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Biphosphonate-associated osteonecrosis can be controlled by nonsurgical management

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Biphosphonate-associated osteonecrosis can be controlled by nonsurgical management
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  Biphosphonate-associated osteonecrosis can be controlled bynonsurgical management Lucio Montebugnoli, MD, DDS, a Laura Felicetti, DDS, b Davide Bartolomeo Gissi, DDS, b Angelo Pizzigallo, MD, c Gian Andrea Pelliccioni, MD, DDS, d and Claudio Marchetti, MD, DDS, e Bologna, Italy UNIVERSITY OF BOLOGNA AND S. ORSOLA HOSPITAL Sixteen patients with jaw biphosphonate-osteonecrosis and with exposed bone areas were subdivided into 2treatment groups. The first group (7 patients) underwent superficial or radical surgical therapy, while the second (9patients) underwent antibiotic treatment. A slight reduction of the necrotic areas was observed in 5 of 7 patients in thefirst group, whereas no change was observed in the remaining 2 patients at 22- and 24-month follow-up. A slightreduction of the necrotic areas was observed in 7 of 9 patients in the second group, whereas no change was observedin the remaining 2 patients at 5- and 24-month follow-up. The statistical analysis showed that the treatment regimendid not significantly influence the dimensional change in the exposed bone. The preliminary results seem to suggestthat biphosphonate-associated osteonecrosis can be well controlled by a nonsurgical protocol consisting in long-termadministration of antibiotics.  (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:473-7) Since 1995, biphosphonates have been increasinglyused in the management of multiple myeloma andmetastatic disease spread to the bone, and to preventosteoporosis in men and women. 1-4 A relative increasein jaw osteonecrosis has been reported in recent yearsparticularly among patients receiving nitrogen-contain-ing biphosphonates like pamidronate and zole-dronate. 4-6 The disorder has been defined as “the un-expected development of necrotic bone in the oralcavity of a patient receiving biphosphonate treatmentand who was not receiving radiotherapy to the head andneck.” 7, p508 The typical clinical manifestation of biphosphonate-associated bone necrosis is an area of devitalized ex-posed bone surrounded by an inflamed gingiva or mu-cosa. 7-8 Areas of exposed bone can appear anywhere inthe maxilla or mandible, either spontaneously or morecommonly after a surgical procedure, in adjacent teethor even in edentulous zones. 9-11 To date, several recommendations have been madeto establish effective procedures to treat biphosphonate-associated osteonecrosis, but no consensus on a stan-dard of care has yet been reached nor is there anyagreement on the surgical or nonsurgical approach tothe issue. 6,9,12,13,18 This is probably because of the lack of randomized clinical trials in the literature comparingdifferent management strategies designed to recover thebone-exposed areas.The aim of this prospective study was to see whetheran antibiotic regimen could be effective in reducingnecrotic areas or at least in limiting or preventing thetime-related progression of the process and also tocompare the effectiveness of a surgical and nonsurgi-cal approach to treat biphosphonate-associated bonenecrosis. MATERIAL AND METHODS Sixteen consecutive patients with jaw osteonecrosistreated with pamidronate (3 patients), zoledronate (10patients), or both (5 patients), presenting at the Depart-ment of Oral Science of the University of Bolognaduring the past 2 years, were enrolled if they had areasof devitalized exposed jawbone without bleeding onprobing. No patient had evidence of metastasis or ahistory of radiation therapy. Ten patients had multiplemyeloma, 3 had metastatic breast carcinoma, and 3metastatic prostate carcinoma.The median time to diagnosis of osteonecrosis fromthe beginning of the biphosphonate treatment was 18months (range 10-30). The necrotic bone appeared aftera dental extraction in 10 patients, whereas it appearedspontaneously in 2 patients, and in edentulous areas in4 patients with partial denture.After radiological and computed tomography scananalysis, the patients were assigned to 2 treatment a Professor, Department of Oral Science, University of Bologna. b Graduate Student, Department of Oral Science, University of Bologna. c Assistant, Department of Maxillofacial Surgery, S. Orsola Hospital. d Professor, Department of Oral Science, University of Bologna. e Professor, Department