- Email: [email protected]
Severe Osteomyelitis of the Mandible Associated With the Use of Non–Nitrogen-Containing Bisphosphonate (Disodium Clodronate): Report of a Case
562
DISODIUM CLODRONATE–ASSOCIATED MANDIBULAR OSTEOMYELITIS
J Oral Maxillofac Surg 65:562-565, 2007
Severe Osteomyelitis of the Mandible Associated With the Use of Non–NitrogenContaining Bisphosphonate (Disodium Clodronate): Report of a Case Figen Cizmeci Senel, DDS, PhD,* Umut Saracoglu Tekin, DDS, PhD,† Ahmet Durmus, MD,‡ and Bora Bagis, DDS, PhD§ Bisphosphonate-associated osteonecrosis of the jaws (ONJ) is a very topical subject. Painful exposure of bone in the mandible and maxilla of patients receiving bisphosphonates was first reported by Marx in 2003.1 Subsequently, many dental professionals, especially oral and maxillofacial surgeons, have identified numerous cases, and several authors have reported additional cases.2-5 Bisphosphonates have been the standard of care for managing the osteoporosis associated with malignancy. There are 2 classes of bisphosphonates: nitrogen-containing and non–nitrogen-containing. Non–nitrogen-containing bisphosphonates are metabolized rapidly,6 whereas nitrogen-containing bisphosphonates are much more potent and are not metabolized.6,7 This previously unrecognized complication is seen predominantly with the nitrogen-containing bisphosphonates, such as pamidronate (Aredia; Novartis Pharmaceuticals, East Hanover, NJ), alendronate (Fosamax; Merck, West Point, PA), and zoledronate (Zometa; Novartis Pharmaceuticals); it has
*Assistant Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Karadeniz Technical University, Trabzon, Turkey. †Assistant Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Kirikkale, Kirikkale, Turkey. ‡Instructor, Department of Hematology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. §Assistant Professor, Department of Prosthetic Dentistry, Faculty of Dentistry, Karadeniz Technical University, Trabzon, Turkey. Address correspondence and reprint requests to Dr. Saracoglu Tekin: Ozanlar Sokak No 6/1, Kurtulus 06600, Ankara, Turkey; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6503-0032$32.00/0 doi:10.1016/j.joms.2006.10.043
not been reported in patients taking non–nitrogencontaining bisphosphonates, such as etidronate (Didronel; Procter and Gamble, Cincinnati, OH) and disodium clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and tiludronate (Skelid; Sanofi Aventis, Bridgewater, NJ). This report presents a case of osteomyelitis in the jaw of a patient who had received chronic non– nitrogen-containing bisphosphonate (disodium clodronate) therapy for prevention of bone disease due to multiple myeloma.
Report of a Case The patient, a 72-year-old female, was referred to our department in February 2004 because of severe pain and swelling of the left mandible. These complications developed several days after the tooth extraction, which was done approximately 2 years prior to her application to our clinic. In addition, it was learned that she had also been diagnosed with multiple myeloma 7 years prior to her application. During this application she had been treated with oral disodium clodronate (1,600 mg/day) for 5 years and with pulse therapy with melphalan and prednisone. Intraorally, the alveolar bone at the extraction site was exposed, and a purulent discharge was observed in the mucosa (Fig 1). A panoramic radiograph showed osteomyelitis of the mandible after dental extraction. Figure 2 shows the outlines of the extraction sockets, together with dense sequestra of bone lying in a poorly circumscribed radiolucency. An incisional biopsy of the infected bone was performed. The histopathologic examination revealed necrotic bone, dense infiltration of plasma cells, polymorphonuclear leukocytes and lymphocytes, and numerous Actinomyces colonies (Fig 3). Local alveoloplasty was performed, followed by antibiotherapy with massive doses of penicillin G. Clinical response was good, with progressive healing of the infection. One year after diagnosis and treatment of osteomyelitis, there no local signs of recurrent infection were evident.
