saving faces changing lives® American Association of Oral and Maxillofacial Surgeons
Medication-Related Osteonecrosis of the Jaw—2014 Update Special Committee on Medication-
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 justified 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 significant morbidity. Strategies for management of Department of Oral and Maxillofacial Surgery, patients with, or at risk for, MRONJ were set forth in the 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 knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements 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 reflect current Dentistry, Los Angeles, CA knowledge in this field. 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 Center, Oakland, CA The purpose of this updated position paper is to provide: 1. Risk estimates of developing MRONJ2. Comparisons of the risks and benefits 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 b. MRONJ prevention measures and management strategies for patients with MRONJ based on the ecules disrupting the angiogenesis-signaling cascade. These novel medications have demonstrated efficacy in the 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 first 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-specific survival of the IV bisphosphonates pamidronate (Aredia®) and remains controversial, these medications have had a signif- zoledronic acid (Zometa®), notified 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 management of osteoporosis.14 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 Definition
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 definition of MRONJ has been modified 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 there is a reduction in the risk of vertebral, non-vertebral, 1. Current or previous treatment with antire- and hip fractures in osteoporotic patients.20,21 Denosumab sorptive or antiangiogenic agents; (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 fistula(e) in monthly.22,23 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.
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, fibro-osseous 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 infection.53-55 Although tooth extraction was performed in most of the initial reported cases of ONJ, these Although the first MRONJ case was reported over a de- teeth commonly had existing periodontal or periapical cade ago, the pathophysiology of the disease has not been disease.1,56-59 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 inflammation or bacterial infection and systemic lying MRONJ pathophysiology.29-32 Proposed hypotheses antiresorptives are sufficient to induce ONJ.46,60-64 that attempt to explain the unique localization of MRONJ Inflammation or infection has long been considered an exclusively to the jaws include altered bone remodel- important component of ONJ. Early studies identified 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 deficiency, soft tissue BP ONJ.65 The presence of bacteria has prompted studies toxicity, and inflammation or infection.29,33-40 to evaluate the possibility of a complex biofilm on A. Inhibition of osteoclastic bone resorption and
exposed bone.66 These studies have identified bacteria in combination with fungi and viruses, which may require more sophisticated therapies to combat the Bisphosphonates (BP), and other antiresorptives multiorganism ONJ-associated biofilm.67-70 such as denosumab, inhibit osteoclast differentiation and function, and increase apoptosis, all leading C. Inhibition of Angiogenesis
to decreased bone resorption and remodeling.41-45 Angiogenesis is a process that involves growth, migra- Osteoclast differentiation and function plays a vital tion and differentiation of endothelial cells to form new role in bone healing and remodeling in all skeletal blood vessels. Angiogenesis favorably influences tumor sites, but osteonecrosis of the jaws only occurs growth and also influences tumor invasion of vessels, primarily within the alveolar bone of the maxilla and resulting in tumor metastasis. Angiogenesis requires mandible.46 An increased remodeling rate in the jaws binding of signaling molecules such as vascular may explain the differential predisposition to ONJ endothelial growth factor (VEGF) to receptors on the compared to other bones in the axial or appendicular endothelial cells. This signaling promotes new blood skeleton. Long term studies in the large animal model vessel growth.
demonstrate decreased intracortical bone turnover with dynamic histomorphometry.30,47 The central role Osteonecrosis is classically considered an interruption of bone remodeling inhibition is further corroborated in vascular supply or avascular necrosis, and therefore, by a similar incidence of ONJ observed with other it is not surprising that inhibition of angiogenesis is a antiresorptive medications such as denosumab.48-50 leading hypothesis in ONJ pathophysiology.30-32,71 In Preliminary evidence exists demonstrating the vitro experiments consistently demonstrate a reduction improved extraction socket healing in animals in angiogenesis in response to zoledronic acid.40,72 receiving systemic zoledronic acid when treated with Studies in cancer patients treated with zoledronic acid parathyroid hormone, possibly due to its positive effect support these data with decreased circulating VEGF on osteoclasts to increase bone remodeling.51,52 levels.73 Moreover, there is a growing body of literature linking osteonecrosis of the jaw and other bones in patients receiving novel antiangiogenic drugs (tyrosine Both systemic and local oral risk factors have been kinase inhibitors and monoclonal antibody targeting implicated in ONJ pathogenesis, where several human VEGF). However, inhibition of angiogenesis has not studies have implicated dental disease or bacterial been reported with denosumab.
PAGE 3 Medication-Related Osteonecrosis of the Jaw – 2014 Update D. Other Hypotheses 1. Soft tissue toxicity Although BPs primarily target the osteoclast and bind to hydroxyapatite in bone, soft tissue toxicity has been reported.29,74 Multiple cell types underwent increased apoptosis or decreased proliferation after exposure to BPs in vitro including cervical, to limit the inclusion of studies to: 1) those published prostate, and oral epithelial cells.75-77 Since BPs since the last report (2009), 2) studies with the highest are excreted renally after only a few hours in the levels of evidence for the available topic, eg systematic circulation, their concentration in tissues outside reviews of several randomized control trials (RCTs) bone is minimal.78 In contrast to BP's, no soft tissue or prospective cohort studies, individual RCTs, pro- toxicity has been reported with denosumab.
