J Clin Periodontol 2015; doi: 10.1111/jcpe.12322
Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis, and dental implant removal Fern andez Ayora A, Herion F, Rompen E, Reginster JY, Magremanne M, Lambert F. Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis and dental implant removal. J Clin Periodontol 2015; doi: 10.1111/ jcpe.12322.
Abstract Introduction: Osteoporosis affects millions of elderly patients, and anti-resorptive drugs (ARD) such as bisphosphonates (BP) represent the first-line therapy. Despite the benefits related to the use of these medications, osteonecrosis of the jaw is a significant complication in a subset of patients receiving these drugs. Case presentation: This report documents a case of dramatic bisphosphonaterelated osteonecrosis associated with periodontitis and dental implant removal in an osteoporotic patient treated with per os bisphosphonates for an uninterrupted period of 15 years. Conclusion: The aim of this report was to discuss the administration period of BP in the treatment of osteoporosis, the decision-making and clinical management of severe MRONJ and the indications for dental implant placement in these specific patients.
Bisphosphonates (BPs) have been used since 1968 for the treatment of bone diseases such as bone metastases, multiple myeloma, Paget’s disease and calcium metabolism disorders (osteoporosis) (Fleisch 1998). After being deposited on the bone surface, BPs are internalized by osteoclasts and induce the apoptosis of Conflict of interest and source of funding statement No external funding, apart from the support of the authors’ institution, was available for this case report. The authors declare that they have no conflicts of interest in this case report.
osteoclasts, resulting in the disruption of bone turnover and the healing process (Fleisch 1998, Magopoulos et al. 2007). Because of their confirmed effectiveness in reducing osteoporosis-related bone fractures, oral BPs such as ibandronate (Bonvivaâ, Hoffmann, La Roche, Basel, Switzerland), alendronate (Fosamaxâ, Merck Sharp & Dhome, White House Station, NJ, USA) and risedronate (Actonelâ, Sanofi-Aventis, Paris, France) and intravenous BP, such as zoledronate (Aclastaâ, Novartis, Basel, Switzerland), are considered first-line therapy in the treatment of osteoporosis and are widely prescribed anti-
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ndez Ayora1, Francine Alberto Ferna Herion1, Eric Rompen1, Jean Yves le Magremanne3 Reginster2, Miche and France Lambert4,5 1
Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liege, Belgium; 2Department of Public Health, Epidemiology and Health Economics, Faculty of Medicine, University of Liege, Liege, Belgium; 3Oral and Maxillofacial Surgery, Faculty of Medicine and Dentistry, Catholique de Louvain, Louvain, Universite Belgium; 4Department of Periodontology and ge, Lie ge, Belgium; Oral Surgery, CHU of Lie 5 Dental Biomaterials Research Unit (DBRU), Faculty of Medicine, University of Liege, Liege, Belgium
Key words: alendronate; implant; medication related osteonecrosis of the jaw; osteonecrosis; osteoporosis; periodontitis Accepted for publication 14 October 2014
resorptive agents (Black et al. 1996, Reginster et al. 2000, Kanis et al. 2013). Despite the benefits of these drugs, bisphosphonate-related osteonecrosis of the jaw (BRONJ), a severe side effect of bisphosphonate therapy, was first described in the literature in 2003 (Marx 2003). Since this initial identification, many cases have been reported, typically when massive doses of BP were administered intravenously, usually for oncologic reasons (Dimitrakopoulos et al. 2006). Recently, similar cases of osteonecrosis of the jaw have been reported in patients treated with denosumab (DMab), a human
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monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand (RANKL), used intravenously for the management of postmenopausal osteoporosis. The more recent designation of these secondary effects is Medication-Related OsteoNecrosis of the Jaw (MRONJ) (Neuprez et al. 2014). The associated main risk factor of MRONJ is dento-alveolar trauma, periodontal disease or tooth extraction (2006, Bamias et al. 2005). Subsets of edentulous and dentate patients have developed MRONJ spontaneously (Kanis et al. 2013). These complications are extremely difficult to control and, despite innovative surgical protocols that have been newly described; the recommended standard of care remains a conservative non-surgical approach to limit osteomyelitis dissemination. The incidence of BRONJ varies from 0% to 27,5% with high dose IV administration of BPs (specially for the treatment of multiple myeloma and metastases) (Campisi et al. 2014), but the reported occurrence remains insignificant (0.004%) when BPs are administered per os for the management of osteoporosis or Paget’s disease of the bone (Mariotti 2008). This report documents a case of dramatic bisphosphonate-related osteonecrosis of the jaw associated with periodontitis and dental implant removal in an osteoporotic patient treated with per os BP for an uninterrupted period of 15 years. The specificity and the management of this case are discussed. Case Report
An 82-year-old female was referred to the Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege in March 2011 with chief complaints of pain on chewing and gingival swelling in the left lower molar area for three months. Six months earlier, the patient underwent implant removal in the lower left mandible performed by her general dentist who diagnosed a peri-implantitis (Figs 1 and 2). The implant was placed 5 years earlier, and according to the dentist, the removal procedure was uneventful. Two months after the explantation, the site failed to heal properly and
Fig. 1. First panoramic radiograph in 2005 shortly after implant placement at the lower jaw.
Fig. 2. Periapical radiograph in before the implant was removed.