563
SENEL ET AL
FIGURE 1. Intraoral view of the patient. Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
Discussion Bisphosphonate-associated ONJ is clearly a new and different clinical entity. Marx1 and Miglioratti3 have suggested that bisphosphonates may be directly responsible for ONJ in their patients. Although the data show an association between bisphosphonates and osteonecrosis, they do not establish a causal relationship. Bisphosphonates are a class of pyrophosphate analogs containing a phosphate-carbon-phosphate (PC-P) backbone. This structure confers the ability to chelate calcium ions and, consequently, the ability to target to bone mineral in vivo. The geminal carbon of the P-C-P group has 2 side chains, R1 and R2. The R1 side chain is usually a hydroxyl group, which enhances the affinity of the compounds for bone mineral but has little influence on the antiresorptive po-
FIGURE 3. The histopathologic examination showing necrotic bone, dense infiltration of plasma cells, polymorphonuclear leukocytes and lymphocytes, and numerous Actinomyces colonies. (Hematoxylin and eosin; original magnification ⫻100.) Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
tency.8 The major determinant of antiresorptive potency is the structure and conformation of the R2 side chain.8 First-generation bisphosphonate drugs (non-N R2 side chain) have a short R2 side chain, such as ⫺CH3 (as in etidronate) or ⫺Cl (as in clodronate). Second-generation aminobisphosphonates contain a nitrogen group (which have an R2 side chain containing a primary amino group), such as alendronate and pamidronate, and are 10- to 1,000-fold more potent than first-generation bisphosphonates. The third-generation bisphosphonates, such as risedronate and zoledronic acid, contain a nitrogen atom within a heterocyclic ring (N-heterocyclic R2 side chain), and are 10,000-fold more potent than the first-generation compounds.9
FIGURE 2. Panoramic radiograph showing osteomyelitis of the mandible after dental extraction. The outlines of the extraction sockets can be seen, together with dense sequestrations of bone lying in a poorly circumscribed radiolucency. Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
564
DISODIUM CLODRONATE–ASSOCIATED MANDIBULAR OSTEOMYELITIS
Several studies have suggested that aminobisphosphonates have a molecular mechanism of action different than or in addition to that of the nonaminobisphosphonates.10 The second- and third-generation bisphosphonates are significantly more potent than their first-generation predecessors (etidronate, clodronate, and tiludronate). They inhibit bone resorption by osteoclastic inhibition through selective concentration at the interface of the active osteoclast and the bone resorption surface. The specific mechanism of this inhibition is unknown, but there is evidence of several actions, including inhibition of osteoclast development from precursor cells,11 increase in osteoclast apoptosis,12 stimulation of osteoclast inhibitory factor,13 reduction of osteoclast activity,14 and downregulation of matrix metalloproteinases.15 The resulting reduction in osteoclastic activity reduces bone resorption. The exact molecular mechanisms by which bisphosphonates affect osteoclasts seem to be different in first-generation bisphosphonates compared with second- and third-generation bisphosphonates, which contain a nitrogen moiety. Nitrogen-containing bisphosphonates recently were shown to induce apoptosis and inhibit bone resorption by osteoclasts by inhibiting farnesyl diphosphate synthase,16 an enzyme in the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme prevents the synthesis of isoprenoid lipids required for the prenylation of small guanosine triphosphate– binding proteins, such as Rho