spective cohort studies, retrospective cohort studies, 2. Innate or acquired immune dysfunction or case-control studies, and 3) studies with clinical ascertainment of MRONJ. Older studies, case reports The first animal model could not consistently induce and case series, and studies that rely on medical record ONJ unless BPs were combined with steroids in a review or insurance-claim data were excluded from tooth extraction defect.37 Since then, many other studies showed mucosal ulceration, delayed healing, exposed bone, and histologic necrosis and inflam- Due to the low frequency of disease, studies with mation when BPs and chemotherapy are adminis- small samples (<500 subjects) need to be interpreted tered in rodents undergoing extractions.34,63,79,80 cautiously. It is particularly challenging to obtain good estimates of disease frequency when studying low As described above, many hypotheses exist, and frequency events, ie cases of MRONJ. Consistently, as many of the animal models above show evidence the sample size increases, MRONJ disease frequency that the disease may be multifactorial. To begin estimates get smaller. Therefore when reviewing the to develop effective therapies for patients with literature cited below, the reader should weight more ONJ, clinically relevant animal models are para- heavily studies with large sample sizes than a com- mount. Whether it is early diagnosis, prevention, parable study with a smaller sample size (ie disease or targeted therapy, therapeutic strategies cannot estimates of a study with a sample size of 10,000 be developed or tested without these models. As should be weighted more heavily than a study with 500 more studies uncover the mechanisms, large animal models will be critical in closely replicating human MRONJ with frank bone exposure and stage 0 1. MRONJ risk among cancer patients To measure the risk for ONJ among patients Risk factors for MRONJ
exposed to a medication, we must know the risk for ONJ in patients not exposed to antiresorptive A. Medication-related risk factors
or antiangiogenic medications. The risk for ONJ
among cancer patients enrolled in clinical trials
To interpret MRONJ disease frequency estimates, two and assigned to placebo groups ranges from 0%
parameters need to be considered: therapeutic indica- to 0.019% (0-1.9 cases per 10,000 cancer pa-
tions and type of medications. The therapeutic indi- cations are grouped into two categories: osteoporosis/ osteopenia or malignancy. Medications will be grouped Among cancer patients exposed to zolendronate, into two categories, BP and non-BP (other antiresorp- the cumulative incidence of MRONJ is in the low tive or antiangiogenic medications). Disease frequency single digits (range = 0.7% - 6.7%).82,84 When lim- will be reported as incidence (number of new cases ited to studies with Level 1 evidence, ie systematic per sample [or population] per unit time) or prevalence reviews or RCTs, the risk of MRONJ in subjects (number of cases in the sample [or population] reported exposed to zolendronate approximates 1% (100 as a percentage).
cases per 10,000 patients).81-83,85 The risk of ONJ
among cancer patients exposed to zolendronate
Given the proliferation of data since MRONJ was ranges between 50-100 times higher than cancer
originally reported in 2003, the committee has tried patients treated with placebo.
PAGE 4 Medication-Related Osteonecrosis of the Jaw – 2014 Update Among cancer patients exposed to denosumab, a RANK L inhibitor, the risk of MRONJ ranges from 0.7% - 1.9% (70-90 cases per 10,000 patients).81,85 The risk for ONJ among cancer patient exposed
to denosumab is comparable to the risk of ONJ
in patients exposed to zolendronate.22,23,86
The risk for ONJ among cancer patients exposed to bevacizumab, an antiangiogenic agent, is 0.2%. (20 as TKIs and VEGF inhibitors being implicated in cases per 10,000).87 The risk may be higher among the development of ONJ in the absence of concomi- patients exposed to both bevacizumab and zolen- tant antiresorptive medication use.
dronate, 0.9% (90 cases per 10,000).87 This preliminary level of evidence supporting the There are several case reports describing jaw necro- association of antiangiogenic medications with the sis in cancer patients receiving targeted therapies, development of jaw necrosis is primarily based on specifically tyrosine kinase inhibitors (TKIs) and case reports (Level V evidence). While the FDA monoclonal antibody targeting VEGF.88-90 In 2009 has issued an ONJ advisory only for bevacizumab Brunello and colleagues reported consecutive and sunitinib99,100 the committee remains concerned episodes of ONJ, characterized by cutaneous fistula about a similar potential risk associated with several and bone sequestration, in a patient with renal cell other medications within the same drug class carcinoma treated with bisphosphonates and the which have a similar mechanism of action. Further tyrosine kinase inhibitor (TKI) sunitinib.91 Disease controlled, prospective studies will be required to improved after discontinuation of sunitinib and then characterize the risk of jaw necrosis associated with rapidly worsened with resumption of sunitinib. The these agents.
investigators hypothesized "that the antiangiogenic 2. MRONJ risk among osteoporosis patients activity of sunitinib may amplify the inhibition of bone remodeling exerted by amino bisphosphonates Most dentists and oral and maxillofacial surgeons entrapped within the osteonecrotic matrix, antag- see patients in their practices who have been onize mucosal healing and expose to infections exposed to antiresorptive therapy, eg oral BPs, for during treatment." Subsequent reports have high- management of osteoporosis. When evaluated by lighted the potential additive toxic effect of anti- age, 5.1 million patients over the age of 55 years angiogenic drugs (TKIs and monoclonal antibody received a prescription for a bisphosphonate in targeting VEGF) in patients receiving or having year 2008. A recent federal study estimated that the a history of bisphosphonate medication use.
prevalence of BP exposure was 7 for every 100 US Beuselink, et al, reported an overall incidence of population receiving a prescription for a bisphos- ONJ to be 10% in renal cell carcinoma patients with phonate in the outpatient setting for the treatment bone metastasis treated with oral TKIs and con- of osteoporosis.101 Ironically, the studies estimating MRONJ risk in this patient population have the 97 They concluded that the combined use of bisphosphonates and TKIs in weakest levels of evidence of the various study renal cell carcinoma patients with bone involvement groups, eg survey or retrospective cohort studies probably improves treatment efficacy but is associ- with ascertainment of disease based on a combina- ated with a high incidence of ONJ. Smidt-Hansen, tion of examination or review of medical records.101 et al, in a retrospective study of renal cell carcinoma 2a. Risk for ONJ among osteoporotic patients exposed patients who received zoledronic acid and sirolimus found that patients who developed ONJ had a sig- In a survey study of over 13,000 Kaiser Permanente nificantly improved median survival of 31.6 months members, the prevalence of BRONJ in patients compared to 14.5 months in patients without ONJ.98 receiving long-term oral bisphosphonate therapy Moreover, there have been multiple case reports was reported at 0.1% (10 cases per 10,000) which detailing the development of ONJ in patients re- increased to 0.21 (21 cases per 10,000) among ceiving these targeted antiangiogenic therapies who patients with greater than 4 years of oral BP ex- are bisphosphonate naïve.88-90 These case reports posure.102 Felsenberg and Hoffmeister reported a underscore the potential for novel medications such prevalence of MRONJ among patients treated with PAGE 5 Medication-Related Osteonecrosis of the Jaw – 2014 Update bisphosphonates for osteoporosis of 0.00038% (<1 case per 100,000 exposed), based on reports of 3 cases to the German Central Registry of Necrosis of the Jaw.103 In a more recent report, Malden, et al, derived an incidence of 0.004% (0.4 cases per 10,000 patient-years of exposure to alendronate) from 11 cases of MRONJ reported in a population of 90,000 people living in southeast Scotland.104 ONJ was, respectively, 0.5 and 0.8% at 1 year, 1.0 2b. MRONJ risk among osteoporotic patients exposed and 1.8% at 2 years, and 1.3 and 1.8% at 3 years.86 to IV BP or RANK-L inhibitors For patients receiving oral bisphosphonate therapy Studies analyzing patients with osteoporosis ex- to manage osteoporosis, the prevalence of ONJ posed to yearly zolendronate therapy for 3 years increases over time from near 0 at baseline to reported a risk for MRONJ of 0.017% (1.7 cases 0.21% after four or more years of BP exposure (see per 10,000 subjects).105 An extension of this study Figure 1). The median duration of BP exposure for through 6 years did not demonstrate a change in patients with ONJ and ONJ-like features was frequency of MRONJ.106 In recent reports study- 4.4 years. For patients without ONJ, the median ing patients exposed to denosumab, the risk for exposure to oral BPs was 3.5 years.101,102 MRONJ is 0.04% (4 cases per 10,000 subjects).21 When compared to cancer patients receiving
Interestingly, among patients with osteoporosis antiresorptive treatment, the risk of ONJ for
exposed to placebo medications, the risk for ONJ patients with osteoporosis exposed to antiresorp-
ranges from 0% to 0.02% (0-2 cases per 10,000 tive medications is about 100 times smaller.