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was infected. The general dentist performed curettage of the granulation tissues and the extraction of the first left lower molar (Fig. 3). After several weeks, the patient was referred to a specialized centre, the Department of Periodontology and Oral Surgery of the University of Liege, Belgium. The intra-oral examination showed necrotic bone exposure with swelling and pus discharge through a fistula and a fibrotic, burgeoning, and neoplastic-like soft tissue lesion. A hard and soft tissues biopsy was performed for the differential diagnosis. The biopsy excluded malignancy and demonstrated sequestrum infiltrated with chronic inflammatory cells. The radiographic exams showed an increased bone marrow density with bone sequestration on the panoramic X-ray (Fig. 4), and the CT images demonstrated cortical bone destruction in the left lower edentulous area including the upper component of the ramus. Based on these clinical, histopathological and radiographic examinations, the patient was diagnosed with a grade 2 MRONJ. The medical history revealed hypothyroidism,
neurodegeneration and weekly administration of oral risedronate (35 mg Actonel) for 15 years for the treatment of osteoporosis. No further medication was involved. The serum C-terminal cross-linked telopeptide of type I collagen (CTX) level was measured at 313 pg/ml. The cessation of bisphosphonate therapy was immediately recommended. According to the AAOMS position paper, the standard of care for a grade 2 MRONJ is a conservative approach to contain the infection process. The remaining granulated tissue and the necrotic bone were debrided, and the wound was irrigated monthly with a solution of doxycycline (100 mg/ml). At each wound irrigation, small necrotic bone fragments were expelled through multiple fistulas (Fig. 4). Doxycycline resistance was detected in the antibiogram, and the doxycycline irrigations were replaced by a metronidazole solution (500 mg/ 20 ml). For each acute infection episode, a broad-spectrum course of antibiotics was prescribed. The initial antibiotic therapy of choice was a combination of amoxicillin and clavulanic acid TID 875 mg and metronidazole BID 500 mg. Because penicillin resistance was identified some months later, the combination of cefadroxil 500 mg and metronidazole 500 mg was given. In a few months, the severity and the rapidity of the progression of the osteonecrosis were unexpected. The patient was referred to the Maxillofacial Department but the option of undergoing a hemimandibulectomy and jaw reconstruction was rejected. Extensive surgery was not recommended because of the age of the patient and general anaesthesia related risks. However,
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Medication-Related Osteonecrosis of the jaws
Fig. 3. Panoramic radiograph when the patient was seen for the first time in the Department of Periodontology and Oral Surgery, University of Liege, Belgium. The large osseous crater on left lower edentulous area is the radiological sign of the BRONJ (July 2011).
Fig. 4. Panoramic radiograph shows the progression of the BRONJ and lost of the teeth in the left lower jaw and the evolution to a grade 3 BRONJ (April 2012).
Fig. 5. Panoramic radiograph shows progress of the osteonecrosis and lost of the spontaneous exfoliation of the teeth in the left lower jaw (January 2013).
the conservative approach did not provide relief of the symptoms or prevent BRONJ evolution. All the mandibular teeth (13 in total) were lost due to the progressive necrosis of the periodontal tissues and spontaneous exfoliation (Fig. 5). In 2 years, the osteonecrosis has disseminated to the entire jaw and the left mandible condyle (Figs 6 and 7). The patient has lost hearing on the left side and is extremely affected
physically and psychologically. At this level, treatment options are limited and a palliative approach is carried out. Discussion
The present case report describes a dramatic and rapidly progressing grade 2 BRONJ diagnosed in a patient treated with per os bisphosphonate.
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The risk of MRONJ development has been described to be significantly higher in patients treated with high doses of BP intravenously for oncologic reasons. The prevalence varies from 0% to 27.5% (Mariotti 2008). For patients taking BPs via the oral route, typically for the treatment of osteoporosis, the estimated prevalence is approximately 0.00007– 0.04% (Mariotti 2008). According to some authors, this difference is due to the low lipid solubility of orally administered BP, which results in the intestinal absorption of only 0.63% of the drug. The American Dental Association (ADA) (2006) and the AAOMS (Ruggiero et al. 2009) have confirmed that this risk is dose/time dependent. BPs are retained in the skeleton for more than 10 years, and their administration over a long time period might result in high-dose accumulation in the jawbones, increasing the risk of BRONJ even through the oral route of administration (Ott 2011). Some studies have reported that the weekly consumption of per os BP for 3 years (156 week doses) is required for the development of MRONJ, and the risk might increase with each additional year of BP use (Black et al. 2012). The serum CTx test (C-terminal telopeptide of type I collagen, or ITCP), a marker of bone turnover that assesses the elimination of specific fragments produced by type I collagen hydrolysis, can be used as a parameter to assess the risk of developing MRONJ (Marx et al. 2007). However its role as a predictive marker of MRONJ remains controversial (Otto et al. 2011), incidentally, in this particular case the measured values represented a minimal risk value. In this case report, the patient did not show any risk factors, such as tobacco use, chemotherapy, or corticoid intake, but she took BP orally weekly for 15 years and this long and uninterrupted exposure to the molecule might have contributed to the severity of the complications after implant removal. This long-term therapy is questionable because the majority of the data about the safety and efficacy of bisphosphonate drugs to treat osteoporosis is focused on BP intake for less than 5 years (Ott 2011). The evidence of fracture risk reduction in BPs given for osteoporosis is derived
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Fig. 6. The BRONJ has disseminated to the entire jaw and the left mandible condyle. Fractures are visible under the left condyle and on the left horizontal part of the mandible (March 2013).
Fig. 7. Exposed necrotic bone of the alveolar process bilaterally in the mandible.