and Rac, necessary for osteoclast function and survival.17 However, the mevalonate pathway does not seem to be affected by the bisphosphonates that lack a nitrogen, such as clodronate.17 Bisphosphonates, including clodronate, act on the bony skeleton to reduce normal and abnormal bone resorption. Clodronate alters the activity of osteoclasts and osteoblasts, changing the balance of bone resorption and bone formation, resulting in reduced bone turnover. In responsive patients, inhibition of abnormal bone resorption by clodronate leads to reduced hypercalcemia of malignancy presenting with or without demonstrable skeletal metastases. Recently, several authors reported ONJ associated with the use of nitrogen-containing bisphosphonates.1-3,18 Gotcher and Jee19 reported that dichloromethylene diphosphonate (Cl2MDP) may produce ONJ-like lesions in rice rats. Non–nitrogen-containing bisphosphonates (eg, clodronate, etidronate, residronate, and tiludronate) are in common use today and do not cause bone necrosis.1,3 There are no reports in the literature of ONJ in humans associated with the use of non–nitrogen-containing bisphosphonates. This is the first report of a patient with osteomyelitis of the jaw after chronic non–nitrogen-con-
taining bisphosphonate (disodium clodronate) therapy for bone disease prevention. Montonen et al20 reported that disodium clodronate is useful in treating the recurrent pain of diffuse sclerosing osteomyelitis (DSO) of the mandible, but these authors did not investigate the effect of clodronate on DSO. However, it should be noted that chronic use of clodronate caused osteomyelitis in our case. Osteomyelitis of the jaw in long-term survivors of multiple myeloma who are receiving chronic biphosphonate therapy may be a new clinical entity. Although it is not possible to prove beyond doubt an etiologic link between biphosphonate therapy and the occurrence of osteomyelitis of the jaw, the association of multiple myeloma with severe immunosuppression, the prolonged biphosphonate therapy, and the localization to the jaw all point to a relationship.21 Because the jaws are the only bones of the skeleton exposed to the external environment and thus subject to frequent trauma, local inflammation, and abscess, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis, especially among patients suffering from severe and prolonged immunosuppression, such as in our patient.22-26 The local presence of Actinomyces was demonstrated in our patient. Actinomyces is an indolent infection that colonizes the mouth; after disruption of the mucosal barrier, it may spread hematogeneously, with possible general dissemination. Clinically, infections with Actinomyces occur most frequently in the oral, cervical, and facial areas, with a particular predilection for the angle of the jaw.27 Further studies are needed to elucidate the precise relationship between bisphosphonates and osteonecrosis. Initiation of non–nitrogen-containing bisphosphonate therapy should be deferred until dental and oral surgical treatments have been completed, because non–nitrogen-containing bisphosphonates may cause osteomyelitis of the jaws.
References 1. Marx RE: Pamidronate (Aredia)- and zoldronate (Zometa)- induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 3. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253, 2003 4. Melo MD, Obeid G: Osteonecrosis of the maxilla in a patient with history of bisphosphonate therapy. J Can Dent Assoc 71:111, 2005 5. Carter GD, Gross AN: Bisphosphonates and avascular necrosis of the jaw. Aust Dent J 48:268, 2003 6. Frith JC, Mokkonen J, Blackburn GM, et al: Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosire 5=-(beta, gamma-dichloromethylene)
SENEL ET AL
7.
8. 9.
10. 11. 12. 13. 14. 15. 16.
triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358, 1997 Tenenbaum HC, Shelemay A, Girard B, et al: Bisphosphonates and periodontics: Potential applications for regulation of bone mass in the periodontium and other therapeutic/diagnostic uses. J Periodontol 73:813, 2002 Van Beek E, Hoekstra M, Van de Ruit M, et al: Structural requirements for bisphosphonate actions in vitro. J Bone Miner Res 9:1875, 1994 Geddes AD, D’Souza SM, Ebetino FH, et al: Bisphosphonates: Structure–activity relationships and therapeutic implications, in Heersche JNM, Kanis JA (eds): Bone and Mineral Research. Amsterdam, Elsevier Science, 1994, p 265 Boonekamp PM, van der Wee-Pals LJ, van Wijk-van Lennep MM, et al: Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1:27,1986 Hughes DE, MacDonald BR, Russell RG, et al: Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest 83:1930, 1989 Hughes DE, Wright KR, Uy HL, et al: Bisphosphonates promote apoptosis in murine osteoclast in vitro and in vivo. J Bone Miner Res 10:1478, 1995 Vitte C, Fleisch H, Guenthes HL: Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclastic-mediated resorbtion. Endocrinology 137:2324, 1996 Sato M, Grasser W: Effects of bisphosphonates on isolated cat osteoclast as examined by reflected light microscopy. J Bone Miner Res 5:31, 1990 Teronen O, Heikkila P, Konttinen YT, et al: MMP inhibition and down-regulation by bisphosphonates. Ann NY Acad Sci 878: 453, 1999 Dunford JE, Thompson K, Coxon FP, et al: Structure–activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296:235, 2001
565 17. Coxon FP, Helfrich MH, Van’t Hof R, et al: Protein geranylgeranylation is required for osteoclast formation, function, and survival: Inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 15:1467, 2000 18. Migliorati CA, Casiglia J, Epstein J, et al: Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 136:1658, 2005 19. Gotcher JE, Jee WSS: The progress of the periodontal syndrome in the rice rat: The effects of a bisphosphonate on the periodontium. J Periodontal Res 16:441, 1981 20. Montonen M, Kalso L, Pylkkaren B, et al: Disodium clodronate in the treatment of diffuse sclerosing osteomyelitis (DSO) of the mandible. Int J Oral Maxillofac Surg 30:313, 2001 21. Lugassy G, Shaham R, Nemets A, et al: Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: A new clinical entity. Am J Med 117:440, 2004 22. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567, 2005 23. Hellstein JW, Marek CL: Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682, 2005 24. Pogrel MA: Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 62:391, 2004 25. Sarathy AP, Bourgeois SL Jr, Goodell GG: Bisphosphonateassociated osteonecrosis of the jaw and endodontic treatment: Two case reports. J Endod 31:759, 2005 26. Wooltorton E: Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. CMAJ 172: 1684, 2005 27. Russo TA: Agents of actinomycosis, in Mandell GL, Barrett JE, Dolin R (eds): Principles and Practice of Infectious Diseases (ed 6). New York, Churchill Livingstone, 2005
DISODIUM CLODRONATE–ASSOCIATED MANDIBULAR OSTEOMYELITIS
J Oral Maxillofac Surg 65:562-565, 2007
Severe Osteomyelitis of the Mandible Associated With the Use of Non–NitrogenContaining Bisphosphonate (Disodium Clodronate): Report of a Case Figen Cizmeci Senel, DDS, PhD,* Umut Saracoglu Tekin, DDS, PhD,† Ahmet Durmus, MD,‡ and Bora Bagis, DDS, PhD§ Bisphosphonate-associated osteonecrosis of the jaws (ONJ) is a very topical subject. Painful exposure of bone in the mandible and maxilla of patients receiving bisphosphonates was first reported by Marx in 2003.1 Subsequently, many dental professionals, especially oral and maxillofacial surgeons, have identified numerous cases, and several authors have reported additional cases.2-5 Bisphosphonates have been the standard of care for managing the osteoporosis associated with malignancy. There are 2 classes of bisphosphonates: nitrogen-containing and non–nitrogen-containing. Non–nitrogen-containing bisphosphonates are metabolized rapidly,6 whereas nitrogen-containing bisphosphonates are much more potent and are not metabolized.6,7 This previously unrecognized complication is seen predominantly with the nitrogen-containing bisphosphonates, such as pamidronate (Aredia; Novartis Pharmaceuticals, East Hanover, NJ), alendronate (Fosamax; Merck, West Point, PA), and zoledronate (Zometa; Novartis Pharmaceuticals); it has
*Assistant Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Karadeniz Technical University, Trabzon, Turkey. †Assistant Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Kirikkale, Kirikkale, Turkey. ‡Instructor, Department of Hematology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. §Assistant Professor, Department of Prosthetic Dentistry, Faculty of Dentistry, Karadeniz Technical University, Trabzon, Turkey. Address correspondence and reprint requests to Dr. Saracoglu Tekin: Ozanlar Sokak No 6/1, Kurtulus 06600, Ankara, Turkey; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6503-0032$32.00/0 doi:10.1016/j.joms.2006.10.043
not been reported in patients taking non–nitrogencontaining bisphosphonates, such as etidronate (Didronel; Procter and Gamble, Cincinnati, OH) and disodium clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and tiludronate (Skelid; Sanofi Aventis, Bridgewater, NJ). This report presents a case of osteomyelitis in the jaw of a patient who had received chronic non– nitrogen-containing bisphosphonate (disodium clodronate) therapy for prevention of bone disease due to multiple myeloma.
