saving faces|changing lives® Position Paper American Association of Oral and Maxillofacial Surgeons Medication-Related Osteonecrosis of the Jaw—2014 Update Special Committee on Medication- Introduction Related Osteonecrosis of the Jaws: The Special Committee recommends changing the Salvatore L. Ruggiero, DMD, MD, Clinical nomenclature of bisphosphonate-related osteonecrosis of Professor, Division of Oral and Maxillofacial the jaw (BRONJ). The Special Committee favors the term Surgery, Stony Brook School of Dental Medicine, medication-related osteonecrosis of the jaw (MRONJ). Hofstra North Shore-LIJ School of Medicine, The change is justifed to accommodate the growing New York Center for Orthognathic and Maxillo- number of osteonecrosis cases involving the maxilla and facial Surgery, Lake Success, NY mandible associated with other antiresorptive (denosumab) and antiangiogenic therapies. Thomas B. Dodson, DMD, MPH, Professor and Chair, Associate Dean for Hospital Affairs, MRONJ adversely affects the quality of life, produc- University of Washington School of Dentistry, ing signifcant morbidity. Strategies for management of Department of Oral and Maxillofacial Surgery, patients with, or at risk for, MRONJ were set forth in the Seattle, WA American Association of Oral and Maxillofacial Sur- geons (AAOMS) updated Position Paper on Bisphospho- John Fantasia, DDS, Chief, Division of Oral nate-Related Osteonecrosis of the Jaws and approved by Pathology, Hofstra North Shore-LIJ School of the Board of Trustees in 2009.1 The Position Paper was Medicine , New Hyde Park, NY developed by a Special Committee appointed by the Board Reginald Goodday, Professor, Department of Oral and composed of clinicians with extensive experience in and Maxillofacial Sciences, Dalhousie University, caring for these patients and basic science researchers. The Halifax, NS knowledge base and experience in addressing MRONJ has expanded, necessitating modifcations and refnements Tara Aghaloo DDS, MD, PhD, Associate Pro- to the previous Position Paper. This Special Committee fessor, Oral and Maxillofacial Surgery, Assistant met in September 2013 to appraise the current literature Dean for Clinical Research, UCLA School of and revise the guidelines as indicated to refect current Dentistry, Los Angeles, CA knowledge in this feld. This update contains revisions to diagnosis, staging, and management strategies, and high- Bhoomi Mehrotra, MD, Director, Cancer Institute lights current research status. AAOMS considers it vitally at St. Francis Hospital, Roslyn, NY important that this information be disseminated to other Felice O’Ryan, DDS, Division of Maxillofacial relevant health care professionals and organizations. Surgery, Kaiser Permanente Oakland Medical Purpose Center, Oakland, CA The purpose of this updated position paper is to provide: 1. Risk estimates of developing MRONJ 2. Comparisons of the risks and benefts of medications related to osteonecrosis of the jaw (ONJ) in order to facilitate medical decision-making for the treating physician, dentist, dental specialist, and patients 3. Guidance to clinicians regarding: PAGE 1 Medication-Related Osteonecrosis of the Jaw – 2014 Update a. the differential diagnosis of MRONJ in patients with a history of exposure to antiresorptive and/or antiangiogenic agents Position Paper b. MRONJ prevention measures and management strategies for patients with MRONJ based on the disease stage Background ecules disrupting the angiogenesis-signaling cascade. These novel medications have demonstrated effcacy in the Antiresorptive medications treatment of gastrointestinal tumors, renal cell carcinomas, Intravenous (IV) bisphosphonates (BPs) are antiresorp- neuroendocrine tumors and others. tive medications used to manage cancer-related conditions Risks of jaw necrosis related to antiresorptive therapy including hypercalcemia of malignancy, skeletal-related events (SRE) associated with bone metastases in the con- Oral and maxillofacial surgeons frst recognized and text of solid tumors such as breast cancer, prostate cancer reported cases of non-healing exposed bone in the max- and lung cancers, and for management of lytic lesions in illofacial region in patients treated with IV bisphospho- the setting of multiple myeloma.2-13 While the potential nates.24,25 In September 2004, Novartis, the manufacturer for bisphosphonates to improve cancer-specifc survival of the IV bisphosphonates pamidronate (Aredia®) and remains controversial, these medications have had a signif- zoledronic acid (Zometa®), notifed healthcare profession- icant positive effect on the quality of life for patients with als of additions to the labeling of these products, which advanced cancer involving the skeleton. provided cautionary language related to