bisphosphonate induced osteonecrosis of the jaws clinical imaging and histopathology findings

Vol 118 No October 2014 Bisphosphonate-induced osteonecrosis of the jaws: clinical, imaging, and histopathology findings Elias Franco-Pretto, DDS,a Maikel Pacheco, MD,b Andrey Moreno, MD,c Oscar Messa, MD,d and Juan Gnecco, DDSe Hospital Militar Central, Instituto Nacional de Cancerología, and Universidad Militar Nueva Granada, Bogotá, DC, Colombia Objective To assess the main clinical, radiographic, and histopathologic features of patients with bisphosphonate-induced osteonecrosis of the jaws (BIONJ) Study Design Patients with BIONJ diagnosed and treated at the Head and Neck Department, Instituto Nacional de Cancerologı´a, Bogota´, DC, Colombia, between January 2012 and February 2014 were retrospectively included Patients treated with sequestrectomy or curettage were excluded Specimens from selected patients were reexamined under a light microscope Clinical and imaging findings and sociodemographic variables were also reviewed Results Five stage BIONJ cases were included Imaging found massive osteolysis Histopathology found devitalized trabecular bone, an absence of osteoblastic rimming, osteoclastic necrosis, and viable periosteum Actinomyces spp colonies were limited to superficial layers Conclusions BIONJ histopathology is different from that of other necrotizing and inflammatory bone diseases This relates to the known antiresorptive mechanism of bisphosphonates, which is the basis of their therapeutic action Nevertheless, further study with larger series should be accomplished (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:408-417) Bisphosphonates have been used for decades to treat patients with osteoporosis and to control malignancies that compromise bone integrity.1 The clinical benefit of bisphosphonates is a result of their ability to decrease bone turnover via the inhibition of osteoclastic processes Scientific evidence has confirmed an increased risk of developing osteonecrosis of the jaws in patients treated with this group of drugs.1,2 Despite the clinical criteria established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2007,3 bisphosphonate-induced osteonecrosis of the jaws (BIONJ) may be confused clinically with other conditions, such as osteoradionecrosis and osteomyelitis, owing to similar symptoms and radiographic findings.4 Specificity is conferred by the use of bisphosphonate therapy in the This study was presented as a poster in the bisphosphonates category at the Latin American Association of Oral and Maxillofacial Surgery and Traumatology (ALACIBU) meeting, Margarita, Venezuela, July 1-4, 2013 a Chief Resident, Oral and Maxillofacial Surgery Program, Hospital Militar Central, Universidad Militar Nueva Granada b General Surgeon and Surgical Oncology Fellow, Instituto Nacional de Cancerología, Universidad Militar Nueva Granada c Head and Neck Surgeon, Head and Neck Surgery Department, Instituto Nacional de Cancerología d Oncology Pathologist, Pathology group, Instituto Nacional de Cancerología e Oral and Maxillofacial Surgeon, Head and Neck Surgery Department, Instituto Nacional de Cancerología Received for publication Jan 9, 2014; returned for revision Mar 10, 2014; accepted for publication Apr 6, 2014 Ó 2014 Elsevier Inc All rights reserved 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.04.017 408 medical history Therefore, it becomes essential to assess the histopathologic features of BIONJ A few authors have assessed the histologic findings of BIONJ, and the following histopathologic features have been described: numerous bacterial colonies, acellular necrotic bone, osteolysis, and massive inflammatory infiltration.5-8 However, there is scarce documentation that correlates current theories concerning the mechanism and histopathologic features of BIONJ The purpose of this study was to assess the histopathologic features of specimens obtained from patients diagnosed with BIONJ, identifying the main clinical and radiographic findings MATERIALS AND METHODS Charts of patients diagnosed with BIONJ and treated at the Head and Neck Department, Instituto Nacional de Cancerología, Bogotá, DC, Colombia, between January 2012 and February 2014 were retrospectively included The BIONJ diagnosis was established according to the AAOMS Task Force definition of BIONJ.3 The case definition is as follows: the presence of nonhealing exposed necrotic bone in the maxillofacial region that Statement of Clinical Relevance This series included patients diagnosed with bisphosphonate-induced osteonecrosis of the jaws treated by block resection The histopathologic features described herein may explain the physiopathology of this disease, which is different from other necrotizing and inflammatory conditions such as osteoradionecrosis and suppurative osteomyelitis ORIGINAL ARTICLE Franco-Pretto et al 409 Anterior mandible 24 Intravenous (monthly) Zoledronic acid Prostate cancer Female Male 55 Male 78 Posterior right maxilla 24 Intravenous or oral 4/2.5 (monthly/daily) Zoledronic acid/ibandronate Posterior left mandible 24 Intravenous (monthly) Zoledronic acid Metastatic prostatic adenocarcinoma