subjects).21,105 The risk for ONJ among patients
treated with either zolendronate or denosumab
B. Local factors
(0.017 – 0.04%) approximates the risk for ONJ
1. Operative treatment of patients enrolled in placebo groups (0%-
Dentoalveolar surgery is considered a major risk factor for developing MRONJ. Several studies Based on this current review of data, the risk of de- report that among patients with MRONJ, tooth veloping ONJ among osteoporotic patients exposed extraction is a common predisposing event rang- to oral, IV BPs, or denosumab is real but remains ing from 52 to 61% of patients reporting tooth very low. The frequency of cases reported in the extraction as the precipitating event.84,108,109 In a population (albeit very small) is best explained by case-control study among cancer patients exposed the large number of patients, 5.1 million over the to zolendronate, tooth extraction was associated age of 55, exposed to these drugs.107 with a 16-fold increased risk for ONJ when com- 3. Duration of medication therapy as a risk factor for pared to cancer patients without ONJ (odds ratio [OR] = 16.4; 95% confidence interval [CI], 3.4 – 79.6).110 In a longitudinal cohort study in a sample Regardless of indications for therapy, the duration of cancer patients exposed to intravenous BPs of BP or antiresorptive therapy continues to be (predominately zolendronate), tooth extraction was a risk factor for developing ONJ. Among cancer associated with a 33-fold increased risk for ONJ.84 patients exposed to zolendronate or denosumab, the incidence of developing ONJ was, respectively, 0.6 The above information, while important, is not what and 0.5% at 1 year, 0.9 and 1.1% at 2 years, and 1.3 most patients or clinicians want to know. Most cli- and 1.1% at 3 years with the risk for ONJ among nicians and patients want to know: "Among patients denosumab-exposed subjects plateauing between exposed to antiresorptive medications, what is the years 2 and 3.86 In a study by Saad, et al, the risk for developing ONJ following tooth extraction investigators combined three-blinded phase three (or other dentoalveolar procedures such as implant trials and found similar results, including a plateau placement or periodontal procedures)?" The best after 2-years for patients exposed to denosumab.108 current estimate for the risk of ONJ among patients Among cancer patients exposed to zolendronate or exposed to oral bisphosphonates following tooth denosumab (n=5723), the incidence of developing extraction is 0.5%.111 The estimate was derived from a prospective evaluation of 194 patients exposed to PAGE 6 Medication-Related Osteonecrosis of the Jaw – 2014 Update oral BPs that underwent extraction of > 1 tooth. In this sample, one patient developed ONJ after tooth Estimates for developing ONJ after tooth extraction among cancer patients exposed to intravenous BPs ranges from 1.6 to 14.8%. In a retrospective cohort study composed of a sample of cancer patients exposed to zolendronate (n=27), 4 (14.8%) subjects inflammatory dental disease is tooth extraction, develop ONJ after tooth extraction.112 In a prospec- pre-existing dental disease may confound the tive cohort study composed of 176 subjects with relationship between tooth extraction and risk for cancer who were exposed to zolendronate, 5 (2.8%) MRONJ noted above. It would be valuable to see an developed ONJ.113 In a prospective cohort study of estimate of the association between tooth extraction 63 subjects with a history of cancer and intravenous and MRONJ adjusted for pre-existing inflammatory BP exposure who underwent extraction of > 1 tooth, dental disease.
one subject (1.6%) developed ONJ.114 Among the C. Demographic and systemic factors and other
studies reported above, the prospective studies should be weighted more heavily due to the larger sample sizes and the prospective, not retrospective, Age and sex are variably reported as risk factors study designs.