the development of osteonecrosis of the jaws.26 This was followed in 2005 IV BPs, ie once yearly infusion of zolendronate (Reclast®) by a broader drug class warning of this complication for all and a parenteral formulation of ibandronate (Boniva®) bisphosphonates including the oral preparations.27,28 More administered every three months, have FDA approval for recently, other antiresorptive agents and novel anti-cancer 14 management of osteoporosis. drugs have been linked to the development of jaw necrosis Oral bisphosphonates are approved for treatment of (Appendix I, II). osteoporosis and are frequently used to treat osteopenia MRONJ Case Defnition as well.15 They are also used for a variety of less common conditions such as Paget’s disease of bone, and osteogen- In order to distinguish MRONJ from other delayed healing esis imperfecta.16,17 The most common use, however, is for conditions and address evolving clinical observations and osteopenia and osteoporosis.18,19 concerns about under-reporting of disease, the working defnition of MRONJ has been modifed from the 2009 RANK ligand inhibitor (denosumab) is an antiresorptive AAOMS Position Paper:1 agent that exists as a fully humanized antibody against RANK ligand (RANK-L) and inhibits osteoclast func- Patients may be considered to have MRONJ if all tion and associated bone resorption. When denosumab of the following characteristics are present: (Prolia®) is administered subcutaneously every 6 months 1. Current or previous treatment with antire- there is a reduction in the risk of vertebral, non-vertebral, sorptive or antiangiogenic agents; and hip fractures in osteoporotic patients.20,21 Denosumab (Xgeva®) is also effective in reducing SRE related to met- 2. Exposed bone or bone that can be probed astatic bone disease from solid tumors when administered through an intraoral or extraoral fstula(e) in 22,23 monthly. Denosumab therapy is not indicated for the the maxillofacial region that has persisted for treatment of multiple myeloma. Interestingly, in contrast more than eight weeks; and to bisphosphonates, RANK ligand inhibitors do not bind to bone and their effects on bone remodeling are mostly 3. No history of radiation therapy to the jaws or diminished within 6 months of treatment cessation. obvious metastatic disease to the jaws. Antiangiogenic medications It is important to understand that patients at risk for or with established MRONJ can also present with other com- Angiogenesis inhibitors interfere with the formation of mon clinical conditions not to be confused with MRONJ. new blood vessels by binding to various signaling mol- PAGE 2 Medication-Related Osteonecrosis of the Jaw – 2014 Update Commonly misdiagnosed conditions may include, but are not limited to: alveolar osteitis, sinusitis, gingivitis/ periodontitis, caries, periapical pathology, fbro-osseous Position Paper lesion, sarcoma, chronic sclerosing osteomyelitis, and TMJ disorders. It is also important to remember that ONJ occurs in patients not exposed to antiresorptive or antiangiogenic agents. infection.53-55 Although tooth extraction was performed Pathophysiology in most of the initial reported cases of ONJ, these Although the frst MRONJ case was reported over a de- teeth commonly had existing periodontal or periapical 1,56-59 cade ago, the pathophysiology of the disease has not been disease. From these clinical studies, several animal fully elucidated.24,25 A source of great debate among clini- models have been developed to demonstrate that cians and researchers are the potential mechanisms under- both infammation or bacterial infection and systemic 46,60-64 lying MRONJ pathophysiology.29-32 Proposed hypotheses antiresorptives are suffcient to induce ONJ. that attempt to explain the unique localization of MRONJ Infammation or infection has long been considered an exclusively to the jaws include altered bone remodel- important component of ONJ. Early studies identifed ing or oversuppression of bone resorption, angiogenesis bacteria, especially Actinomyces species, in biopsied inhibition, constant microtrauma, suppression of innate or specimens of necrotic bone removed in patients with acquired immunity, vitamin D defciency, soft tissue BP ONJ.65 The presence of bacteria has prompted studies toxicity, and infammation or infection.29,33-40 to evaluate the possibility of a complex bioflm on exposed bone.66 These studies have identifed bacteria A. Inhibition of osteoclastic bone resorption and in combination with fungi and viruses, which may remodeling require more sophisticated therapies to combat the Bisphosphonates (BP), and other antiresorptives multiorganism ONJ-associated bioflm.67-70 such as denosumab, inhibit osteoclast differentiation and function, and increase apoptosis, all leading