Clinical staging of DrugRelated OsteoNecrosis of the Jaws: a new proposal Celentano A, Sadile G, Leuci S, Adamo D, Sammartino G, Mignogna MD, Ruoppo E Dept. of Neurosciences, Reproductive and odontostomatological Sciences: Oral Medicine Complex Unit, Federico II University of Naples, 5 Via Pansini, 80131 Napoli, Italy Introduction Drug related osteonecrosis of the jaws (DRONJ) is the most recent definition of a well studied disease that has been the subject of extensive discussion during the past 10 years. DRONJ encompasses all cases of osteonecrosis reported in the literature which are related to treatment with certain drugs such as bisphosphonates, anti-resorptive agents and anti-angiogenic factors. 1,2,3 These agents have effects on vascularity or osteoclast activity similar to that of the bisphosphonates. As for as vascularity is concerned, Bevacizumab, a recombinant humanized monoclonal antibody, blocks angiogenesis by binding to vascular endothelial growth factor (VEGF). Denosumab, instead, is a monoclonal receptor activator of nuclear factor-kappa B ligand (RANKL) antibody that reduces the differentiation, activity, and survival of osteoclasts, and lowers the rate of bone resorption. It is indicated for the treatment of bone metastases, multiple myeloma and osteoporosis. It is well accepted that the occurrence of ONJ in patients treated with bisphosphonates is strongly related to long-term therapy and large accumulating doses. We believe that in the next future, due to the long-term use and high dosage of drugs such as bevacizumab, denosumab or some others anti-angiogenic and anti-osteoclastic agents, we will assist a growth of DRONJ number of cases, independent from bisphosphonates. This new trend may remember the spread of cases related to bisphosphonates in the last ten years. At present the staging system of DRONJ, developed by Ruggiero et al. in the American Association of Oral and Maxillofacial Surgeons Position Paper8, consists of 3 stages integrated with a non-exposed variant of the disease. Bagan et al3 proposed a newer classification based on the previous one except the part in which stage 2 had two clinical variants depending on the therapy response. Mawardi et al2 also studied stage 0 as presence of DRONJ without bone exposure in oral cavity divided in symptomatic (stage 0ss) and non-symptomatic (stage 0sa) patients in which are observed clinical and/or radiographical findings.1,2 These classifications (and some others similar released during the last 3 years) don’t exclude each other hence this led to a confusion in diagnostic phase, especially for the general dental practitioner. Methods From the Oral Medicine Unit of “Federico II” University of Naples we assembled 90 cases of DRONJ between 2005-2011. Patients were classified by age, gender, drug assumed, main disease, DRONJ-site and stage. Applying the procedure of Mignogna et al4 we re-staged all the cases retrospectively. The stage was assigned due to the presence of inflammatory/infectious symptoms, independently from the presence of bone exposure in oral cavity. Hence patients previously classified as ‘stage 0 non-symptomatic’ were re-assigned to stage 1 and patients previous belongings to ‘stage 0 symptomatic’ were re-assigned to stage 2. Stage 0 symptomatic patients presenting any complications (oro-antral communication, extra-oral fistula, pathological fracture, paresthesia) were classified as stage 3. Results We reported 12 cases belonging to stage 1 (13,3%), 43 cases to stage 2 (47,7%) and 35 stage-3-patients (38,8%). None of the cases was left unstaged. 7 cases previously staged as stage 0 were reassigned as stage 1 (n=2) stage 2 (n=4) and stage 3 (n=1). The series consisted of 29 males (32,2%) and 61 females (67,7%); the mean age was 67,6 years; the site on DRONJ was lower jaw 60,0%, upper jaw 32,2%, both jaws 7,7%; the drug related to the osteonecrosis was zoledronic acid 33%, pamidronic acid + zoledronic acid 16,6%, alendronic acid 5,5%, risedronic acid 3,3%, ibandronic acid 2,2%, Sunitinib + zoledronic acid 2,2 %, alendronic acid + zoledronic acid 1,1%, clodronic acid + zoledronic acid 1,1%. The main disease of the patients was breast cancer 43,3%, multiple myeloma 18,8%, prostate cancer 14,4%, osteoporosis 4,4%, rheumatoid arthritis 5,5%, lung cancer 3,3%, liver cancer 2,2%, kidney cancer 2,2%, gastric cancer 1,1%, ovarian cancer 1,1%, non-Hodgkin lymphoma 1,1%. The trigger of the disease was a tooth extraction 76,6%, periodontitis 14,4%, prosthetic 3,3%, implant surgery 1,1%, unknown 4,4%. Discussion Although the present staging5,6,7 system is quite complex (Stage 0 Sa and Ss, stage 1, stage 2a and 2b, stage 3) for some patients it fails to assign a stage.8 Since these various classification systems are not mutually exclusive, we strongly believe that our proposed classification would be extremely useful to the clinical practitioner who needs clear guidelines to identify and treat DRONJ patients. Further investigations are needed to clarify the etio-pathogenesis of DRONJ in order to better understand severity of the disease, to prevent the development of osteonecrosis in at-risk patients and to manage properly anti-resorptive agents and anti-angiogenic factors in selected patients. Conclusions Using our classification system we successfully assigned a stage for all the 90 cases we treated. This means a simplification in the care of DRONJ patients by facilitating the choice of specific treatment protocols at each stage with the option of restaging after the initial treatment period. We believe that by using the stage definition as the indicator for the success of treatment we can more effectively evaluate if a given therapy has been effective. A reduction in the assigned stage is an indicator of clinical remission Gender Age Drug DRONJ-Site Main disease DRONJ-Stage Trigger F 71 alendronate upper jaw Rheumatoid arthritis I tooth extraction 85 Osteoporosis II 78 lower jaw 74 62 both jaws III 75 alendronate + zoledronate clodronate + zoledronate Ovarian cancer 60 ibandronate Breast cancer 64 pamidronate+zoledronate 54 periodontitis 66 56 M 67 Multiple myeloma 76 70 prosthetic 65 risedronate sunitinib + zoledronate Prostate cancer Kidney cancer unknown 79 zoledronate 82 37 77 Liver cancer Lung cancer 63 52 73 80 59 69 Gastric cancer 51 55 83 implant 61 47 NHL 81 45 39 68 57 92 72 49 Fig. 1,2. Female patient, 70 years, kidney cancer, history of 5 infusions of zoledronic acid and 1 year treatment of Sunitinib still on therapy. Tab.1 References 1.Hellstein JW, Adler RA et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: Executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2011 Nov 2.Koch FP, Walter C et al. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg. 2011 Mar 3.Guarneri V, Miles D et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat. 2010 Jul;122(1):181-8 4.MIgnogna MD, Sadile G, Leuci S. Drug related osteonecrosis of the jaw: exposure or not exposure, that is the question. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, May 2012 5.Mawardi H, Treister N, Richardson P, et al: Sinus tracts: An early sign of bisphosphonate-associated osteonecrosis of the jaws? J Oral Maxillofac Surg 2009 Mar 6.Bagan JV, Jimenez Y, Diaz JM et al. Osteonecrosis of the jaws in intravenous bisphosphonate use: Proposal for a modification of the clinical classification. Oral Oncol. 2009 Jul 7.American Association of Oral and Maxillofacial Surgeons Position Paper on bisphosphonate-related osteonecrosis of the jaws—2009 Update. J Oral Maxillofac Surg 67(5 suppl) 8.Bagan JV, Hens-Aumente E et al. Bisphosphonate-related osteonecrosis of the jaws: Study of the staging system in a series of clinical cases. Oral Oncol. 2012 Mar