for MRONJ.84,108,110,112,115 The higher prevalence of this complication in the female population is likely The risk of developing ONJ among patients who a reflection of the underlying disease for which the have been exposed to antiresorptive medications agents are being prescribed (ie osteoporosis, breast for other dentoalveolar operations such as dental cancer). There are very limited data describing the implant placement and endodontic or periodontal occurrence of MRONJ in the pediatric population. In procedures is unknown. Absent data, the committee an observational study, Brown, et al, reviewed a total considers the risk for ONJ after dental implant of 42 pediatric patients who had received IV bisphos- placement and endodontic or periodontal proce- phonate therapy (mean duration of therapy 6.5 years) dures that require exposure and manipulation of for a variety of metabolic bone diseases. No cases of bone to comparable to the risk associated with tooth ONJ were reported despite invasive dental treatment in 11 patients.116 The risk of developing MRONJ in the 2. Anatomic factors pediatric population certainly requires more complete Limited new information regarding anatomic risk factors for MRONJ is available. MRONJ Corticosteroids are associated with an increased risk is more likely to appear in the mandible (73%) for MRONJ.108,115 Antiangiogenic agents, when given than the maxilla (22.5%) but can appear in both in addition to antiresorptive medications, are associated jaws (4.5%).108 Denture use was associated with with an increased risk of ONJ.87,108 an increased risk for ONJ among cancer patients Co-morbid conditions among cancer patients that exposed to zolendronate (OR = 4.9; 95% CI =1.2 – are inconsistently reported to be associated with an 20.1).110 In a study by Vahtsevanos, et al, a sample increased risk for MRONJ include anemia (hemoglo- of 1,621 cancer patients treated with intravenous bin < 10g/dL) and diabetes.108,115 Cancer type is also zolendronate, ibandronate, or pamidronate, there variably reported as a risk factor.81,84 was a 2-fold increased risk for ONJ among denture Tobacco use has been inconsistently reported as a risk factor for MRONJ. In a case-control study, tobacco 3. Concomitant oral disease use approached statistical significance as a risk factor Pre-existing inflammatory dental disease such as for ONJ in cancer patients (OR=3.0; 95% CI= 0.8 - periodontal disease or periapical pathology is a 10.4).110 In a more recent case-controlled study, tobacco well-recognized risk factor.112,115 Among cancer use was not associated with ONJ in a sample of cancer patients with MRONJ, pre-existing inflammatory patients exposed to zolendronate.115 Vahtsevanos did dental disease was a risk factor among 50% of not report an association between tobacco use and the cases.108,112 Given that a common treatment of PAGE 7 Medication-Related Osteonecrosis of the Jaw – 2014 Update D. Genetic factors
Since the previous position paper there have been
several reports describing single nucleotide polymor- phisms (SNPs) that were associated with the devel- opment MRONJ. Most of these SNPs were located within regions of the gene associated with either bone turnover, collagen formation, or certain metabolic bone diseases. Katz reported an ONJ event rate of 57% when retrospective fashion to patients who did not undergo SNPs were present in 5 candidate genes that were re- dental preventive measures.53,55,108,137,138 sponsible for bone turnover.117 In a genome wide study, Dimopoulos found a statistically significant, almost Nicoletti reported that patients with an SNP in the threefold reduction in the incidence of osteonecrosis RBMS3 gene (associated with bone density and colla- in patients when preventive measures were applied.53 gen formation) were 5.8 times more likely to develop Bonacina did not report any new cases of ONJ in ONJ.118 In a study that analyzed polymorphisms related patients who received dental screening and necessary to farnesyl diphosphate synthase activity (the enzyme dental treatment before initiating IV bisphosphonate specifically inhibited by bisphosphonates) a positive treatment.137 Vandone found the incidence rate of correlation was established with the carrier status and developing ONJ was reduced by 50% in patients who ONJ.119 Collectively, these studies suggest that a germ were screened and received preventive dental care line sensitivity to bisphosphonates may exist.
before initiating drug therapy.138 In summary, the current literature reaffirms that the Treatment planning for patients who may be prescribed risk of MRONJ is significantly greater in cancer antiresorptive or antiangiogenic therapy should include patients receiving antiresorptive therapy as compared thorough examination of the oral cavity and a radio- to treatment regimens for osteoporosis. Moreover, graphic assessment when indicated. It is important the risk of MRONJ in osteoporosis patients receiving to identify both acute infection and sites of potential antiresorptive therapy continues to be very low re- infection to prevent future sequelae that could be gardless of drug type (bisphosphonates, denosumab) exacerbated once drug therapies begin. Considerations or dosing schedule. Targeted cancer therapies (VEGF during the clinical and radiographic assessment in- and tyrosine kinase inhibitors) are also associated jaw clude: patient motivation, patient education regarding necrosis but further studies with these medications are dental care, fluoride application, chlorhexidine rinses, tooth mobility, periodontal disease, presence of root Management Strategies for Patients Treated
fragments, caries, periapical pathology, edentulism, and denture stability.139 with Antiresorptives or Antiangiogenics
1. Prevention of MRONJ An additional benefit of early dental consultation when the use of antiresorptive or antiangiogenic therapy is The AAOMS Special Committee on MRONJ supports being considered is that the patient is being informed a multi-disciplinary approach to the treatment of pa- of the low risk associated with these drug therapies and tients who benefit from antiresorptive or antiangiogenic the risk incurred by not undergoing recommended den- medications. This approach would include consultation tal preventive measures before consenting to treatment.
with an appropriate dental professional when it is determined a patient would benefit from an antire- 2. Cessation of at-risk medication therapy prior to tooth sorptive or antiangiogenic drug. There is considerable extraction or other procedures, which involve osseous support for early screening and initiation of appropriate injury (eg dental implant placement, periodontal or dental care, which not only decreases the incidence of apical endodontic treatment) ONJ but would also accrue the benefits that all patients a. Antiresorptive Therapy for Osteoporosis/Osteopenia enjoy with optimum oral health.32,87,98,109,110,120-136 The concept of a drug holiday in individuals The implementation of dental screening and receiving oral bisphosphonates or denosumab who appropriate dental measures before initiating require tooth extractions has been an ongoing area antiresorptive therapy reduced the risk of ONJ in of controversy with little data to support current several prospective studies when compared in a recommendations. The AAOMS Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw, PAGE 8 Medication-Related Osteonecrosis of the Jaw – 2014 Update revised in 2009, recommended discontinuing oral bisphosphonates for 3 months prior to and 3 months following invasive dental surgery – systemic con- ditions permitting.1 However there is currently no evidence that interrupting bisphosphonate therapy alters the risk of ONJ in patients following tooth extraction. In 2011 the ADA Council on Scientific Affairs revised their prior recommendation of a Individuals receiving monthly intravenous bisphos- drug holiday and suggested that patients receiving phonates or denosumab for treatment of oncologic lower cumulative doses of bisphosphonate (<2 disease have an increased risk of developing ONJ years) or denosumab may continue antiresorptive following tooth extraction and thus these proce- therapy during invasive dental treatment.126 An dures should be avoided if possible. Increased International ONJ Task Force recommended a drug awareness, preventive dental care and early recogni- holiday in patients at higher risk for developing tion of the signs and symptoms of ONJ have result- ONJ, including those with greater cumulative ed in earlier detection. Data are scant regarding the bisphosphonate exposure (>4 years), and those with effect of discontinuing intravenous bisphosphonates comorbid risk factors such as rheumatoid arthritis, prior to invasive dental treatments should these be prior or current glucocorticoid exposure, diabetes necessary. However, if ONJ develops the oncologist and smoking until the site has healed.140 In a 2011 may consider discontinuing antiresorptive therapy summary document on the long term safety of until soft tissue closure has occurred, depending on bisphosphonate therapy for osteoporosis, the FDA disease status.
