- Email: [email protected]
Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update
Oral Oncology 45 (2009) 551–554
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update Jose Bagan a,b,*, Crispian Scully c,d,e, Vicente Sabater b, Yolanda Jimenez a a
Valencia University, Valencia, Spain University General Hospital, Valencia, Spain c UCL-EDI, Eastman, London, UK d WHO Collaborating Centre for Research, Education and Service in Oral Health, Disability and Culture, Eastman, London, UK e Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman, London, UK b
a r t i c l e
i n f o
Article history: Received 30 November 2008 Received in revised form 24 December 2008 Accepted 2 January 2009 Available online 28 February 2009 Keywords: Osteonecrosis Bisphosphonates Cancer Jaws
s u m m a r y Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe complication seen most frequently in patients on intravenous bisphosphonates treatment for malignant diseases. High potency bisphosphonates are generally implicated and risk factors also include dental extractions. Prevention is of paramount importance. Management is controversial but there is little evidence basis and the consensus is to be conservative. Recent advances in this area are summarised in this concise review. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Osteonecrosis of the jaws (ONJ) or bisphosphonate-related osteonecrosis of the jaws (BRONJ) was first reported by Marx (2003).1 This severe complication occurs most frequently in patients on intravenous bisphosphonates treatment for malignant diseases such as multiple myeloma or metastatic malignant disease, mainly breast cancer. Bisphosphonates prevent, reduce and delay cancerrelated skeletal complications.2 Many authors however, consider that the benefits of bisphosphonate treatment in malignant disease generally outweigh any risks.3 Some cases of BRONJ have also been reported in patients on oral bisphosphonates treatment for osteoporosis.4,5 but millions of patients are on oral bisphosphonates treatment for osteoporosis, and the risk of ONJ is very low indeed6 overall incidence ranging from 1/10,000-1/100,000 treatments,7 and these oral drugs are helpful in preventing hip fractures in older women in particular. Pathogenesis Bisphosphonates inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, block osteoclast protein * Corresponding author. Address: Hospital General Universitario, Servicio de Estomatología, Avda/Tres Cruces s/n, 46014 Valencia, Spain. Tel.: +34 96 197 21 27; fax: +34 96 394 18 54. E-mail address: [email protected] (J. Bagan). 1368-8375/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2009.01.002
prenylation, and thus block osteoclast-mediated bone resorption.8 This predisposes to BRONJ. There is an inhibition of osteoclast development from monocytes, increased osteoclast apoptosis and prevention of osteoclast development and recruitment from bone marrow precursors.9 Other possible mechanisms include an antiangiogenic effect and a suppressive effect on endothelial cells with no effect on vascular endothelial growth factor receptor10 but reduced serum levels of interleukin 17.11 Ruggiero and Drew12 described the elective involvement of the jaws compared to other bone sites and may be due to the healing of an open bone wound and that bisphosphonates are preferentially deposited in bones with high turnover rates as the jaws.
Incidence BRONJ is far more frequently induced by intravenous bisphosphonates than by oral bisphosphonates. Hoff et al.13 found that 16 out of 1338 patients with breast cancer (1.2%) and 13 of 548 with myeloma (2.4%) on intravenous bisphosphonate treatment developed BRONJ. Wang et al.14 reported a slightly greater incidence both in myeloma (3.8%), in breast cancer (2.5%) and prostate cancer (2.9%) but Mavrokokki et al.15 reported a lower overall incidence. Recently Stumpe et al.16 found a global incidence of 0.94% (6/638 cases). A figure of the order of 1–3% for BRONJ in cancer patients on intravenous bisphosphonate therapy is easily remembered.