from the Fracture Intervention Trial Research Group (FIT) and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Extension trial (HORIZON). These studies suggested that the discontinuation of per os alendronate for up to 5 years and of IV zoledronate for up to 3 years does not appear to significantly increase the fracture risk. Some recent studies reported that the incidence of other secondary complications of BP, such as atypical subtrochanteric and diaphyseal femoral fractures, decreases after the discontinuation of oral BP therapy, and a prolonged therapy might influence the occurrence of MRONJ (Shane et al. 2014). The available data suggest that bisphosphonates might be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trials have delineated how long the drug benefits are maintained after drug cessation. To optimize the efficacy of
bisphosphonates in reducing the fracture risk, decisions to continue treatment must be based on the individual assessment of the risks and benefits and on patient preference (Whitaker et al. 2012). Patients at mild risk are recommended to stop the treatment after 5 years and to remain off therapy as long as the bone mineral density is stable. Higher risk patients should be treated for 10 years and have a holiday of 1–2 years after 5 years of taking BPs; eventually non-anti-resorptive drug treatment could be provided during the BP interruption (Whitaker et al. 2012). According to these guidelines, the present patient likely received excessive doses of ARD, especially because the risk of fracture was mild. The management AAOMS (2007) recommendations for a stage 2 MRONJ is the non-surgical debridement of necrotic bone combined with mouth rinses, BP interruption, pain control, and antibiotic therapy in cases of acute infection (Ruggiero
et al. 2004, Magopoulos et al. 2007). The monthly irrigation of the wound was performed with a low dose of doxycycline (100 mg/ml) for its ability to join the calcium ions of bone hydroxyapatite (Grevstad & Boe 1995, Holmes et al. 2004), its antimetalloprotease activity preventing the destruction of the extracellular matrix and its contribution on fibroblast and epithelial cells adhesion potentially influencing soft tissue healing (Rompen et al. 1993, Almazin et al. 2009). In this case, such measures did not achieve resolution of the clinical findings. The multiple antibiotic resistances likely contributed to the acceleration of the dissemination of the necrosis. The maxillofacial team according to age and physical status of the patient and the risk of the general anaesthesia did not consider any kind of large surgical resection and mandibular reconstruction. According to the literature (Engroff & Kim 2007, Ferrari et al. 2008, Seth et al. 2010, Sacco et al. 2011), radical surgical treatment must be considered when the MRONJ seems to involve a large area of the jaw, if the disease is not resolved by conservative therapy and if the donor site of the patient is well perfused and exempt of bone metastases. In the light of these statements, and considering the absence of cancer morbidities (bisphosphonates were prescribed for osteoporosis reasons), and the poor medical status of the patient, a segmental mandibulectomy without reconstruction might have been the treatment option of choice when the MRONJ was still limited at the left horizontal branch of the mandible. In this case, if the mucosal defect was important, reconstruction with a pedicled pectoralis major flap could have been proposed, with or without a titanium plate. Nevertheless, given the highly progressive MRONJ, the success of the surgical resective treatment would not have been ensured. At this more advanced stage of the MRONJ involving the chin and vertical branch of the mandible, other surgical modalities such as mandibulectomy reconstruction with a vascularized flap might be considered (Mucke et al. 2009, Nocini et al. 2009). In any case, it is a clinical decision that depends on many factors as the risk of the surgery, the maxillofacial team
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Medication-Related Osteonecrosis of the jaws experience, the patient, age, family or economic costs. Alveolar bone surgery represents one of the main risk factors for the development of MRONJ (Badros et al. 2006). Madrid and Sanz (Madrid & Sanz 2009) reviewed one prospective and three retrospective studies and reported that there were no cases of MRONJ after implant placements in 217 patients who took oral BPs for less than 5 years. They concluded that oral BP administration did not affect the short-term implant success rate from 1–4 years. More recently, some studies showed that ligatures-induced periodontitis in rats can initiate MRONJ development. The physiopathological bone remodelling related to periodontitis would not occur because of the lack of osteoclast activity and the periodonthopathogens would directly colonize the necrotic bone (Kang et al. 2013). In this case, the origin of the MRONJ process is questionable. It is difficult to determine whether the periodontitis on teeth 36/peri-implantitis or implant removal or a combination of both triggered the MRONJ. In the periapical radiograph performed before implant removal (Fig. 2) displays radiolucency and an open bifurcation on tooth 36 and peri-implant bone resorption. The open furcation was already visible in the panoramic x-ray 5 years earlier and it can be assumed that the implant was placed in a patient while the periodontal disease was not controlled. Considering that the initial steps of therapy provided to this patient are retrospective, the clear identification of the initial cause of this dramatic osteonecrosis remains uncertain. Finally, the importance of a comprehensive oral examination and preventive treatment before the initiation of treatment with an inhibitor of osteoclastic resorption should be considered to decrease MRONJ development as suggested by some authors for before IV administration of BPs (Dimopoulos et al. 2009, Ripamonti et al. 2009, AAOMS, 2014). Conclusions
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This report serves to alert dentists and ARD prescribers about the potential complication of
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bone necrosis in patients receiving this type of therapy. As the ageing population grows, the number of patients with osteoporosis increases, and the number of patients taking BPs for the treatment of osteoporosis is increasing. Prescribers of these drugs should be aware that potential consequences could occur at any time during treatment. Not all bisphosphonates are the same, so recommendations for the discontinuation of bisphosphonates need to be drug-specific, although recommendations about monitoring after drug discontinuation and reinitiating anti-fracture therapy await further studies. Despite the low risk of MRONJ in oral BPs users, role of active periodontitis and the fate of dental implants in these patients remain uncertain. Patients at risk should be given a full explanation of the potential risks of implant failure and BRONJ development.
References American Dental Association Council on Scientific Affairs (2006) Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. Journal of the American Dental Association 137, 1144–1150. American Association of Oral and Maxillofacial Surgeons (2014) American Association of Oral and Maxillofacial Surgeons position paper. Medication Related Osteonecrosis of the Jaw2014 update. Advisory Task Force on Biphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons (2007) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery 65, 369–376. Almazin, S. M., Dziak, R., Andreana, S. & Ciancio, S. G. (2009) The effect of doxycycline hyclate, chlorhexidine gluconate, and minocycline hydrochloride on osteoblastic proliferation and differentiation in vitro. Journal of Periodontology 80, 999–1005. Badros, A., Weikel, D., Salama, A., Goloubeva, O., Schneider, A., Rapoport, A., Fenton, R., Gahres, N., Sausville, E., Ord, R. & Meiller, T. (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. Journal of Clinical Oncology 24, 945–952. Bamias, A., Kastritis, E., Bamia, C., Moulopoulos, L. A., Melakopoulos, I., Bozas, G., Koutsoukou, V., Gika, D., Anagnostopoulos, A., Papadimitriou, C., Terpos, E. & Dimopoulos, M. A. (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates:
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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incidence and risk factors. Journal of Clinical Oncology 23, 8580–8587. Black, D. M., Bauer, D. C., Schwartz, A. V., Cummings, S. R. & Rosen, C. J. (2012) Continuing bisphosphonate treatment for osteoporosis–for whom and for how long? New England Journal of Medicine 366, 2051– 2053. Black, D. M., Cummings, S. R., Karpf, D. B., Cauley, J. A., Thompson, D. E., Nevitt, M. C., Bauer, D. C., Genant, H. K., Haskell, W. L., Marcus, R., Ott, S. M., Torner, J. C., Quandt, S. A., Reiss, T. F. & Ensrud, K. E. (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348, 1535– 1541. Campisi, G., Fedele, S., Fusco, V., Pizzo, G., di Fede, O. & Bedogni, A. (2014) Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncology 10, 257–275. Dimitrakopoulos, I., Magopoulos, C. & Karakasis, D. (2006) Bisphosphonate-induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. International Journal of Oral and Maxillofacial Surgery 35, 588–593. Dimopoulos, M. A., Kastritis, E., Bamia, C., Melakopoulos, I., Gika, D., Roussou, M., Migkou, M., Eleftherakis-Papaiakovou, E., Christoulas, D., Terpos, E. & Bamias, A. (2009) Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Annals of Oncology 20, 117–120. Engroff, S. L. & Kim, D. D. (2007) Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction? Journal of Oral and Maxillofacial Surgery 65, 2374–2385. Ferrari, S., Bianchi, B., Savi, A., Poli, T., Multinu, A., Balestreri, A. & Ferri, A. (2008) Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. Journal of Oral and Maxillofacial Surgery 66, 999–1003. Fleisch, H. (1998) Bisphosphonates: mechanisms of action. Endocrine Reviews 19, 80–100. Grevstad, H. J. & Boe, O. E. (1995) Effect of doxycycline on surgically induced osteoclast recruitment in the rat. European Journal of Oral Sciences 103, 156–159. Holmes, S. G., Still, K., Buttle, D. J., Bishop, N. J. & Grabowski, P. S. (2004) Chemically modified tetracyclines act through multiple mechanisms directly on osteoclast precursors. Bone 35, 471–478. Kang, B., Cheong, S., Chaichanasakul, T., Bezouglaia, O., Atti, E., Dry, S. M., Pirih, F. Q., Aghaloo, T. L. & Tetradis, S. (2013) Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. Journal of Bone and Mineral Research 28, 1631–1640. Kanis, J. A., McCloskey, E. V., Johansson, H., Cooper, C., Rizzoli, R. & Reginster, J. Y. (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis International 24, 23–57. Madrid, C. & Sanz, M. (2009) What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clinical Oral Implants Research 20 (Suppl 4), 87–95.