determined that there was "no substantial data available to guide decisions regarding the initiation As a fully humanized antibody, denosumab blocks or duration of a drug holiday." the receptor-mediated activation of osteoclasts and has no binding affinity for bone matrix. Therefore, Damm and Jones proposed several alternatives to unlike bisphosphonates, the antiresorptive effects a drug holiday in BP-exposed patients who require of denosumab should be mostly dissipated within 6 invasive dental treatment.141 While there are no months of stopping the drug. However, there are no studies to support these recommendations their ap- studies to support or refute the strategy of stopping proach is based on bone physiology and pharmaco- denosumab therapy in the prevention or treatment kinetics of the antiresorptive medications and merit consideration (Level 5 evidence). They note that since 50% of serum BP undergoes renal excretion There are no data to support or refute the cessation the major reservoir of BP is the osteoclast whose of antiangiogenic therapy in the prevention or life span is 2 weeks. Thus the majority of free BP management of MRONJ and therefore continued within the serum would be extremely low 2 months research in the area is indicated.
following the last dose of an oral bisphosphonate and a 2-month drug free period should be adequate prior to an invasive dental procedure.
The major goals of treatment for patients at risk of devel- This committee recognized that there are limited oping or who have MRONJ are: data to support or refute the benefits of a drug • Prioritization and support of continued oncologic holiday for osteoporosis patients receiving antire- treatment in patients receiving IV antiresorptive and sorptive therapy. However, a theoretical benefit may still apply for those patients with extended exposure o Oncology patients can benefit greatly from the histories (>4 yrs). Therefore the committee consid- therapeutic effect of antiresorptive therapy by ers the modified drug holiday strategy as described controlling bone pain and reducing the incidence of by Damm and Jones to be a prudent approach for other skeletal complications those patients at risk.141 o The antiangiogenic class of chemotherapy agents b. Oncology Patients Receiving Monthly Antiresorp- have demonstrated efficacy in the treatment of a va- riety of malignancies with proven survival benefits PAGE 9 Medication-Related Osteonecrosis of the Jaw – 2014 Update • Preservation of quality of life through: o Patient education and reassuranceo Control of pain o Control of secondary infectiono Prevention of extension of lesion and development of new areas of necrosis At the initiation of treatment, patients should be educated as to the potential risks of MRONJ as the an- tiresorptive therapy is likely to exceed beyond 4 years A. Patients about to initiate intravenous antiresorptive or
treatment. The importance of optimizing dental health antiangiogenic treatment for cancer therapy
throughout this treatment period and beyond should be The treatment objective for this group of patients is to minimize the risk of developing MRONJ. Although a C. Asymptomatic patients receiving intravenous bisphos-
small percentage of patients receiving antiresorptives phonates or antiangiogenic drugs for cancer
develop osteonecrosis of the jaw spontaneously, the majority of affected patients experience this com- Maintaining good oral hygiene and dental care is of plication following dentoalveolar surgery.108,112,142-144 paramount importance in preventing dental disease Therefore if systemic conditions permit, initiation of that may require dentoalveolar surgery. Procedures antiresorptive therapy should be delayed until dental that involve direct osseous injury should be avoided. health is optimized.53,55,145 This decision must be made Non-restorable teeth may be treated by removal of in conjunction with the treating physician and dentist the crown and endodontic treatment of the remaining and other specialists involved in the care of the patient.
roots.146 Placement of dental implants should be avoided in the oncology patient receiving intravenous Non-restorable teeth and those with a poor prognosis antiresorptive therapy or antiangiogenic medications. should be extracted. Other necessary elective den- There is no data regarding the risk of ONJ associated toalveolar surgery should also be completed at this with implant placement in patients receiving time. Based on experience with osteoradionecrosis, it appears advisable that antiresorptive or antiangiogenic therapy should be delayed, if systemic conditions D. Asymptomatic patients receiving antiresorptive
permit, until the extraction site has mucosalized (14-21 therapy for osteoporosis
days) or until there is adequate osseous healing. Dental Sound recommendations based on strong clinical re- prophylaxis, caries control and conservative restorative search designs are still lacking for patients taking oral dentistry are critical to maintaining functionally sound bisphosphonates. The committee strategies outlined teeth. This level of care must be continued indefinitely.
below have been updated from those in the original Patients with full or partial dentures should be exam- Position Paper and are based on clinical studies that ined for areas of mucosal trauma, especially along demonstrate a low prevalence of disease. The risk of the lingual flange region. It is critical that patients be developing MRONJ associated with oral bisphospho- educated as to the importance of dental hygiene and nates increased when duration of therapy exceeded regular dental evaluations, and specifically instructed four years.102 Although the current level of evidence is to report any pain, swelling or exposed bone.
not strong, the committee continues to consider these Medical oncologists should evaluate and manage strategies for patients receiving oral bisphosphonates as patients scheduled to receive IV antiresorptive or anti- a prudent set of guidelines that will not compromise the angiogenic therapy similar to those patients scheduled long-term management of their osteoporosis. As more to initiate radiation therapy to the head and neck. The data become available and a better level of evidence is osteoradionecrosis prevention protocols are guidelines obtained, these strategies will be updated and modified that are familiar to most oncologists and general as necessary.