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J. Bagan et al. / Oral Oncology 45 (2009) 551–554
Risk factors Several studies have focussed on the risk factors for developing BRONJ. Treatment with high potency (nitrogenated) intravenous bisphosphonates such as zoledronic acid and pamidronate, and dental extractions, are important risk factors.17,18 The duration of bisphosphonate treatment, the number of infusions and the total infusion hours may also be risk factors for BRONJ.16,19 Other suspected risk factors, which have largely been excluded, include concomitant therapy with corticosteroids,18,20 thalidomide
or bortezomib.18 Oral health appears not to be a risk factor for BRONJ.20 Obesity and smoking were recently associated with BRONJ, but the same study showed that the most relevant risk factor was zoledronate use.21 Delayed-onset BRONJ associated with zoledronic acid has also been described.22 Genetic factors also influence the risk for BRONJ. Sarasquete et al.23 reported that single nucleotide polymorphism rs1934951 of the drug-metabolising enzyme cytochrome P450 CYP2C8 was significantly associated with a higher risk. The authors concluded
Figure 1 Osteonecrosis of the upper jaw; stage 1. The patient had no symptoms.
Figure 4 Osteonecrosis of the jaw; stage 3. The patient had an extraoral (cutaneous) fistula.
Figure 2 Osteonecrosis of the jaw; stage 1. A more extensive area of necrotic bone is exposed than in Fig. 1. The patient had no symptoms.
Figure 5 An initial stage of osteonecrosis without visible necrotic bone.
Figure 3 Osteonecrosis of the jaw; stage 2. A more extensive area of necrosis and with symptoms.
Figure 6 Necrotic cortical bone of the mandible with enlarged osteocytic lacunae and colonies of actinomyces. H–E 20.
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that individuals homozygous for the T allele had an increased likelihood for developing BRONJ. Prognostication Marx et al.5 described collagen C-terminal telopeptide (CTX) test as a useful serological marker for the risk of BRONJ, but this has not been supported by other authors.24,25 and we found no statistically significant relationship between the serum CTX and the number of exposed bone necrotic areas and the size of BRONJ.26 New clinical forms of presentation The main clinical signs and symptoms are pain, areas of exposed and necrotic bone with tooth mobility, mucosal swelling, erythema, and ulceration, abscesses and fistulas.12 Ruggiero et al.27 described three stages in BRONJ patients (Figs. 1–6), but some authors have suggested the need to include in this classification early stages where patients without bone exposed may be presented.28 However, Junquera and Gallego29 presented two cases of BRONJ without bone exposure (Figs. 7 and 8). Diagnostic methods for assessing the extent of lesions Computed tomography (CT) scan is helpful to assess the size and the extent of bone necrosis30 but magnetic resonance imaging (MRI) is also an effective tool31 though findings are not specific.30
Table 1 Recommendations for bisphosphonate patients.7 Pain Infection
Surgical treatment
Altering bisphosphonate therapy regimen Other considerations
Deal with appropriately Topical chlorhexidine. Systemic antibiotics if infection (penicillin; levoflaxacin; doxycycline; azithromycin; metronidazole) Maintain an infection-free oral environment Should be delayed or be conservative Remove sharp edges to stop soft tissue trauma Remove loose bony sequestra Segmental jaw resection for symptomatic patients with large segments of necrotic bone or pathological fracture Some experts suggest stopping bisphosphonate therapy in cancer patients with established ONJ Nutritional supplements important e.g. tube feeding Hyperbaric oxygen effectiveness not established
Adapted from Khosla et al. (2007)7.
Management Management of BRONJ remains controversial. The consensus is to manage patients with BRONJ conservatively7,32 when at least 23–53% of patients achieve resolution of mucosal discontinuities (Table 1).13,33 However, some patients need surgery. Wutzl et al.34 conducting the first prospective study showed that minimal resection of necrotic bone and local soft closure resulted in success in 58.5%. Other authors have reported that surgery can improve the patient’s symptoms and may resolve BRONJ.35 Hyperbaric oxygen has been suggested and recommended by some authors as a complementary therapy.36,37 Others have found that the discontinuation of bisphosphonate therapy has not helped reverse the osteonecrosis, that surgical manipulation of the involved sites appears to worsen the underlying bone pathology, and that hyperbaric oxygen was of no definitive benefit.38 Prevention
Figure 7 Extensive necrosis of the bone matrix with fat cells broken down to form irregular fat cysts, and calcification. H–E 20.