Breast cancer Male 74 Anterior left maxilla 12 Intravenous (monthly) Zoledronic acid Multiple myeloma Male 61 Imaging findings Location Posterior left mandible 36 Intravenous or oral 4/2.5 (monthly/daily) Zoledronic acid/ibandronate Prostate cancer Duration (mo) Route of administration Dosage (mg) Bisphosphonate Disease Age (y) Gender Case A 61-year-old man was diagnosed with multiple myeloma in May 2011 He was treated by the oncology department with 10-cycle chemotherapy (cisplatin, Case Case A 57-year-old man was diagnosed in January 2009 with prostate cancer Medical treatment included intravenous mg of monthly zoledronic acid and 2.5 mg of daily oral ibandronate, both for years After 30 doses of zoledronic acid, his dentist removed the left mandibular second premolar because of chronic periodontitis By December 2011, the patient presented to his dentist with swelling and painful exposed bone in the extraction area The patient was initially prescribed clindamycin, 300 mg times daily; however, after weeks of no response this was changed to azithromycin, which also failed to control the apparent infection By January 2012, the patient was submitted by his dentist to the Head and Neck Department The initial examination found left mandibular bone exposure with orocutaneous fistulas in the third quadrant of the oral cavity Imaging findings included evidence of stage BIONJ (Figure 1, A) The histopathology findings included bone necrosis with devitalized trabecular bone, empty lacunae, and osteoclastic necrosis without inflammatory infiltrate or metastasis (see Figure 1, B-E) The patient was treated by partial hemimandibulectomy without immediate reconstruction Table I Clinicopathologic features of patients diagnosed with bisphosphonate-induced osteonecrosis of the jaws RESULTS A total of patients satisfied the inclusion criteria; were men and was a woman Age ranged from 55 to 78 years, with the average being 66.5 (SD Ỉ 11.5) Four patients were classified as having AAOMS BIONJ stage and one as having stage at the time of consultation The clinicopathologic features of all cases are summarized in Table I 57 has persisted for more than weeks in a patient who has received a systemic bisphosphonate but has no history of radiation therapy of the jaws Patients treated with sequestrectomy or curettage were excluded Patients treated by block resection were included so as to perform a comprehensive analysis of the histopathologic features and overall structures involved in BIONJ Each specimen was reexamined under a light microscope at  10,  40, and  100 magnification The clinical, radiologic, and sociodemographic data were obtained from charts of patients included in the study and were tabulated No institutional review board approval was necessary to perform this retrospective study The authors have read the Helsinki Declaration and have followed the guidelines in this investigation Osteolytic process, inferior border compromise Cortical bone destruction, alveolar loss of continuity Osteolytic process, radiolucent lesion with perilesional sclerosing Generalized sclerosis of lamina dura and posterior right maxilla Generalized sclerotic changes of lamina dura OOOO Volume 118, Number ORAL AND MAXILLOFACIAL SURGERY 410 Franco-Pretto et al OOOO October 2014 Fig A, Radiolucent diffuse image with osteolytic pattern in left mandibular body compromising basal mandibular region B, Partial bone necrosis with empty lacunae and apoptotic detached 4-nuclei osteoclast (arrow) (hematoxylin-eosin, original magnification  40) C, Trabecular bone layer in proximity to the oral cavity heavily influenced by the presence of an inflammatory infiltrate, including numerous neutrophils (arrow) (hematoxylin-eosin, original magnification  100) D, Necrotic trabecular bone with empty osteocytic lacunae (short arrows) and detached osteoclast (long arrow) (hematoxylin-eosin, original magnification  40) E, Trabecular bone layer in proximity to the marrow space devoid of inflammatory cells with empty osteocytic lacunae (arrows) (hematoxylin-eosin, original magnification  40) etoposide) along with dexamethasone and zoledronic acid, mg intravenously, on a monthly schedule for year By June 2012, after 12 doses of zoledronic acid, he presented to the Head and Neck Department with pain and swelling over the left maxilla His left maxillary alveolar process was exposed, and a slight suppurative exudate arose from the exposed bone There was no evidence of oronasal or oroantral fistulas The patient was initially treated by curettage and oral clindamycin (300 mg times daily) without success Three months after his referral, the area of bone exposure continued to enlarge and then developed drainage The patient was treated by left hemimaxillectomy and fibula flap reconstruction Tomographic imaging confirmed the clinical findings (Figure 2, A) Histopathologic findings included extended bone necrosis with devitalized bone trabeculae and empty lacunae without inflammatory infiltrate (see Figure 2, B-F) The superficial zones of the specimen contained plasmocytes with positive reactivity to CD38 and multiple myeloma oncogene (MUM1), which is compatible with