Patients receiving antiresorptive therapy for osteopo- rosis are also at risk for developing MRONJ, but to a B. Patients about to initiate antiresorptive treatment for
much lesser degree than those treated with intravenous antiresorptive therapy.101,102 MRONJ can develop PAGE 10 Medication-Related Osteonecrosis of the Jaw – 2014 Update spontaneously or after minor trauma. In general, these patients seem to have less severe manifestations of necrosis and respond more readily to stage specific treatment regimens.147,148 Elective dentoalveolar surgery does not appear to be contraindicated in this group. It is recommended that patients be adequately informed of the very small risk (<1%) of compromised bone healing. The risk of developing MRONJ associated 2. For those patients who have taken an oral bis- with oral bisphosphonates, while exceedingly small, phosphonate for less than four years and have also appears to increase when the duration of therapy ex- taken corticosteroids or antiangiogenic medications ceeds 4 years.101 This time frame may be shortened in concomitantly, the prescribing provider should be the presence of certain comorbidities, such as chronic contacted to consider discontinuation of the oral corticosteroid or antiangiogenic use.87,108,115 If systemic bisphosphonate (drug holiday) for at least two conditions permit, the clinician may consider discon- months prior to oral surgery, if systemic conditions tinuation of oral bisphosphonates for a period of two permit. The antiresorptive should not be restarted months prior to and three months following elective until osseous healing has occurred. These strategies invasive dental surgery in order to lower the risk of are based on reports that corticosteroid and antian- MRONJ. The rationale for this approach is based on giogenic agents, in combination with antiresorptive extrapolated data that demonstrate fluctuations of therapy, may increase the risk of developing osteoclast function, which is related to bisphospho- MRONJ and that a drug holiday may mitigate nate therapy, and recent outcomes studies that show this risk. Long-term, prospective studies however improved outcome of MRONJ treatment with drug are still required to establish the efficacy of drug holidays in reducing the risk of MRONJ for these The efficacy of utilizing a systemic marker of bone turnover to assess the risk of developing jaw necrosis 3. For those patients who have taken an oral bisphos- in patients at risk has not been validated.111,149-153 phonate for more than four years with or without Therefore the use of systemic markers of bone turnover any concomitant medical therapy, the prescribing as a measure of MRONJ risk is not recommended provider should be contacted to consider discon- although the Committee supports continued research in tinuation of the antiresorptive for two months prior this area.53,55,145,154 to oral surgery, if systemic conditions permit. The 1. For individuals who have taken an oral bisphospho- bisphosphonate should not be restarted until osse- nate for less than four years and have no clinical ous healing has occurred. The risk of long-term oral risk factors, no alteration or delay in the planned bisphosphonate therapy requires continued analysis surgery is necessary. This includes any and all pro- and research.
cedures common to oral and maxillofacial surgeons, E. Patients with established MRONJ
periodontists and other dental providers.
Treatment objectives for patients with an established It is suggested that if dental implants are placed, diagnosis of MRONJ are to eliminate pain, control informed consent should be provided related to infection of the soft and hard tissue, and minimize the possible long-term implant failure and the low progression or occurrence of bone necrosis. Patients risk of developing osteonecrosis of the jaws if with established MRONJ should avoid elective den- the patient continues to take an antiresorptive toalveolar surgical procedures, since these surgical agent. These concerns are based on recent animal sites may result in additional areas of exposed studies that have demonstrated impaired long-term necrotic bone.
implant healing.155 Such patients should be placed on a regular recall schedule. It is also advisable to Since the publication of the 2009 guidelines there have contact the provider who originally prescribed the been several reports of successful treatment outcomes oral bisphosphonate and suggest monitoring such for all stages of MRONJ following operative therapy patients and considering either alternate dosing of (sequestrectomy, resection)148,156-160 and non-operative the bisphosphonate, drug holidays, or an alternative therapy.161-165 Except for the more advanced cases of to the bisphosphonate therapy.
Stage 3 disease or in those cases with a well-defined PAGE 11 Medication-Related Osteonecrosis of the Jaw – 2014 Update sequestrum, it appears that a more prudent approach would be to consider operative therapies when non- operative strategies have failed.161,163 Regardless of the stage of disease, areas of necrotic bone that are a constant source of soft tissue irritation and loose bony sequestra should be removed or recontoured so that soft tissue healing can be optimized.166 The extraction of symptomatic teeth within exposed, necrotic bone rosis, persistent extraction sockets, etc, to define a case of should be considered, since it appears unlikely that MRONJ.177,178 The Special Committee members recognize the extraction will exacerbate the established necrotic the potential benefits and risks of diagnosing MRONJ based on radiographic signs alone. The Special Committee A randomized controlled trial of hyperbaric oxygen elected to not use radiographic signs alone in the case defi- therapy (HBO) as an adjunct to non-surgical and nition. The committee members accepted the consequence surgical treatment of MRONJ demonstrated some that the current case definition may underestimate the true improvement in wound healing, long-term pain scores frequency of the disease. Revising the definition to include and quality of life scores.167,168 However given the cases with radiographic signs alone may overestimate the small sample size, there was no statistically significant true disease frequency by including false positives in the difference between the control and HBO group with numerator, eg cases with radiographic findings suggestive regard to complete gingival coverage which was a of MRONJ, but are not MRONJ.
major study endpoint. Therefore the use of HBO as In order to direct rational treatment guidelines and collect the sole treatment modality for MRONJ cannot be data to assess the prognosis in patients who have used supported at this time.
either IV or oral antiresorptive and antiangiogenic agents, Case reports with small sample sizes have documented the Committee proposes use of the following revised stag- the use of other non-surgical treatment strategies, such as platelet rich plasma,169,170 low-level laser Patients at risk
128,171,172 parathyroid hormone173, and bone morphogenic protein.169,174 The efficacy of these No apparent necrotic bone in asymptomatic patients who treatment modalities needs to be established through have been treated with IV or oral antiresorptive or antian- additional research and controlled studies.