The importance of preventive measures is thus highlighted.12,39,40 One prospective study found that the risk of BRONJ decreased after the implementation of preventive dental procedures41 and this was supported by another that showed a reduction in BRONJ incidence from 3.2% to 1.3% after a preventive programme.42 Finally, the risk of BRONJ diminishes when the frequency of administration of bisphosphonates is reduced, so a reduced drug schedule may be a useful tool to prevent this severe adverse effect.43 Conflict of interest statement None declared. References
Figure 8 The cellular haematopoietic marrow has disappeared and fat necrosis is shown. H–E 20.
1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115–7. 2. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420–32. 3. Wutzl A, Biedermann E, Wanschitz F, Seemann R, Klug C, Baumann A, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 2008;30(9):1224–30. 4. Novince CM, Ward BB, McCauley LK. Osteonecrosis of the jaw: an update and review of recommendations. Cells Tissues Organs 2008 [Epub ahead of print]. 5. Marx RE, Cillo Jr JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65(12):2397–410. 6. Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with
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J. Bagan et al. / Oral Oncology 45 (2009) 551–554 oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clin Ther 2007;29(8):1548–58. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10):1479–91. Ruggiero SL, Mehrotra B. Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and treatment. Ann Rev Med 2008 [Epub ahead of print]. Capsoni F, Longhi M, Weinstein R. Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist’s role. Arthritis Res Ther 2006;8(5):219. Alonci A, Allegra A, Bellomo G, Quartarone E, Oteri G, Nastro E, et al. Patients with bisphosphonate-associated osteonecrosis of the jaw have unmodified levels of soluble vascular endothelial growth factor receptor 1. Leuk Lymphoma 2007;48(9):1852–4. Oteri G, Allegra A, Bellomo G, Alonci A, Nastro E, Penna G, et al. Reduced serum levels of Interleukin 17 in patients with osteonecrosis of the jaw and in multiple myeloma subjects after bisphosphonates administration. Cytokine 2008;43(2):103–4. Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res 2007;86(11):1013–21. Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23(6):826–36. Wang EP, Kaban LB, Strewler GJ, Raje N, Troulis MJ. Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J Oral Maxillofac Surg 2007;65(7):1328–31. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65(3):415–23. Stumpe MR, Chandra RK, Yunus F, Samant S. Incidence and risk factors of bisphosphonate-associated osteonecrosis of the jaws. Head Neck 2008 [Epub ahead of print]. Bagan JV, Jimenez Y, Murillo J, Hernandez S, Poveda R, Sanchis JM, et al. Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 2006;42(3):327–9. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008;44(9):857–69. Carmagnola D, Celestino S, Abati S. Dental and periodontal history of oncologic patients on parenteral bisphosphonates with or without osteonecrosis of the jaws: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 [Epub ahead of print]. Estilo CL, Van Poznak CH, Wiliams T, Bohle GC, Lwin PT, Zhou Q, et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 2008;13(8):911–20. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study. J Oral Maxillofac Surg 2008;66(4):625–31. Borrás-Blasco J, Rosique-Robles D, Giner-Marco V, Galan-Brotons A, Casterá E, Costa S. Possible delayed onset of osteonecrosis of the jaw in association with zoledrónico acid. J Clin Pharm Ther 2007;32(6):651–4. Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 2008;112(7):2709–12. Lehrer S, Montazem A, Ramanathan L, Pessin-Minsley M, Pfail J, Stock RG, et al. Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106(3):389–91. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, et al. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using