Report of a Case The patient, a 72-year-old female, was referred to our department in February 2004 because of severe pain and swelling of the left mandible. These complications developed several days after the tooth extraction, which was done approximately 2 years prior to her application to our clinic. In addition, it was learned that she had also been diagnosed with multiple myeloma 7 years prior to her application. During this application she had been treated with oral disodium clodronate (1,600 mg/day) for 5 years and with pulse therapy with melphalan and prednisone. Intraorally, the alveolar bone at the extraction site was exposed, and a purulent discharge was observed in the mucosa (Fig 1). A panoramic radiograph showed osteomyelitis of the mandible after dental extraction. Figure 2 shows the outlines of the extraction sockets, together with dense sequestra of bone lying in a poorly circumscribed radiolucency. An incisional biopsy of the infected bone was performed. The histopathologic examination revealed necrotic bone, dense infiltration of plasma cells, polymorphonuclear leukocytes and lymphocytes, and numerous Actinomyces colonies (Fig 3). Local alveoloplasty was performed, followed by antibiotherapy with massive doses of penicillin G. Clinical response was good, with progressive healing of the infection. One year after diagnosis and treatment of osteomyelitis, there no local signs of recurrent infection were evident.
563
SENEL ET AL
FIGURE 1. Intraoral view of the patient. Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
Discussion Bisphosphonate-associated ONJ is clearly a new and different clinical entity. Marx1 and Miglioratti3 have suggested that bisphosphonates may be directly responsible for ONJ in their patients. Although the data show an association between bisphosphonates and osteonecrosis, they do not establish a causal relationship. Bisphosphonates are a class of pyrophosphate analogs containing a phosphate-carbon-phosphate (PC-P) backbone. This structure confers the ability to chelate calcium ions and, consequently, the ability to target to bone mineral in vivo. The geminal carbon of the P-C-P group has 2 side chains, R1 and R2. The R1 side chain is usually a hydroxyl group, which enhances the affinity of the compounds for bone mineral but has little influence on the antiresorptive po-
FIGURE 3. The histopathologic examination showing necrotic bone, dense infiltration of plasma cells, polymorphonuclear leukocytes and lymphocytes, and numerous Actinomyces colonies. (Hematoxylin and eosin; original magnification ⫻100.) Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
tency.8 The major determinant of antiresorptive potency is the structure and conformation of the R2 side chain.8 First-generation bisphosphonate drugs (non-N R2 side chain) have a short R2 side chain, such as ⫺CH3 (as in etidronate) or ⫺Cl (as in clodronate). Second-generation aminobisphosphonates contain a nitrogen group (which have an R2 side chain containing a primary amino group), such as alendronate and pamidronate, and are 10- to 1,000-fold more potent than first-generation bisphosphonates. The third-generation bisphosphonates, such as risedronate and zoledronic acid, contain a nitrogen atom within a heterocyclic ring (N-heterocyclic R2 side chain), and are 10,000-fold more potent than the first-generation compounds.9
FIGURE 2. Panoramic radiograph showing osteomyelitis of the mandible after dental extraction. The outlines of the extraction sockets can be seen, together with dense sequestrations of bone lying in a poorly circumscribed radiolucency. Senel et al. Disodium Clodronate–Associated Mandibular Osteomyelitis. J Oral Maxillofac Surg 2007.