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Magopoulos, C., Karakinaris, G., Telioudis, Z., Vahtsevanos, K., Dimitrakopoulos, I., Antoniadis, K. & Delaroudis, S. (2007) Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. American Journal of Otolaryngology 28, 158– 163. Mariotti, A. (2008) Bisphosphonates and osteonecrosis of the jaws. Journal of Dental Education 72, 919–929. Marx, R. E. (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. Journal of Oral and Maxillofacial Surgery 61, 1115–1117. Marx, R. E., Cillo, J. E..Jr & Ulloa, J. J. (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. Journal of Oral and Maxillofacial Surgery 65, 2397– 2410. Mucke, T., Haarmann, S., Wolff, K. D. & Holzle, F. (2009) Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. Journal of Cranio-Maxillo-Facial Surgery 37, 291–297. Neuprez, A., Coste, S., Rompen, E., Crielaard, J. M. & Reginster, J. Y. (2014) Osteonecrosis of the jaw in a male osteoporotic patient treated with denosumab. Osteoporosis International 25, 393–395. Nocini, P. F., Saia, G., Bettini, G., Ragazzo, M., Blandamura, S., Chiarini, L. & Bedogni, A. (2009) Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. European Journal of Surgical Oncology 35, 373–379. Ott, S. M. (2011) What is the optimal duration of bisphosphonate therapy? Cleveland Clinic Journal of Medicine 78, 619–630. Otto, S., Abu-Id, M. H., Fedele, S., Warnke, P. H., Becker, S. T., Kolk, A., Mucke, T., Mast, G., Kohnke, R., Volkmer, E., Haasters, F.,
Clinical Relevance
Scientific rationale for the study: Unusual clinical complications and clinically relevant observations are important to report especially for the emphasis of rare but dramatic drug side effects.
Lieger, O., Iizuka, T., Porter, S., Campisi, G., Colella, G., Ploder, O., Neff, A., Wiltfang, J., Ehrenfeld, M., Kreusch, T., Wolff, K. D., Sturzenbaum, S. R., Schieker, M. & Pautke, C. (2011) Osteoporosis and bisphosphonatesrelated osteonecrosis of the jaw: not just a sporadic coincidence–a multi-centre study. Journal of Cranio-Maxillo-Facial Surgery 39, 272–277. Reginster, J., Minne, H. W., Sorensen, O. H., Hooper, M., Roux, C., Brandi, M. L., Lund, B., Ethgen, D., Pack, S., Roumagnac, I. & Eastell, R. (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporosis International 11, 83–91. Ripamonti, C. I., Maniezzo, M., Campa, T., Fagnoni, E., Brunelli, C., Saibene, G., Bareggi, C., Ascani, L. & Cislaghi, E. (2009) 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. Annals of Oncology 20, 137–145. Rompen, E. H., Kohl, J., Nusgens, B. & Lapiere, C. M. (1993) Kinetic aspects of gingival and periodontal ligament fibroblast attachment to surface-conditioned dentin. Journal of Dental Research 72, 607–612. Ruggiero, S. L., Dodson, T. B., Assael, L. A., Landesberg, R., Marx, R. E. & Mehrotra, B. (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws– 2009 update. Journal of Oral and Maxillofacial Surgery 67, 2–12. Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J. & Engroff, S. L. (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of Oral and Maxillofacial Surgery 62, 527–534.
Principal findings: Rapidly progressive MRONJ was found in a patient treated with per os bisphosphonate for an uninterrupted period of 15 years. Practical implications: Although MRONJ rarely occurs in patients
Sacco, R., Sacco, G., Acocella, A., Sale, S., Sacco, N. & Baldoni, E. (2011) A systematic review of microsurgical reconstruction of the jaws using vascularized fibula flap technique in patients with bisphosphonate-related osteonecrosis. Journal of Applied Oral Science 19, 293– 300. Seth, R., Futran, N. D., Alam, D. S. & Knott, P. D. (2010) Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 120, 2165–2171. Shane, E., Burr, D., Abrahamsen, B., Adler, R. A., Brown, T. D., Cheung, A. M., Cosman, F., Curtis, J. R., Dell, R., Dempster, D. W., Ebeling, P. R., Einhorn, T. A., Genant, H. K., Geusens, P., Klaushofer, K., Lane, J. M., McKiernan, F., McKinney, R., Ng, A., Nieves, J., O’keefe, R., Papapoulos, S., Howe, T. S., van der Meulen, M. C., Weinstein, R. S. & Whyte, M. P. (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. Journal of Bone and Mineral Research 29, 1–23. Whitaker, M., Guo, J., Kehoe, T. & Benson, G. (2012) Bisphosphonates for osteoporosis–where do we go from here? New England Journal of Medicine 366, 2048–2051.
Address: France Lambert Department of Periodontology and Oral Surgery CHU de Li ege, Domaine du Sart Tilman Bat B-35 B-4000 Li ege, Belgium E-mail: [email protected]
receiving per os bisphosphonate, these complications can occur. Comprehensive oral examination and preventive treatment before the initiation of anti-resorptive drugs treatment might be of interest.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis, and dental implant removal Fern andez Ayora A, Herion F, Rompen E, Reginster JY, Magremanne M, Lambert F. Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis and dental implant removal. J Clin Periodontol 2015; doi: 10.1111/ jcpe.12322.