of Maxillofacial Surgery, S. Orsola Hospital.Received for publication Oct 5, 2006; returned for revision Nov 9,2006; accepted for publication Jan 3, 2007.1079-2104/$ - see front matter© 2007 Mosby, Inc. All rights reserved.doi:10.1016/j.tripleo.2007.01.008  473  groups, depending on the presence or absence of evi-dent radiopaque bone sequestra.Group 1 comprised 7 patients with evident bonesequestra: 4 men and 3 women aged 54 to 75 years,mean 64.7  7.9 (6 with exposed bone in the mandibleand 1 in the maxilla) with a mean (  SD) bone expo-sure area of 4.42  2.70. Four patients underwent localdebridement of necrotic bone consisting of a nonag-gressive superficial removal of bone sequestra. Threepatients had an extensive debridement and sequestrec-tomy until healthy bone was found (1 patient withoroantral communication secondary to posterior max-illary involvement and 2 with severe osteonecrosis in-volving more than half of the vertical length of themandible). All patients received continuous antibiotictherapy after surgery.Group 2 comprised 9 patients: 5 women and 4 menaged 45 to 74 years, mean 58.5  11.3 (5 with exposedbone in the mandible and 4 in the maxilla) withoutevident signs of bone sequestra and a mean (   SD)exposed bone area of 3.17  2.00. All patients receivedcontinuous antibiotic therapy without surgery. The an-tibiotic protocol consisted of a combination therapywith amoxicillin/clavulanate potassium 1-g tablets ev-ery 12 hours and metronidazole 500-mg tablets every 8hours. All patients were recalled monthly and the sizeof bone-exposed areas carefully measured by an exter-nal observer who did not know to which group thepatient belonged.Unpaired Student  t   test was applied to disclose anyage- or site- (maxilla/mandible) related differences inexposed bone areas, and to compare the extension of exposed bone areas between the 2 treatment groups atthe first appointment. A linear model was fitted toevaluate any relationship between the duration of bi-phosphonate therapy and the size of any exposed bonearea, and to disclose any relationship between the du-ration of biphosphonate therapy and any size changesafter treatment in both groups. After fitting a generallinear model, a multiple regression analysis of variance(ANOVA) for repeated measures was applied to deter-mine any significant interference of time and type of treatment (surgical or nonsurgical) on size changes inexposed bone areas. RESULTS No statistical difference ( t   0.5; NS) was found inthe extension of exposed bone areas between mandible(4.0  2.7 cm) and maxilla (3.1  1.4 cm) or betweenthe extension of the areas in the group of patients whounderwent surgery and in the group of patients receiv-ing antibiotic therapy alone ( t   1.05; NS). No signif-icant relationship was found between the extension of the areas and the duration of biphosphonate therapy(F  0.76; NS).All patients described a regression of pain a fewweeks after both surgical and antibiotic treatment. Aslight but not statistically significant reduction in theareas of exposed bone was found both in the group of patients who had surgical treatment (from 4.42  2.7 to3.75  2.6; NS) and in the group of patients receivingantibiotic therapy alone (from 3.11  2.1 to 2.33  2.4;NS).A slight reduction of the necrotic bone areas(  1 cm) was observed in 5 of 7 patients (3 patients of the 4 who underwent superficial debridement where thereduction was detected after 3, 7, and 7 months, respec-tively, and 2 patients of the 3 who underwent radicaldebridement, where the reduction was achieved after 2and 12 months respectively). Recovery is still ongoingafter 3, 11, 11, 6, and 16 months of follow-up respec-tively. No size change in the necrotic bone areas wasobserved in the remaining 2 patients of this group even22 and 24 months, respectively, after the surgical treat-ment.A slight reduction of the necrotic bone areas(  1 cm) was observed in 7 of 9 patients in the secondgroup at 2 (in 5 patients), 3, and 4 months, respectively,after the beginning of antibiotic therapy. Recovery isstill ongoing after 3 (2 patients), 5, 7, 8, 9, and 24months (1 patient each) of follow-up, respectively. Twopatients did not show any size changes after 5 and 24months, respectively. Table I shows the clinical find-ings in the entire population.The results of fitting a general linear model relatingthe centimeters of exposed bone to the 2 predictivefactors (time and treatment) showed that either thetreatment regimen or the duration of follow-up did notsignificantly influence the size change in the areas of exposed bone (F    0.7; NS) (Fig. 1). Further, nosignificant relationship was detected between thechange in the areas of exposed bone and the duration of therapy with biphosphonates ( r   0.05; NS) or the sitesof exposed bone (F  0.27; NS). DISCUSSION There is considerable evidence that long-term bi-phosphonate therapy can induce jaw osteonecrosis, andthat necrotic processes are mostly initiated by localtraumas or dental procedures. 