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serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2008;66(6):1320–1. [author reply 1321–2]. Bagan JV, Jiménez Y, Gómez D, Sirera R, Poveda R, Scully C. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol 2008 [Epub ahead of print]. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(4):433–41. Bagan JV, Jimenez Y, Diaz JM, Murillo J, Sanchis JM, Poveda R. Osteonecrosis of the jaws in intravenous bisphosphonate use: proposal for a modification of the clinical classification. Oral Oncol 2008. Junquera L, Gallego L. Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant? J Oral Maxillofac Surg 2008;66(7):1516–7. Bisdas S, Chambron Pinho N, Smolarz A, Sader R, Vogl TJ, Mack MG. Biphosphonate-induced osteonecrosis of the jaws: CT and MRI spectrum of findings in 32 patients. Clin Radiol 2008;63(1):71–7. García-Ferrer L, Bagán JV, Martínez-Sanjuan V, Hernandez-Bazan S, García R, Jiménez-Soriano Y, et al. MRI of mandibular osteonecrosis secondary to bisphosphonates. AJR Am J Roentgenol 2008;190(4):949–55. Montebugnoli L, Felicetti L, Gissi DB, Pizzigallo A, Pelliccioni GA, Marchetti C. Biphosphonate-associated osteonecrosis can be controlled by nonsurgical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(4):473–7. Van den Wyngaert T, Claeys T, Huizing MT, Vermorken JB, Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol 2008 [Epub ahead of print]. Wutzl A, Biedermann E, Wanschitz F, Seemann R, Klug C, Baumann A, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 2008;30(9):1224–30. Longobardi G, Boniello R, Gasparini G, Pagano I, Pelo S. Surgical therapy for osteonecotic lesions of the jaws in patients in therapy with bisphosphonates. J Craniofac Surg 2007;18(5):1012–7. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, Kraft KH, Boneta O, Moon RE, et al. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 2007;65(7):1321–7. Shimura K, Shimazaki C, Taniguchi K, Akamatsu S, Okamoto M, et al. Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonateinduced osteonecrosis of the jaw in a patient with multiple myeloma. Int J Hematol 2006;84(4):343–5. Nastro E, Musolino C, Allegra A, Oteri G, Cicciù M, Alonci A, et al. Bisphosphonate-associated osteonecrosis of the jaw in patients with multiple myeloma and breast cancer. Acta Haematol 2007;117(3):181–7. Infante Cossío P, Cabezas Macián A, Pérez Ceballos JL, Palomino Nicas J, Gutiérrez Pérez JL. Bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma. Med Oral Patol Oral Cir Bucal 2008;13(1):E52–7. Bagán J, Blade J, Cozar JM, Constela M, García Sanz R, Gómez Veiga F, et al. Recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates. Med Oral Patol Oral Cir Bucal 2007;12(4):E336–40. Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2008 [Epub ahead of print]. Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 2008 [Epub ahead of print]. Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G, et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007;21(7):1545–8.
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update Jose Bagan a,b,*, Crispian Scully c,d,e, Vicente Sabater b, Yolanda Jimenez a a
Valencia University, Valencia, Spain University General Hospital, Valencia, Spain c UCL-EDI, Eastman, London, UK d WHO Collaborating Centre for Research, Education and Service in Oral Health, Disability and Culture, Eastman, London, UK e Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman, London, UK b
a r t i c l e
i n f o
Article history: Received 30 November 2008 Received in revised form 24 December 2008 Accepted 2 January 2009 Available online 28 February 2009 Keywords: Osteonecrosis Bisphosphonates Cancer Jaws
s u m m a r y Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe complication seen most frequently in patients on intravenous bisphosphonates treatment for malignant diseases. High potency bisphosphonates are generally implicated and risk factors also include dental extractions. Prevention is of paramount importance. Management is controversial but there is little evidence basis and the consensus is to be conservative. Recent advances in this area are summarised in this concise review. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Osteonecrosis of the jaws (ONJ) or bisphosphonate-related osteonecrosis of the jaws (BRONJ) was first reported by Marx (2003).1 This severe complication occurs most frequently in patients on intravenous bisphosphonates treatment for malignant diseases such as multiple myeloma or metastatic malignant disease, mainly breast cancer. Bisphosphonates prevent, reduce and delay cancerrelated skeletal complications.2 Many authors however, consider that the benefits of bisphosphonate treatment in malignant disease generally outweigh any risks.3 Some cases of BRONJ have also been reported in patients on oral bisphosphonates treatment for osteoporosis.4,5 but millions of patients are on oral bisphosphonates treatment for osteoporosis, and the risk of ONJ is very low indeed6 overall incidence ranging from 1/10,000-1/100,000 treatments,7 and these oral drugs are helpful in preventing hip fractures in older women in particular. Pathogenesis Bisphosphonates inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, block osteoclast protein * Corresponding author. Address: Hospital General Universitario, Servicio de Estomatología, Avda/Tres Cruces s/n, 46014 Valencia, Spain. Tel.: +34 96 197 21 27; fax: +34 96 394 18 54. E-mail address: [email protected] (J. Bagan). 1368-8375/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2009.01.002
prenylation, and thus block osteoclast-mediated bone resorption.8 This predisposes to BRONJ. There is an inhibition of osteoclast development from monocytes, increased osteoclast apoptosis and prevention of osteoclast development and recruitment from bone marrow precursors.9 Other possible mechanisms include an antiangiogenic effect and a suppressive effect on endothelial cells with no effect on vascular endothelial growth factor receptor10 but reduced serum levels of interleukin 17.11 Ruggiero and Drew12 described the elective involvement of the jaws compared to other bone sites and may be due to the healing of an open bone wound and that bisphosphonates are preferentially deposited in bones with high turnover rates as the jaws.
Incidence BRONJ is far more frequently induced by intravenous bisphosphonates than by oral bisphosphonates. Hoff et al.13 found that 16 out of 1338 patients with breast cancer (1.2%) and 13 of 548 with myeloma (2.4%) on intravenous bisphosphonate treatment developed BRONJ. Wang et al.14 reported a slightly greater incidence both in myeloma (3.8%), in breast cancer (2.5%) and prostate cancer (2.9%) but Mavrokokki et al.15 reported a lower overall incidence. Recently Stumpe et al.16 found a global incidence of 0.94% (6/638 cases). A figure of the order of 1–3% for BRONJ in cancer patients on intravenous bisphosphonate therapy is easily remembered.
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J. Bagan et al. / Oral Oncology 45 (2009) 551–554
Risk factors Several studies have focussed on the risk factors for developing BRONJ. Treatment with high potency (nitrogenated) intravenous bisphosphonates such as zoledronic acid and pamidronate, and dental extractions, are important risk factors.17,18 The duration of bisphosphonate treatment, the number of infusions and the total infusion hours may also be risk factors for BRONJ.16,19 Other suspected risk factors, which have largely been excluded, include concomitant therapy with corticosteroids,18,20 thalidomide
or bortezomib.18 Oral health appears not to be a risk factor for BRONJ.20 Obesity and smoking were recently associated with BRONJ, but the same study showed that the most relevant risk factor was zoledronate use.21 Delayed-onset BRONJ associated with zoledronic acid has also been described.22 Genetic factors also influence the risk for BRONJ. Sarasquete et al.23 reported that single nucleotide polymorphism rs1934951 of the drug-metabolising enzyme cytochrome P450 CYP2C8 was significantly associated with a higher risk. The authors concluded
Figure 1 Osteonecrosis of the upper jaw; stage 1. The patient had no symptoms.
Figure 4 Osteonecrosis of the jaw; stage 3. The patient had an extraoral (cutaneous) fistula.
Figure 2 Osteonecrosis of the jaw; stage 1. A more extensive area of necrotic bone is exposed than in Fig. 1. The patient had no symptoms.
Figure 5 An initial stage of osteonecrosis without visible necrotic bone.
Figure 3 Osteonecrosis of the jaw; stage 2. A more extensive area of necrosis and with symptoms.