Abstract Introduction: Osteoporosis affects millions of elderly patients, and anti-resorptive drugs (ARD) such as bisphosphonates (BP) represent the first-line therapy. Despite the benefits related to the use of these medications, osteonecrosis of the jaw is a significant complication in a subset of patients receiving these drugs. Case presentation: This report documents a case of dramatic bisphosphonaterelated osteonecrosis associated with periodontitis and dental implant removal in an osteoporotic patient treated with per os bisphosphonates for an uninterrupted period of 15 years. Conclusion: The aim of this report was to discuss the administration period of BP in the treatment of osteoporosis, the decision-making and clinical management of severe MRONJ and the indications for dental implant placement in these specific patients.
Bisphosphonates (BPs) have been used since 1968 for the treatment of bone diseases such as bone metastases, multiple myeloma, Paget’s disease and calcium metabolism disorders (osteoporosis) (Fleisch 1998). After being deposited on the bone surface, BPs are internalized by osteoclasts and induce the apoptosis of Conflict of interest and source of funding statement No external funding, apart from the support of the authors’ institution, was available for this case report. The authors declare that they have no conflicts of interest in this case report.
osteoclasts, resulting in the disruption of bone turnover and the healing process (Fleisch 1998, Magopoulos et al. 2007). Because of their confirmed effectiveness in reducing osteoporosis-related bone fractures, oral BPs such as ibandronate (Bonvivaâ, Hoffmann, La Roche, Basel, Switzerland), alendronate (Fosamaxâ, Merck Sharp & Dhome, White House Station, NJ, USA) and risedronate (Actonelâ, Sanofi-Aventis, Paris, France) and intravenous BP, such as zoledronate (Aclastaâ, Novartis, Basel, Switzerland), are considered first-line therapy in the treatment of osteoporosis and are widely prescribed anti-
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ndez Ayora1, Francine Alberto Ferna Herion1, Eric Rompen1, Jean Yves le Magremanne3 Reginster2, Miche and France Lambert4,5 1
Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liege, Belgium; 2Department of Public Health, Epidemiology and Health Economics, Faculty of Medicine, University of Liege, Liege, Belgium; 3Oral and Maxillofacial Surgery, Faculty of Medicine and Dentistry, Catholique de Louvain, Louvain, Universite Belgium; 4Department of Periodontology and ge, Lie ge, Belgium; Oral Surgery, CHU of Lie 5 Dental Biomaterials Research Unit (DBRU), Faculty of Medicine, University of Liege, Liege, Belgium
Key words: alendronate; implant; medication related osteonecrosis of the jaw; osteonecrosis; osteoporosis; periodontitis Accepted for publication 14 October 2014
resorptive agents (Black et al. 1996, Reginster et al. 2000, Kanis et al. 2013). Despite the benefits of these drugs, bisphosphonate-related osteonecrosis of the jaw (BRONJ), a severe side effect of bisphosphonate therapy, was first described in the literature in 2003 (Marx 2003). Since this initial identification, many cases have been reported, typically when massive doses of BP were administered intravenously, usually for oncologic reasons (Dimitrakopoulos et al. 2006). Recently, similar cases of osteonecrosis of the jaw have been reported in patients treated with denosumab (DMab), a human
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monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand (RANKL), used intravenously for the management of postmenopausal osteoporosis. The more recent designation of these secondary effects is Medication-Related OsteoNecrosis of the Jaw (MRONJ) (Neuprez et al. 2014). The associated main risk factor of MRONJ is dento-alveolar trauma, periodontal disease or tooth extraction (2006, Bamias et al. 2005). Subsets of edentulous and dentate patients have developed MRONJ spontaneously (Kanis et al. 2013). These complications are extremely difficult to control and, despite innovative surgical protocols that have been newly described; the recommended standard of care remains a conservative non-surgical approach to limit osteomyelitis dissemination. The incidence of BRONJ varies from 0% to 27,5% with high dose IV administration of BPs (specially for the treatment of multiple myeloma and metastases) (Campisi et al. 2014), but the reported occurrence remains insignificant (0.004%) when BPs are administered per os for the management of osteoporosis or Paget’s disease of the bone (Mariotti 2008). This report documents a case of dramatic bisphosphonate-related osteonecrosis of the jaw associated with periodontitis and dental implant removal in an osteoporotic patient treated with per os BP for an uninterrupted period of 15 years. The specificity and the management of this case are discussed. Case Report
An 82-year-old female was referred to the Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege in March 2011 with chief complaints of pain on chewing and gingival swelling in the left lower molar area for three months. Six months earlier, the patient underwent implant removal in the lower left mandible performed by her general dentist who diagnosed a peri-implantitis (Figs 1 and 2). The implant was placed 5 years earlier, and according to the dentist, the removal procedure was uneventful. Two months after the explantation, the site failed to heal properly and
Fig. 1. First panoramic radiograph in 2005 shortly after implant placement at the lower jaw.
Fig. 2. Periapical radiograph in before the implant was removed.