14-17 There is a broad agreement among researchers thatthe standard goal for controlling jaw osteonecrosis is toprevent it. Patients prescribed biphosphonate treatmentshould be referred to a specialized dentist for oralexamination, and dental treatment is recommended toeliminate infections and prevent the need for futureinvasive procedures once biphosphonate therapy has OOOOE  474  Montebugnoli et al. October 2007   begun. This may include caries control, dental restora-tions, root canal treatment, periodontal surgery, toothextraction, and replacement of any incongruous pros-thetic appliance. 5,7,8,15 On the other hand, no consensushas yet been reached on the best strategies to repair theexposed bone once bone necrosis has developed.Numerous clinical protocols to treat areas of exposedbone have been proposed, reporting a reduction or evenresolution of osteonecrosis in patients treated with re-moval of sequestra, withdrawal of biphosphonates, orsystemic or local antibiotics and mouth rinses, whereasextensive and radical surgical resections have neverresulted in wound closure and have sometimes led toworsening of the disease. 6,9,10,12,13 Current disagree-ment on the issue could be because most of the data inthe literature come from case reports or retrospectivestudies, whereas randomized prospective clinical trialscomparing different forms of management are lacking.The present prospective longitudinal study treatedpatients with jaw osteonecrosis by 2 different proce-dures. Although the cohort is small, our preliminaryfindings are in accordance with most of the recom-mended protocols, i.e., that jaw osteonecrosis can bewell controlled by strictly conservative manage-ment. 7,12,13,15 We found that medical management alone did yieldgood long-term outcomes in terms of pain relief andprevention of progression of the process. A slight re-duction, although not statistically significant, of thenecrotic bone areas was observed in 7 of 9 patientsearly after the beginning of antibiotic therapy, and all 9patients did not show any size changes after long-termfollow-up, as none of our 16 patients showed anyworsening of the clinical situation even after severalmonths of follow-up (median 8 months with a range of 3-24 months). As far as the comparison between sur-gical and conservative management is concerned, sta-tistical analysis failed to disclose any difference be-tween the outcomes obtained by superficial or radicalsurgical therapy and those obtained by long-term anti-biotic therapy alone. However, because of the smallsize of the population, the results from statistical anal-ysis must be confirmed in a larger population.These results cannot support the major role of host-bacterial interaction in the development and progressionof biphosphonate-induced osteonecrosis, but are in linewith the hypothesis that the efficacy of antibiotic treat-ment in controlling disease progression can be attributedto the control of local infection in the exposed areas. 19 Biphosphonate-associated jaw osteonecrosis is char- Table I.  Clinical findings in 16 patients with jaw osteonecrosis Patient Age/sex  Biphosphonatetreatment, mo Location Treatment Size (cm) of exposed bone areasFollow-up, mo Before treatment After treatment  1 74/M 11 Mandible Superficial debridement 4 3 112 59/M 30 Mandible Superficial debridement 10 9 113 54/M 22 Mandible Superficial debridement 2 2 244 64/M 10 Mandible Superficial debridement 2 1 35 59/F 27 Maxilla Sequestrectomy 5 4 166 68/F 10 Mandible Sequestrectomy 4 3 67 75/F 24 Mandible Sequestrestomy 4 4 228 45/F 13 Mandible Antibiotic therapy 4 3 99 50/F 20 Maxilla Antibiotic therapy 2 1 810 52/F 11 Mandible Antibiotic therapy 2 1 611 74/F 29 Maxilla Antibiotic therapy 4 3 712 64/M 18 Mandibole Antibiotic therapy 1 0 613 65/M 18 Maxilla Antibiotic therapy 3 3 514 74/M 12 Mandible Antibiotic therapy 3 2 315 45/F 12 Maxilla Antibiotic therapy 1 0 316 58/M 18 Mandible Antibiotic therapy 8 8 24 Fig. 1. The graph shows the results of fitting a general linearmodel relating the centimeters of exposed bone areas to the 2predictive factors (time and treatment). The treatment