Staging and Treatment Strategies
Stage 0 (Non-exposed bone variant)
(See Table 1)
Patients with no clinical evidence of necrotic bone, but 1. Staging
present with non-specific symptoms or clinical and radio- graphic findings, such as, Modifications in the staging system are necessary to ensure that it remains an accurate reflection of disease presentation and to assist in the appropriate stratification • odontalgia not explained by an odontogenic cause of patients. A Stage 0 category was added in 2009 to in- clude patients with non-specific symptoms, or clinical and • dull, aching bone pain in the body of the mandible, radiographic abnormalities that may be due to exposure to which may radiate to the temporomandibular joint an antiresorptive agent. At that time the risk of a patient with Stage 0 disease advancing to a higher disease stage • sinus pain, which may be associated with inflamma- was unknown. Since then several case studies have report- tion and thickening of the maxillary sinus wall ed that up to 50% of patients with Stage 0 have progressed • altered neurosensory function to Stage 1, 2 or 3.175,176 Therefore, it appears that Stage 0 may be a valid disease category that captures patients with Clinical Findings prodromal disease (non-exposed variant). Also, the defini- • loosening of teeth not explained by chronic peri- tion of exposed bone was broadened (see above) to include the presence of cutaneous or mucosal fistulae that probe to bone for Stage 1, 2 and 3 categories. Other research groups • periapical/periodontal fistula that is not associated have proposed including radiographic signs alone, eg scle- with pulpal necrosis due to caries PAGE 12 Medication-Related Osteonecrosis of the Jaw – 2014 Update Radiographic Findings • alveolar bone loss or resorption not attributable to chronic periodontal disease • changes to trabecular pattern—dense woven bone and persistence of unremodeled bone in extraction • regions of osteosclerosis involving the alveolar 2. Stage-Specific Treatment Strategies
bone and/or the surrounding basilar bone At risk – Patients who are at risk of developing MRONJ • thickening/obscuring of periodontal ligament due to an exposure history with an antiresorptive or an (thickening of the lamina dura and decreased size of antiangiogenic drug. They do not have exposed bone nor the periodontal ligament space)153 do they require any treatment. However, these patients should be informed of the risks of developing MRONJ, as These non-specific findings, which characterize this well as the signs and symptoms of this disease process.
non-exposed variant of ONJ, may occur in patients with a prior history of Stage 1, 2, or 3 disease who have healed Stage 0 – Provide symptomatic treatment, and and have no clinical evidence of exposed bone.
conservatively manage other local factors, such as caries and periodontal disease. Systemic management may include the use of medication for chronic pain and control Exposed and necrotic bone, or fistulae that probes to bone, of infection with antibiotics, when indicated. These in patients who are asymptomatic and have no evidence of patients will require close monitoring given the potential infection. These patients may also present with radiograph- for progression to a higher stage of disease. Among ic findings mentioned for Stage 0 which are localized to patients with radiographic signs alone suggesting Stage 0, the alveolar bone region.
(see above), the committee recommends close monitoring for progression to a higher stage of disease. Other diagnoses, eg fibro-osseous disease, chronic sclerosing osteomyelitis should also be considered.
Exposed and necrotic bone, or fistulae that probe to bone, with evidence of infection. These patients are typically Stage 1 – These patients benefit from medical management symptomatic. These patients may also present with radio- including the use of oral antimicrobial rinses, such as graphic findings mentioned for Stage 0 which are localized chlorhexidine 0.12%. No immediate operative treatment is to the alveolar bone region.
Stage 2 – These patients benefit from the use of oral antimicrobial rinses in combination with antibiotic Exposed and necrotic bone, or fistulae that probe to therapy. Although local bone and soft tissue infection bone, with evidence of infection, and one or more of the is not considered the primary etiology for this process, the colonization of the exposed bone is a very common • exposed necrotic bone extending beyond the region occurrence. Most of the isolated microbes have of alveolar bone, ie, inferior border and ramus in been sensitive to the penicillin group of antibiotics. the mandible, maxillary sinus and zygoma in the Quinolones, metronidazole, clindamycin, doxycycline and erythromycin have been used with success in those • pathologic fracture patients who are allergic to penicillin. Microbial cultures should also be analyzed and the antibiotic regimen • extra-oral fistula should be adjusted accordingly. Biofilm formation on the • oral antral/oral nasal communication surface of the exposed bone has been reported in several reports and may be responsible for the failure of systemic • osteolysis extending to the inferior border of the antibiotic therapies that are described in some refractory mandible or sinus floor cases.66,70,179 In such cases, operative therapy directed at reducing the volume of colonized, necrotic bone may serve as a beneficial adjunct to antibiotic therapy.
PAGE 13 Medication-Related Osteonecrosis of the Jaw – 2014 Update Stage 3 – These patients benefit from debridement, including resection, in combination with antibiotic therapy, which may offer long-term palliation with resolution of acute infection and pain. Symptomatic patients with stage 3 disease may require resection and immediate reconstruction with a reconstruction plate or an obturator. The potential for failure of the reconstruction plate because of the generalized effects of the bisphosphonate exposure needs to be recognized by the clinician and patient. Case reports with small sample sizes describe successful immediate reconstruction with vascularized bone.180-182 Regardless of the disease stage, mobile bony sequestra should be removed to facilitate soft tissue healing. The extraction of symptomatic teeth within exposed, necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process. A thorough histologic analysis is indicated for all resected bone specimens (especially for patients with a history a malignant disease) since metastatic cancer has been reported in such specimens.183 Table 1 Staging and Treatment Strategies
At risk category No apparent necrotic bone in patients who have • No treatment indicated
been treated with either oral or IV bisphosphonates • Patient education Stage 0 No clinical evidence of necrotic bone, but non-specific
• Systemic management, including the use of pain medication clinical findings, radiographic changes and symptoms Stage 1 Exposed and necrotic bone, or fistulae that probes to
• Antibacterial mouth rinse bone, in patients who are asymptomatic and have no evidence of infection • Clinical follow-up on a quarterly basis • Patient education and review of indications for continued bisphosphonate therapy Stage 2 Exposed and necrotic bone, or fistulae that probes to
• Symptomatic treatment with oral antibiotics bone, associated with infection as evidenced by pain and ery-thema in the region of the exposed bone with or without purulent • Oral antibacterial mouth rinsedrainage • Debridement to relieve soft tissue irritation and infection control Stage 3 Exposed and necrotic bone or a fistula that probes to
• Antibacterial mouth rinse bone in patients with pain, infection, and one or more of the fol-lowing: exposed and necrotic bone extending beyond the region • Antibiotic therapy and pain control of alveolar bone,(i.e., inferior border and ramus in the mandible, • Surgical debridement/resection for longer term palliation of maxillary sinus and zygoma in the maxilla) resulting in pathologic infection and pain fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor † Exposed or probable bone in the maxillofacial region without resolution for greater than 8 weeks in patients treated with an antire- sorptive and/or an antiangiogenic agent who have not received radiation therapy to the jaws.