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was infected. The general dentist performed curettage of the granulation tissues and the extraction of the first left lower molar (Fig. 3). After several weeks, the patient was referred to a specialized centre, the Department of Periodontology and Oral Surgery of the University of Liege, Belgium. The intra-oral examination showed necrotic bone exposure with swelling and pus discharge through a fistula and a fibrotic, burgeoning, and neoplastic-like soft tissue lesion. A hard and soft tissues biopsy was performed for the differential diagnosis. The biopsy excluded malignancy and demonstrated sequestrum infiltrated with chronic inflammatory cells. The radiographic exams showed an increased bone marrow density with bone sequestration on the panoramic X-ray (Fig. 4), and the CT images demonstrated cortical bone destruction in the left lower edentulous area including the upper component of the ramus. Based on these clinical, histopathological and radiographic examinations, the patient was diagnosed with a grade 2 MRONJ. The medical history revealed hypothyroidism,
neurodegeneration and weekly administration of oral risedronate (35 mg Actonel) for 15 years for the treatment of osteoporosis. No further medication was involved. The serum C-terminal cross-linked telopeptide of type I collagen (CTX) level was measured at 313 pg/ml. The cessation of bisphosphonate therapy was immediately recommended. According to the AAOMS position paper, the standard of care for a grade 2 MRONJ is a conservative approach to contain the infection process. The remaining granulated tissue and the necrotic bone were debrided, and the wound was irrigated monthly with a solution of doxycycline (100 mg/ml). At each wound irrigation, small necrotic bone fragments were expelled through multiple fistulas (Fig. 4). Doxycycline resistance was detected in the antibiogram, and the doxycycline irrigations were replaced by a metronidazole solution (500 mg/ 20 ml). For each acute infection episode, a broad-spectrum course of antibiotics was prescribed. The initial antibiotic therapy of choice was a combination of amoxicillin and clavulanic acid TID 875 mg and metronidazole BID 500 mg. Because penicillin resistance was identified some months later, the combination of cefadroxil 500 mg and metronidazole 500 mg was given. In a few months, the severity and the rapidity of the progression of the osteonecrosis were unexpected. The patient was referred to the Maxillofacial Department but the option of undergoing a hemimandibulectomy and jaw reconstruction was rejected. Extensive surgery was not recommended because of the age of the patient and general anaesthesia related risks. However,
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Medication-Related Osteonecrosis of the jaws
Fig. 3. Panoramic radiograph when the patient was seen for the first time in the Department of Periodontology and Oral Surgery, University of Liege, Belgium. The large osseous crater on left lower edentulous area is the radiological sign of the BRONJ (July 2011).
Fig. 4. Panoramic radiograph shows the progression of the BRONJ and lost of the teeth in the left lower jaw and the evolution to a grade 3 BRONJ (April 2012).
Fig. 5. Panoramic radiograph shows progress of the osteonecrosis and lost of the spontaneous exfoliation of the teeth in the left lower jaw (January 2013).
the conservative approach did not provide relief of the symptoms or prevent BRONJ evolution. All the mandibular teeth (13 in total) were lost due to the progressive necrosis of the periodontal tissues and spontaneous exfoliation (Fig. 5). In 2 years, the osteonecrosis has disseminated to the entire jaw and the left mandible condyle (Figs 6 and 7). The patient has lost hearing on the left side and is extremely affected
physically and psychologically. At this level, treatment options are limited and a palliative approach is carried out. Discussion
The present case report describes a dramatic and rapidly progressing grade 2 BRONJ diagnosed in a patient treated with per os bisphosphonate.
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The risk of MRONJ development has been described to be significantly higher in patients treated with high doses of BP intravenously for oncologic reasons. The prevalence varies from 0% to 27.5% (Mariotti 2008). For patients taking BPs via the oral route, typically for the treatment of osteoporosis, the estimated prevalence is approximately 0.00007– 0.04% (Mariotti 2008). According to some authors, this difference is due to the low lipid solubility of orally administered BP, which results in the intestinal absorption of only 0.63% of the drug. The American Dental Association (ADA) (2006) and the AAOMS (Ruggiero et al. 2009) have confirmed that this risk is dose/time dependent. BPs are retained in the skeleton for more than 10 years, and their administration over a long time period might result in high-dose accumulation in the jawbones, increasing the risk of BRONJ even through the oral route of administration (Ott 2011). Some studies have reported that the weekly consumption of per os BP for 3 years (156 week doses) is required for the development of MRONJ, and the risk might increase with each additional year of BP use (Black et al. 2012). The serum CTx test (C-terminal telopeptide of type I collagen, or ITCP), a marker of bone turnover that assesses the elimination of specific fragments produced by type I collagen hydrolysis, can be used as a parameter to assess the risk of developing MRONJ (Marx et al. 2007). However its role as a predictive marker of MRONJ remains controversial (Otto et al. 2011), incidentally, in this particular case the measured values represented a minimal risk value. In this case report, the patient did not show any risk factors, such as tobacco use, chemotherapy, or corticoid intake, but she took BP orally weekly for 15 years and this long and uninterrupted exposure to the molecule might have contributed to the severity of the complications after implant removal. This long-term therapy is questionable because the majority of the data about the safety and efficacy of bisphosphonate drugs to treat osteoporosis is focused on BP intake for less than 5 years (Ott 2011). The evidence of fracture risk reduction in BPs given for osteoporosis is derived
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Fig. 6. The BRONJ has disseminated to the entire jaw and the left mandible condyle. Fractures are visible under the left condyle and on the left horizontal part of the mandible (March 2013).
Fig. 7. Exposed necrotic bone of the alveolar process bilaterally in the mandible.
from the Fracture Intervention Trial Research Group (FIT) and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Extension trial (HORIZON). These studies suggested that the discontinuation of per os alendronate for up to 5 years and of IV zoledronate for up to 3 years does not appear to significantly increase the fracture risk. Some recent studies reported that the incidence of other secondary complications of BP, such as atypical subtrochanteric and diaphyseal femoral fractures, decreases after the discontinuation of oral BP therapy, and a prolonged therapy might influence the occurrence of MRONJ (Shane et al. 2014). The available data suggest that bisphosphonates might be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trials have delineated how long the drug benefits are maintained after drug cessation. To optimize the efficacy of
bisphosphonates in reducing the fracture risk, decisions to continue treatment must be based on the individual assessment of the risks and benefits and on patient preference (Whitaker et al. 2012). Patients at mild risk are recommended to stop the treatment after 5 years and to remain off therapy as long as the bone mineral density is stable. Higher risk patients should be treated for 10 years and have a holiday of 1–2 years after 5 years of taking BPs; eventually non-anti-resorptive drug treatment could be provided during the BP interruption (Whitaker et al. 2012). According to these guidelines, the present patient likely received excessive doses of ARD, especially because the risk of fracture was mild. The management AAOMS (2007) recommendations for a stage 2 MRONJ is the non-surgical debridement of necrotic bone combined with mouth rinses, BP interruption, pain control, and antibiotic therapy in cases of acute infection (Ruggiero