564
DISODIUM CLODRONATE–ASSOCIATED MANDIBULAR OSTEOMYELITIS
Several studies have suggested that aminobisphosphonates have a molecular mechanism of action different than or in addition to that of the nonaminobisphosphonates.10 The second- and third-generation bisphosphonates are significantly more potent than their first-generation predecessors (etidronate, clodronate, and tiludronate). They inhibit bone resorption by osteoclastic inhibition through selective concentration at the interface of the active osteoclast and the bone resorption surface. The specific mechanism of this inhibition is unknown, but there is evidence of several actions, including inhibition of osteoclast development from precursor cells,11 increase in osteoclast apoptosis,12 stimulation of osteoclast inhibitory factor,13 reduction of osteoclast activity,14 and downregulation of matrix metalloproteinases.15 The resulting reduction in osteoclastic activity reduces bone resorption. The exact molecular mechanisms by which bisphosphonates affect osteoclasts seem to be different in first-generation bisphosphonates compared with second- and third-generation bisphosphonates, which contain a nitrogen moiety. Nitrogen-containing bisphosphonates recently were shown to induce apoptosis and inhibit bone resorption by osteoclasts by inhibiting farnesyl diphosphate synthase,16 an enzyme in the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme prevents the synthesis of isoprenoid lipids required for the prenylation of small guanosine triphosphate– binding proteins, such as Rho and Rac, necessary for osteoclast function and survival.17 However, the mevalonate pathway does not seem to be affected by the bisphosphonates that lack a nitrogen, such as clodronate.17 Bisphosphonates, including clodronate, act on the bony skeleton to reduce normal and abnormal bone resorption. Clodronate alters the activity of osteoclasts and osteoblasts, changing the balance of bone resorption and bone formation, resulting in reduced bone turnover. In responsive patients, inhibition of abnormal bone resorption by clodronate leads to reduced hypercalcemia of malignancy presenting with or without demonstrable skeletal metastases. Recently, several authors reported ONJ associated with the use of nitrogen-containing bisphosphonates.1-3,18 Gotcher and Jee19 reported that dichloromethylene diphosphonate (Cl2MDP) may produce ONJ-like lesions in rice rats. Non–nitrogen-containing bisphosphonates (eg, clodronate, etidronate, residronate, and tiludronate) are in common use today and do not cause bone necrosis.1,3 There are no reports in the literature of ONJ in humans associated with the use of non–nitrogen-containing bisphosphonates. This is the first report of a patient with osteomyelitis of the jaw after chronic non–nitrogen-con-
taining bisphosphonate (disodium clodronate) therapy for bone disease prevention. Montonen et al20 reported that disodium clodronate is useful in treating the recurrent pain of diffuse sclerosing osteomyelitis (DSO) of the mandible, but these authors did not investigate the effect of clodronate on DSO. However, it should be noted that chronic use of clodronate caused osteomyelitis in our case. Osteomyelitis of the jaw in long-term survivors of multiple myeloma who are receiving chronic biphosphonate therapy may be a new clinical entity. Although it is not possible to prove beyond doubt an etiologic link between biphosphonate therapy and the occurrence of osteomyelitis of the jaw, the association of multiple myeloma with severe immunosuppression, the prolonged biphosphonate therapy, and the localization to the jaw all point to a relationship.21 Because the jaws are the only bones of the skeleton exposed to the external environment and thus subject to frequent trauma, local inflammation, and abscess, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis, especially among patients suffering from severe and prolonged immunosuppression, such as in our patient.22-26 The local presence of Actinomyces was demonstrated in our patient. Actinomyces is an indolent infection that colonizes the mouth; after disruption of the mucosal barrier, it may spread hematogeneously, with possible general dissemination. Clinically, infections with Actinomyces occur most frequently in the oral, cervical, and facial areas, with a particular predilection for the angle of the jaw.27 Further studies are needed to elucidate the precise relationship between bisphosphonates and osteonecrosis. Initiation of non–nitrogen-containing bisphosphonate therapy should be deferred until dental and oral surgical treatments have been completed, because non–nitrogen-containing bisphosphonates may cause osteomyelitis of the jaws.