‡ Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed, necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process.
PAGE 14 Medication-Related Osteonecrosis of the Jaw – 2014 Update Future Research
The National Institutes of Health have provided fund-
ing opportunities for research on the pathophysiology of bisphosphonate-associated osteonecrosis of the jaw.184 This has resulted in multiple research efforts focusing on sever- al facets of this disease entity that have occurred since the last position paper. These studies are responsible for many of the new data and information that was presented in this paper. Areas of continued investigation include, but are not The American Association of Oral and Maxillofacial Surgeons limited to: 1) analysis of alveolar bone hemostasis and the (AAOMS) is providing this position paper on Medication Relat- response to antiresorptive therapies; 2) the role of novel ed Osteonecrosis of the Jaw (MRONJ) to inform practitioners, patients and other interested parties. The position paper is based antiangiogenic medications and their effects on jaw bone on a review of the existing literature and the clinical observa- healing; 3) pharmacogenetic research; 4) development of tions of a Special Committee composed of oral and maxillofacial valid MRONJ risk assessment tools; 5) animal studies to surgeons, oral pathologists, and oncologists experienced in the validate existing and proposed treatment and prevention diagnosis, surgical and adjunctive treatment of diseases, injuries and defects involving both the functional and esthetic aspects of the hard and soft tissues of the oral and maxillofacial regions, Continued governmental and institutional support is re- epidemiologists, and basic researchers.
quired in order to further elucidate the underlying patho- The position paper is informational in nature and is not intended physiological mechanisms of MRONJ at the cellular and to set any standards of care. AAOMS cautions all readers that molecular level. Moreover, improved strategies for the the strategies described in the position paper are NOT practice prevention, risk reduction, and treatment of MRONJ need parameters or guidelines and may NOT be suitable for every, or to be developed further so that more accurate judgments any, purpose or application. This position paper cannot substitute about risk, prognosis, treatment selection, and outcome can for the individual judgment brought to each clinical situation by the patient's oral and maxillofacial surgeon. As with all clinical be established for patients with MRONJ.
materials, the position paper reflects the science related to MRONJ at the time of the paper's development, and it should be used with the clear understanding that continued research and practice may result in new knowledge or recommendations. AAOMS makes no express or implied warranty regarding the ac-curacy, content, completeness, reliability, operability, or legality of information contained within the position paper, including, without limitation, the warranties of merchantability, fitness for a particular purpose, and non-infringement of proprietary rights. In no event shall the AAOMS be liable to the user of the position paper or anyone else for any decision made or action taken by him or her in reliance on such information.
PAGE 15 Medication-Related Osteonecrosis of the Jaw – 2014 Update Appendix I: Antiresorptive Preparations Commonly Used in the U.S.
Alendronate Osteoporosis Yes Osteoporosis Yes Osteoporosis Yes Pamidronate Bone Zolendronate Bone Osteoporosis monoclonal 60 mg/6 PAGE 16 Medication-Related Osteonecrosis of the Jaw – 2014 Update Appendix II: Medications Used in the Treatment of Various Cancers that are
Antiangiogenic or Targets of the Vascular Endothelial Growth Factor (VEGF)
Pathway that have been Associated with Jaw Necrosis*.
Mechanism of action
Primary indication
Tyrosine kinase inhibitor GIST, RCC, pNET Tyrosine kinase inhibitor HCC, RCC Bevacizumab Humanized mCRC, NSCLC, Glio, mRCC monoclonal antibody Mammalian target of Organ rejection in renal transplant (Rapamune®) rapamycin pathway Abbreviations: GIST gastrointestinal stromal tumor; RCC renal cell carcinoma; pNET pancreatic neuroendocrine tumor, HCC hepatocellular carcinoma; mCRC metastatic colorectal carcinoma; NSCLC non-squamous non-small cell lung carcinoma; Glio Glioblastoma; mRCC metastatic renal cell carcinoma * While the FDA has issued an ONJ advisory only for  bevacizumab and sunitinib,99,100 the committee remains concerned about a similar potential risk associated with several other medications within the same drug class which have a similar mechanism of action. Therefore further controlled, prospective studies will be required to more fully characterize the risk of jaw necrosis associated with these agents. PAGE 17 Medication-Related Osteonecrosis of the Jaw – 2014 Update
Figure 1 – Frequency of ONJ Over Time107
4/7/2014) page 19. Prevalence of ONJ by BP Duration
ONJ  Prevalence  %   Oral BP Duration (years)
PAGE 18 Medication-Related Osteonecrosis of the Jaw – 2014 Update Figure 2 –
MRONJ Disease Frequency Grouped by Disease Status vs Medication Status

Bevacizumab Bevacizumab Study Design
Guarneri, et al
Scagliotti, et al 1Sample size in parentheses 3Prevalence estimate. All other frequencies reported in the figure are incidences.
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Vol. 3 - No 1 - June 2011 CRCHUM — Research Centre - University of Montreal Hospital Centre CRCHUM: at the forefront of clinical research "Being able to ask questions and improve treatments lies at the heart of the mission of a tertiary and quaternary care hospital like the CHUM," notes Jacques Turgeon, Director of the CHUM's research centre (CRCHUM). In other words, research is an essential ingredient of health care.

Behavioral and Brain Functions ResearchEfficacy of atomoxetine in adult attention-Deficit/Hyperactivity Disorder: a drug-placebo response curve analysisStephen V Faraone*1, Joseph Biederman2, Thomas Spencer2, David Michelson3, Lenard Adler4, Fred Reimherr5 and Stephen J Glatt6 Address: 1Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA, 2Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA 01880, USA, 3Lilly Research Laboratories, Indianapolis, IN 46285, USA, 4New York University School of Medicine, New York, NY 10016, USA, 5Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA and 6Institute of Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0603, USA