plasmatic cell neoplasia (see Figure 2, G-I) The clinical picture was compatible with BIONJ stage Case A 74-year-old man presented with a history of moderately differentiated prostatic adenocarcinoma metastatic to bone diagnosed in August 2009 He was treated with chemotherapeutic management that included OOOO Volume 118, Number ORIGINAL ARTICLE Franco-Pretto et al 411 Fig A, Axial computed tomography scans with bone window settings reveal the destruction of the alveolar bone process of the left maxilla B, Outermost layer of the specimen, revealing an area of periosteal bone formation (arrows) (hematoxylin-eosin, original magnification  100) C, Surface colony of Actinomyces spp is seen (long arrows) along with devitalized trabecular bone ORAL AND MAXILLOFACIAL SURGERY 412 Franco-Pretto et al intravenous zoledronic acid, mg monthly for years, and oral prednisone, mg daily After 21 doses of zoledronic acid, his dentist removed the mesial root of the left mandibular second molar because of chronic periodontitis After months of a nonhealed socket after extraction, he presented to the Head and Neck Department with bone exposure and infection of the mandibular left body with orocutaneous fistula (Figure 3, A, B) A panoramic image found an osteolytic radiolucent process localized in the left mandibular alveolar region (see Figure 3, C) The clinical picture was compatible with BIONJ stage The patient was treated with partial left hemimandibulectomy without reconstruction The histopathologic findings included a combination of zones of bone necrosis with devitalized trabecular bone and empty lacunae and necrotic osteoclasts with evidence of apoptosis without inflammatory infiltrate (see Figure 3, D, E) In other areas of the specimen, surface colonies of Actinomyces spp were found (see Figure 3, F, G) Case A 55-year-old woman was diagnosed in December 2011 with breast cancer metastatic to bone Medical treatment included intravenous mg of monthly zoledronic acid and 2.5 mg of daily oral ibandronate, both for years After 24 doses of zoledronic acid, her dentist removed the right maxillary third molar because of chronic periodontitis By February 2013, the patient presented to her dentist with swelling and painful exposed bone in the extraction area The patient was initially treated by normal saline solution irrigation, followed by alveoloplasty Her dentist did not prescribe any antibiotic treatment By May 2013, the patient was submitted to the Head and Neck Department Intraoral examination found right maxillary bone exposure with oroantral fistulas in the extraction area and suppurative exudate that arose from the exposed bone (Figure 4, A) Surgical treatment included right partial posterior hemimaxillectomy Imaging findings included evidence of stage BIONJ (see Figure 4, B) The histopathologic OOOO October 2014 findings included bone necrosis with devitalized trabecular bone and empty lacunae without inflammatory infiltrate or metastasis (see Figure 4, C, D) Case A 78-year-old man presented with a history of prostate cancer metastatic to bone diagnosed in January 2012 The patient was scheduled for removal of the inferior incisors because of chronic periodontitis, and an inferior denture was placed by his dentist weeks before starting medical treatment He was treated with chemotherapeutic management that included intravenous zoledronic acid, mg monthly for years After 20 doses of zoledronic acid, the patient developed painful zones of spicule-like exposed bone in the anterior mandibular region His dentist removed the exposed bone spicules and prescribed 0.12% chlorhexidine oral rinses times daily By January 2014, the patient was submitted by his dentist to the Head and Neck Department He presented with infected, painful, and exposed alveolar bone limited to the anterior mandibular region A panoramic image found generalized sclerotic changes compromising the lamina dura (Figure 5, A) The clinical picture was compatible with BIONJ stage at this time The patient was initially treated by removing the mobile segments of bony sequestrum, along with doxycycline, 100 mg once daily, without success By February 2014, the area of bone exposure continued to enlarge and then developed extraoral drainage The patient was reclassified then as BIONJ stage and treated by segmental resection of the anterior mandibular alveolar process The histopathologic findings included a combination of zones of bone necrosis with devitalized trabecular bone and empty lacunae (see Figure 5, B) In other areas of the specimen, surface colonies of Actinomyces spp were found (see Figure 5, C) DISCUSSION The clinical and imaging aspects in this case series are consistent with those previously described in the with empty osteocytic lacunae (short arrows) (hematoxylin-eosin, original magnification  40) D, Devitalized lamellar bone with empty osteocytic lacunae (arrows) (hematoxylin-eosin, original magnification  40) E, Necrotic bone and empty marrow spaces, without inflammatory cells or fibrosis Extensive scalloping of bone edges suggestive of interrupted Howship lacunae (arrows) (hematoxylin-eosin, original magnification  40) F, Marrow space is seen to be