et al. 2004, Magopoulos et al. 2007). The monthly irrigation of the wound was performed with a low dose of doxycycline (100 mg/ml) for its ability to join the calcium ions of bone hydroxyapatite (Grevstad & Boe 1995, Holmes et al. 2004), its antimetalloprotease activity preventing the destruction of the extracellular matrix and its contribution on fibroblast and epithelial cells adhesion potentially influencing soft tissue healing (Rompen et al. 1993, Almazin et al. 2009). In this case, such measures did not achieve resolution of the clinical findings. The multiple antibiotic resistances likely contributed to the acceleration of the dissemination of the necrosis. The maxillofacial team according to age and physical status of the patient and the risk of the general anaesthesia did not consider any kind of large surgical resection and mandibular reconstruction. According to the literature (Engroff & Kim 2007, Ferrari et al. 2008, Seth et al. 2010, Sacco et al. 2011), radical surgical treatment must be considered when the MRONJ seems to involve a large area of the jaw, if the disease is not resolved by conservative therapy and if the donor site of the patient is well perfused and exempt of bone metastases. In the light of these statements, and considering the absence of cancer morbidities (bisphosphonates were prescribed for osteoporosis reasons), and the poor medical status of the patient, a segmental mandibulectomy without reconstruction might have been the treatment option of choice when the MRONJ was still limited at the left horizontal branch of the mandible. In this case, if the mucosal defect was important, reconstruction with a pedicled pectoralis major flap could have been proposed, with or without a titanium plate. Nevertheless, given the highly progressive MRONJ, the success of the surgical resective treatment would not have been ensured. At this more advanced stage of the MRONJ involving the chin and vertical branch of the mandible, other surgical modalities such as mandibulectomy reconstruction with a vascularized flap might be considered (Mucke et al. 2009, Nocini et al. 2009). In any case, it is a clinical decision that depends on many factors as the risk of the surgery, the maxillofacial team
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Medication-Related Osteonecrosis of the jaws experience, the patient, age, family or economic costs. Alveolar bone surgery represents one of the main risk factors for the development of MRONJ (Badros et al. 2006). Madrid and Sanz (Madrid & Sanz 2009) reviewed one prospective and three retrospective studies and reported that there were no cases of MRONJ after implant placements in 217 patients who took oral BPs for less than 5 years. They concluded that oral BP administration did not affect the short-term implant success rate from 1–4 years. More recently, some studies showed that ligatures-induced periodontitis in rats can initiate MRONJ development. The physiopathological bone remodelling related to periodontitis would not occur because of the lack of osteoclast activity and the periodonthopathogens would directly colonize the necrotic bone (Kang et al. 2013). In this case, the origin of the MRONJ process is questionable. It is difficult to determine whether the periodontitis on teeth 36/peri-implantitis or implant removal or a combination of both triggered the MRONJ. In the periapical radiograph performed before implant removal (Fig. 2) displays radiolucency and an open bifurcation on tooth 36 and peri-implant bone resorption. The open furcation was already visible in the panoramic x-ray 5 years earlier and it can be assumed that the implant was placed in a patient while the periodontal disease was not controlled. Considering that the initial steps of therapy provided to this patient are retrospective, the clear identification of the initial cause of this dramatic osteonecrosis remains uncertain. Finally, the importance of a comprehensive oral examination and preventive treatment before the initiation of treatment with an inhibitor of osteoclastic resorption should be considered to decrease MRONJ development as suggested by some authors for before IV administration of BPs (Dimopoulos et al. 2009, Ripamonti et al. 2009, AAOMS, 2014). Conclusions
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This report serves to alert dentists and ARD prescribers about the potential complication of
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bone necrosis in patients receiving this type of therapy. As the ageing population grows, the number of patients with osteoporosis increases, and the number of patients taking BPs for the treatment of osteoporosis is increasing. Prescribers of these drugs should be aware that potential consequences could occur at any time during treatment. Not all bisphosphonates are the same, so recommendations for the discontinuation of bisphosphonates need to be drug-specific, although recommendations about monitoring after drug discontinuation and reinitiating anti-fracture therapy await further studies. Despite the low risk of MRONJ in oral BPs users, role of active periodontitis and the fate of dental implants in these patients remain uncertain. Patients at risk should be given a full explanation of the potential risks of implant failure and BRONJ development.
References American Dental Association Council on Scientific Affairs (2006) Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. Journal of the American Dental Association 137, 1144–1150. American Association of Oral and Maxillofacial Surgeons (2014) American Association of Oral and Maxillofacial Surgeons position paper. Medication Related Osteonecrosis of the Jaw2014 update. Advisory Task Force on Biphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons (2007) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery 65, 369–376. Almazin, S. M., Dziak, R., Andreana, S. & Ciancio, S. G. (2009) The effect of doxycycline hyclate, chlorhexidine gluconate, and minocycline hydrochloride on osteoblastic proliferation and differentiation in vitro. Journal of Periodontology 80, 999–1005. Badros, A., Weikel, D., Salama, A., Goloubeva, O., Schneider, A., Rapoport, A., Fenton, R., Gahres, N., Sausville, E., Ord, R. & Meiller, T. (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. Journal of Clinical Oncology 24, 945–952. Bamias, A., Kastritis, E., Bamia, C., Moulopoulos, L. A., Melakopoulos, I., Bozas, G., Koutsoukou, V., Gika, D., Anagnostopoulos, A., Papadimitriou, C., Terpos, E. & Dimopoulos, M. A. (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates:
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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incidence and risk factors. Journal of Clinical Oncology 23, 8580–8587. Black, D. M., Bauer, D. C., Schwartz, A. V., Cummings, S. R. & Rosen, C. J. (2012) Continuing bisphosphonate treatment for osteoporosis–for whom and for how long? New England Journal of Medicine 366, 2051– 2053. Black, D. M., Cummings, S. R., Karpf, D. B., Cauley, J. A., Thompson, D. E., Nevitt, M. C., Bauer, D. C., Genant, H. K., Haskell, W. L., Marcus, R., Ott, S. M., Torner, J. C., Quandt, S. A., Reiss, T. F. & Ensrud, K. E. (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348, 1535– 1541. Campisi, G., Fedele, S., Fusco, V., Pizzo, G., di Fede, O. & Bedogni, A. (2014) Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncology 10, 257–275. Dimitrakopoulos, I., Magopoulos, C. & Karakasis, D. (2006) Bisphosphonate-induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. International Journal of Oral and Maxillofacial Surgery 35, 588–593. Dimopoulos, M. A., Kastritis, E., Bamia, C., Melakopoulos, I., Gika, D., Roussou, M., Migkou, M., Eleftherakis-Papaiakovou, E., Christoulas, D., Terpos, E. & Bamias, A. (2009) Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Annals of Oncology 20, 117–120. Engroff, S. L. & Kim, D. D. (2007) Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction? Journal of Oral and Maxillofacial Surgery 65, 2374–2385. Ferrari, S., Bianchi, B., Savi, A., Poli, T., Multinu, A., Balestreri, A. & Ferri, A. (2008) Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. Journal of Oral and Maxillofacial Surgery 66, 999–1003. Fleisch, H. (1998) Bisphosphonates: mechanisms of action. Endocrine Reviews 19, 80–100. Grevstad, H. J. & Boe, O. E. (1995) Effect of doxycycline on surgically induced osteoclast recruitment in the rat. European Journal of Oral Sciences 103, 156–159. Holmes, S. G., Still, K., Buttle, D. J., Bishop, N. J. & Grabowski, P. S. (2004) Chemically modified tetracyclines act through multiple mechanisms directly on osteoclast precursors. Bone 35, 471–478. Kang, B., Cheong, S., Chaichanasakul, T., Bezouglaia, O., Atti, E., Dry, S. M., Pirih, F. Q., Aghaloo, T. L. & Tetradis, S. (2013) Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. Journal of Bone and Mineral Research 28, 1631–1640. Kanis, J. A., McCloskey, E. V., Johansson, H., Cooper, C., Rizzoli, R. & Reginster, J. Y. (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis International 24, 23–57. Madrid, C. & Sanz, M. (2009) What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clinical Oral Implants Research 20 (Suppl 4), 87–95.