References 1. Marx RE: Pamidronate (Aredia)- and zoldronate (Zometa)- induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 3. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253, 2003 4. Melo MD, Obeid G: Osteonecrosis of the maxilla in a patient with history of bisphosphonate therapy. J Can Dent Assoc 71:111, 2005 5. Carter GD, Gross AN: Bisphosphonates and avascular necrosis of the jaw. Aust Dent J 48:268, 2003 6. Frith JC, Mokkonen J, Blackburn GM, et al: Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosire 5=-(beta, gamma-dichloromethylene)
SENEL ET AL
7.
8. 9.
10. 11. 12. 13. 14. 15. 16.
triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358, 1997 Tenenbaum HC, Shelemay A, Girard B, et al: Bisphosphonates and periodontics: Potential applications for regulation of bone mass in the periodontium and other therapeutic/diagnostic uses. J Periodontol 73:813, 2002 Van Beek E, Hoekstra M, Van de Ruit M, et al: Structural requirements for bisphosphonate actions in vitro. J Bone Miner Res 9:1875, 1994 Geddes AD, D’Souza SM, Ebetino FH, et al: Bisphosphonates: Structure–activity relationships and therapeutic implications, in Heersche JNM, Kanis JA (eds): Bone and Mineral Research. Amsterdam, Elsevier Science, 1994, p 265 Boonekamp PM, van der Wee-Pals LJ, van Wijk-van Lennep MM, et al: Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1:27,1986 Hughes DE, MacDonald BR, Russell RG, et al: Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest 83:1930, 1989 Hughes DE, Wright KR, Uy HL, et al: Bisphosphonates promote apoptosis in murine osteoclast in vitro and in vivo. J Bone Miner Res 10:1478, 1995 Vitte C, Fleisch H, Guenthes HL: Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclastic-mediated resorbtion. Endocrinology 137:2324, 1996 Sato M, Grasser W: Effects of bisphosphonates on isolated cat osteoclast as examined by reflected light microscopy. J Bone Miner Res 5:31, 1990 Teronen O, Heikkila P, Konttinen YT, et al: MMP inhibition and down-regulation by bisphosphonates. Ann NY Acad Sci 878: 453, 1999 Dunford JE, Thompson K, Coxon FP, et al: Structure–activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296:235, 2001
565 17. Coxon FP, Helfrich MH, Van’t Hof R, et al: Protein geranylgeranylation is required for osteoclast formation, function, and survival: Inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 15:1467, 2000 18. Migliorati CA, Casiglia J, Epstein J, et al: Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc 136:1658, 2005 19. Gotcher JE, Jee WSS: The progress of the periodontal syndrome in the rice rat: The effects of a bisphosphonate on the periodontium. J Periodontal Res 16:441, 1981 20. Montonen M, Kalso L, Pylkkaren B, et al: Disodium clodronate in the treatment of diffuse sclerosing osteomyelitis (DSO) of the mandible. Int J Oral Maxillofac Surg 30:313, 2001 21. Lugassy G, Shaham R, Nemets A, et al: Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: A new clinical entity. Am J Med 117:440, 2004 22. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567, 2005 23. Hellstein JW, Marek CL: Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682, 2005 24. Pogrel MA: Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 62:391, 2004 25. Sarathy AP, Bourgeois SL Jr, Goodell GG: Bisphosphonateassociated osteonecrosis of the jaw and endodontic treatment: Two case reports. J Endod 31:759, 2005 26. Wooltorton E: Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. CMAJ 172: 1684, 2005 27. Russo TA: Agents of actinomycosis, in Mandell GL, Barrett JE, Dolin R (eds): Principles and Practice of Infectious Diseases (ed 6). New York, Churchill Livingstone, 2005