncology patients treated with bisphosphonates: prospective experience of a dental oncology referral center. Nicolatou-Galitis O, Papadopoulou E, Sarri, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;12:195-202.
  13. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws–2009 update. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B, et al. J Oral Maxillofac Surg 2009;67(5 Suppl):2-12.
  14. Bisphosphonate-related osteonecrosis of the jaws–a review. Kühl S, Walter C, Acham S, et al. Oral Oncol 2012;48:938-47.
  15. The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Wilde F, Heufelder M, Winter K, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:153-63.
  16. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. Carlson ER, Basile JD. J Oral Maxillofac Surg 2009;67(5 Suppl):85-95.
  17. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.

Lo JC, O’Ryan FS, Gordon NP, Yang J, et al. Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators. J Oral Maxillofac Surg 2010;68:243-53.

Dr. Gary G. Goodell is former professor and chair of the Endodontics Department at the Naval Postgraduate Dental School in Bethesda, Md. He earned his D.D.S. from the University of Iowa, his Certificate of Endodontics from the Naval Postgraduate Dental School, and his master’s degrees from The George Washington and Regents Universities. He is a Diplomate of the American Board of Endodontics and serves on the Journal of Endodontics Advisory Board. He is a member of the AAE Special Committee on Bisphosphonates and a past member of the AAE Board of Directors. Dr. Goodell can be reached at gggoodell@aol.com.