regi-men did not significantly influence the size of the exposedbone areas (F  0.7; NS). OOOOE Volume 104, Number 4 Montebugnoli et al.  475  acterized by a local alteration of the osteoclast/osteo-blast axis, with a relative decrease of osteoclast activity,as well as with a local inhibition of angiogenesis, andan increased bacterial role as compared with osteora-dionecrosis. The clinical symptoms and lesions arerather similar to the lesions seen in patients with osteo-radionecrosis, while multifocality and occurrence of osteonecrosis in both the maxilla and the mandible canbe more frequently observed in biphosphonate-associ-ated osteonecrosis as compared with osteoradionecro-sis, as the avascular necrosis seems to be related to 2quite different mechanisms. 15,20,21 Once an area of bone necrosis is produced by trauma,periodontal or periradicular disease, or any dental pro-cedure, osteoclasts cannot activate or aggregate enoughto remove necrotic bone. When necrotic volumereaches a sufficient size it may produce local changesthat impair bony, vascular, and connective tissue localstructures necessary for self-repair. 19,22-25 In addition,because the oral cavity is never aseptic, superimposedbacterial cofactors inevitably produce sequestrationwith possible osteomyelitis and prevent or inhibit epi-thelial regeneration over exposed bone. 26 The goal of antibiotic therapy must be to interrupt thevicious circle and facilitate self-repair of the area or atleast to stop the progression of the local disorder, beingaware that these patients can and must live with someexposed bone, which itself is not painful and will remainstructurally sound to support normal jaw function. Studiesare in progress to compare the efficacy of uninterruptedantibiotic therapy with a cyclic antibiotic regimen.Aggressive surgery to remove exposed bone did notyield better results in the present study and probablycannot achieve better results because the entire bone isaffected in biphosphonate-induced bone necrosis sothat necrotic bone cannot be completely debrided to adefinitely viable bone margin, contrary to what wasobserved in osteoradionecrosis where the complete de-bridement of necrotic bone is often resolutive. 9-15 Sur-gery should be considered only in limited symptomatic cases when long-term medical management has failedto control the disease. REFERENCES 1. Michaelson MD, Smith MR. Bisphosphonates for treatment andprevention of bone metastases. J Clin Oncol 2005;23:8219-24.2. Hillner BE, Weeks JC, Desch CE, Smith TJ. Pamidronate inprevention of bone complications in metastatic breast cancer: acost-effectiveness analysis. J Clin Oncol 2000;18:72-9.3. 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Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws:risk factors, recognition, prevention, and treatment. J Oral Max-illofac Surg 2005;63:1567-75.9. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) in-duced avascular necrosis of the jaws: a growing epidemic. J OralMaxillofac Surg 2003;61:1115-8.10. Pires FR, Miranda A, Cardoso ES, Cardoso AS, Fregnani ER,Pereira CM, et al. Oral avascular bone necrosis associated withchemotherapy and biphosphonate therapy. Oral Dis 2005;11:365-9.11. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jawsassociated with cancer chemotherapy. J Oral Maxillofac Surg2003;61:1104-7.12. Farrugia MC, Summerlin DJ, Krowiak E, Huntley T, Freeman S,Borrowdale R, et al. Osteonecrosis of the mandible or maxillaassociated with the use of new generation bisphosphonates. La-ryngoscope 2006;116:115-20.13. Ficarra G, Beninati F, Rubino I, Vannucchi A, Longo G, TonelliP, et al. 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October 2007   patients with bone metastases from breast cancer. J Clin Oncol1993;11:491-8.23. Greenberg MS. Intravenous bisphosphonates and osteonecrosis.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:259-60.24. Vincenzi B, Santini D, Rocci L, Tonini G. Bisphosphonates: newantiangiogenic molecules in cancer treatment? Ann Oncol2003;14:806-7.25. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM,et al. Novel antiangiogenic effects of the bisphosphonate com-pound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055-61.26. Hoshino H, Yamazaki K. Mechanisms of action in bisphospho-nates. Clin Calcium 2005;15:88-92.  Reprint requests: Lucio Montebugnoli, MD, DDSUniversity of BolognaDepartment of Oral Sciencevia S. Vitale 5940125 Bologna, Italylucio.montebugnoli@unibo.it OOOOE Volume 104, Number 4 Montebugnoli et al.  477 
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