Figure 6 Necrotic cortical bone of the mandible with enlarged osteocytic lacunae and colonies of actinomyces. H–E 20.
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that individuals homozygous for the T allele had an increased likelihood for developing BRONJ. Prognostication Marx et al.5 described collagen C-terminal telopeptide (CTX) test as a useful serological marker for the risk of BRONJ, but this has not been supported by other authors.24,25 and we found no statistically significant relationship between the serum CTX and the number of exposed bone necrotic areas and the size of BRONJ.26 New clinical forms of presentation The main clinical signs and symptoms are pain, areas of exposed and necrotic bone with tooth mobility, mucosal swelling, erythema, and ulceration, abscesses and fistulas.12 Ruggiero et al.27 described three stages in BRONJ patients (Figs. 1–6), but some authors have suggested the need to include in this classification early stages where patients without bone exposed may be presented.28 However, Junquera and Gallego29 presented two cases of BRONJ without bone exposure (Figs. 7 and 8). Diagnostic methods for assessing the extent of lesions Computed tomography (CT) scan is helpful to assess the size and the extent of bone necrosis30 but magnetic resonance imaging (MRI) is also an effective tool31 though findings are not specific.30
Table 1 Recommendations for bisphosphonate patients.7 Pain Infection
Surgical treatment
Altering bisphosphonate therapy regimen Other considerations
Deal with appropriately Topical chlorhexidine. Systemic antibiotics if infection (penicillin; levoflaxacin; doxycycline; azithromycin; metronidazole) Maintain an infection-free oral environment Should be delayed or be conservative Remove sharp edges to stop soft tissue trauma Remove loose bony sequestra Segmental jaw resection for symptomatic patients with large segments of necrotic bone or pathological fracture Some experts suggest stopping bisphosphonate therapy in cancer patients with established ONJ Nutritional supplements important e.g. tube feeding Hyperbaric oxygen effectiveness not established
Adapted from Khosla et al. (2007)7.
Management Management of BRONJ remains controversial. The consensus is to manage patients with BRONJ conservatively7,32 when at least 23–53% of patients achieve resolution of mucosal discontinuities (Table 1).13,33 However, some patients need surgery. Wutzl et al.34 conducting the first prospective study showed that minimal resection of necrotic bone and local soft closure resulted in success in 58.5%. Other authors have reported that surgery can improve the patient’s symptoms and may resolve BRONJ.35 Hyperbaric oxygen has been suggested and recommended by some authors as a complementary therapy.36,37 Others have found that the discontinuation of bisphosphonate therapy has not helped reverse the osteonecrosis, that surgical manipulation of the involved sites appears to worsen the underlying bone pathology, and that hyperbaric oxygen was of no definitive benefit.38 Prevention
Figure 7 Extensive necrosis of the bone matrix with fat cells broken down to form irregular fat cysts, and calcification. H–E 20.
The importance of preventive measures is thus highlighted.12,39,40 One prospective study found that the risk of BRONJ decreased after the implementation of preventive dental procedures41 and this was supported by another that showed a reduction in BRONJ incidence from 3.2% to 1.3% after a preventive programme.42 Finally, the risk of BRONJ diminishes when the frequency of administration of bisphosphonates is reduced, so a reduced drug schedule may be a useful tool to prevent this severe adverse effect.43 Conflict of interest statement None declared. References
Figure 8 The cellular haematopoietic marrow has disappeared and fat necrosis is shown. H–E 20.
1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115–7. 2. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420–32. 3. Wutzl A, Biedermann E, Wanschitz F, Seemann R, Klug C, Baumann A, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 2008;30(9):1224–30. 4. Novince CM, Ward BB, McCauley LK. Osteonecrosis of the jaw: an update and review of recommendations. Cells Tissues Organs 2008 [Epub ahead of print]. 5. Marx RE, Cillo Jr JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65(12):2397–410. 6. Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with
554
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