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Magopoulos, C., Karakinaris, G., Telioudis, Z., Vahtsevanos, K., Dimitrakopoulos, I., Antoniadis, K. & Delaroudis, S. (2007) Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. American Journal of Otolaryngology 28, 158– 163. Mariotti, A. (2008) Bisphosphonates and osteonecrosis of the jaws. Journal of Dental Education 72, 919–929. Marx, R. E. (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. Journal of Oral and Maxillofacial Surgery 61, 1115–1117. Marx, R. E., Cillo, J. E..Jr & Ulloa, J. J. (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. Journal of Oral and Maxillofacial Surgery 65, 2397– 2410. Mucke, T., Haarmann, S., Wolff, K. D. & Holzle, F. (2009) Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. Journal of Cranio-Maxillo-Facial Surgery 37, 291–297. Neuprez, A., Coste, S., Rompen, E., Crielaard, J. M. & Reginster, J. Y. (2014) Osteonecrosis of the jaw in a male osteoporotic patient treated with denosumab. Osteoporosis International 25, 393–395. Nocini, P. F., Saia, G., Bettini, G., Ragazzo, M., Blandamura, S., Chiarini, L. & Bedogni, A. (2009) Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. European Journal of Surgical Oncology 35, 373–379. Ott, S. M. (2011) What is the optimal duration of bisphosphonate therapy? Cleveland Clinic Journal of Medicine 78, 619–630. Otto, S., Abu-Id, M. H., Fedele, S., Warnke, P. H., Becker, S. T., Kolk, A., Mucke, T., Mast, G., Kohnke, R., Volkmer, E., Haasters, F.,
Clinical Relevance
Scientific rationale for the study: Unusual clinical complications and clinically relevant observations are important to report especially for the emphasis of rare but dramatic drug side effects.
Lieger, O., Iizuka, T., Porter, S., Campisi, G., Colella, G., Ploder, O., Neff, A., Wiltfang, J., Ehrenfeld, M., Kreusch, T., Wolff, K. D., Sturzenbaum, S. R., Schieker, M. & Pautke, C. (2011) Osteoporosis and bisphosphonatesrelated osteonecrosis of the jaw: not just a sporadic coincidence–a multi-centre study. Journal of Cranio-Maxillo-Facial Surgery 39, 272–277. Reginster, J., Minne, H. W., Sorensen, O. H., Hooper, M., Roux, C., Brandi, M. L., Lund, B., Ethgen, D., Pack, S., Roumagnac, I. & Eastell, R. (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporosis International 11, 83–91. Ripamonti, C. I., Maniezzo, M., Campa, T., Fagnoni, E., Brunelli, C., Saibene, G., Bareggi, C., Ascani, L. & Cislaghi, E. (2009) 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. Annals of Oncology 20, 137–145. Rompen, E. H., Kohl, J., Nusgens, B. & Lapiere, C. M. (1993) Kinetic aspects of gingival and periodontal ligament fibroblast attachment to surface-conditioned dentin. Journal of Dental Research 72, 607–612. Ruggiero, S. L., Dodson, T. B., Assael, L. A., Landesberg, R., Marx, R. E. & Mehrotra, B. (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws– 2009 update. Journal of Oral and Maxillofacial Surgery 67, 2–12. Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J. & Engroff, S. L. (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of Oral and Maxillofacial Surgery 62, 527–534.
Principal findings: Rapidly progressive MRONJ was found in a patient treated with per os bisphosphonate for an uninterrupted period of 15 years. Practical implications: Although MRONJ rarely occurs in patients
Sacco, R., Sacco, G., Acocella, A., Sale, S., Sacco, N. & Baldoni, E. (2011) A systematic review of microsurgical reconstruction of the jaws using vascularized fibula flap technique in patients with bisphosphonate-related osteonecrosis. Journal of Applied Oral Science 19, 293– 300. Seth, R., Futran, N. D., Alam, D. S. & Knott, P. D. (2010) Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 120, 2165–2171. Shane, E., Burr, D., Abrahamsen, B., Adler, R. A., Brown, T. D., Cheung, A. M., Cosman, F., Curtis, J. R., Dell, R., Dempster, D. W., Ebeling, P. R., Einhorn, T. A., Genant, H. K., Geusens, P., Klaushofer, K., Lane, J. M., McKiernan, F., McKinney, R., Ng, A., Nieves, J., O’keefe, R., Papapoulos, S., Howe, T. S., van der Meulen, M. C., Weinstein, R. S. & Whyte, M. P. (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. Journal of Bone and Mineral Research 29, 1–23. Whitaker, M., Guo, J., Kehoe, T. & Benson, G. (2012) Bisphosphonates for osteoporosis–where do we go from here? New England Journal of Medicine 366, 2048–2051.
Address: France Lambert Department of Periodontology and Oral Surgery CHU de Li ege, Domaine du Sart Tilman Bat B-35 B-4000 Li ege, Belgium E-mail: [email protected]
receiving per os bisphosphonate, these complications can occur. Comprehensive oral examination and preventive treatment before the initiation of anti-resorptive drugs treatment might be of interest.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