acellular and devoid of extracellular collagen or cellular products along with empty osteocytic lacunae (short arrow), scalloped bone edges representing empty Howship lacunae of varying extension and depth (long arrows) Absence of osteoblastic rimming is also noted (hematoxylin-eosin, original magnification  100) G, Mononuclear and multinucleated neoplastic plasma cells with prominent nucleoli with little stroma (arrows) (hematoxylin-eosin, original magnification  100) H, Nuclear and cytoplasmic positivity of tumor cells for the multiple myeloma oncogene (MUM1) protein confirming differentiated neoplastic plasma cells (MUM1,  100) I, Tumor cells are CD38ỵ (arrows), which conrms the multiple myeloma diagnosis (CD38,  100) OOOO Volume 118, Number ORIGINAL ARTICLE Franco-Pretto et al 413 Fig A, Mandibular alveolar bone exposed with infection signs B, Extraoral left submandibular fistulas (arrow) C, Panoramic image reveals radiolucent osteolytic image bone mesial to inferior left third molar D, Marrow space is seen to be acellular and devoid of extracellular collagen or cellular products, extended bone necrosis without inflammatory infiltrate with empty osteocytic lacunae (hematoxylin-eosin, original magnification  10) E, Devitalized trabecular bone with empty lacunae (short arrows) along with scalloped bony edges pattern (long arrows) (hematoxylin-eosin, original magnification  100) F, Surface colony of Actinomyces spp (arrows) (hematoxylin-eosin, original magnification  40) G, Surface colony of Actinomyces spp (arrows) is seen together with empty marrow spaces without microorganisms (hematoxylin-eosin, original magnification  40) literature.4 All patients presented in the present series were treated with intravenous bisphosphonates and classified as having BIONJ stage Radiologic features of stage BIONJ may not fully explain the pathogenesis of BIONJ However, histopathologic findings such as the presence of viable reactive periosteum indicate that bisphosphonates not affect osteoblasts in a direct manner Because of decreased osteoclastic activity, cytokines for endosteal differentiation of pluripotential marrow-derived stem cells into bone-forming ORAL AND MAXILLOFACIAL SURGERY 414 Franco-Pretto et al OOOO October 2014 Fig A, Right maxillary exposed bone with oroantral communication (arrow) B, Panoramic image reveals sclerotic changes compromising the right posterior maxillary region (short arrow) along with generalized sclerosis compromising lamina dura (arrows) C, Empty osteocytic lacunae (short arrow), marrow space devoid of inflammatory cells or fibrosis Extensive scalloping of bone edges suggestive of interrupted Howship lacunae (arrows) (hematoxylin-eosin, original magnification  40) D, Extended bone necrosis without inflammatory infiltrate with empty osteocytic lacunae (arrowheads), acellular marrow space, devoid of cellular products (hematoxylin-eosin, original magnification  40) Fig A, Panoramic image reveals generalized sclerotic changes compromising lamina dura of postextraction sockets (arrowheads) B, Devitalized trabecular bone with empty osteocytic lacunae (arrowheads) C, Trabecular bone with empty osteocytic lacunae (arrows) along with surface colony of Actinomyces spp (arrowheads) (hematoxylin-eosin, original magnification  40) cells are not released In contrast, periosteal osteoblasts are self-renewing and are independent of bone resorption This finding is consistent with those described in the literature.4 Osteoclasts detached from the bone were also present, along with nonviable osteoclasts, which confirm the osteoclastic apoptotic mechanism induced by bisphosphonates that has been proposed in other articles.4,5-13 Osteoclastic detachment is increasingly thought to be a result of the inhibition of posttranslational prenylation of guanosine triphosphateebinding proteins by bisphosphonates Such inhibition results in loss of the ruffled border and altered cytoskeletal organization in osteoclasts.8,13,14 There were frequent scalloped bone edges representing empty Howship lacunae, which suggest an interruption of the resorption activity due to osteoclastic impaired function This finding coincides with those described in the literature.4 OOOO Volume 118, Number Histopathologic analysis in this case series also found inflammatory infiltrate in several parts of the specimens Favia et al.,5 using biopsy specimens, found specific histologic patterns for BIONJ: Areas with active acute inflammation, acellular necrotic sequestra, and non-necrotic areas without inflammation The infiltrates in this case series were related to superinfection of the exposed bone Infection is frequently associated with stage and BIONJ To find BIONJ histopathology features, it was necessary to perform analysis in zones without the inflammatory infiltrates This finding coincides with those observed by Marx and Tursun.4 They explained that BIONJ physiopathology corresponds to a noninflammatory condition that is the result of a reactive toxicity to bisphosphonates, which is different in nature to other conditions such as osteoradionecrosis (ORN) and suppurative osteomyelitis (SOM).4 Marx and Tursun4 found common histologic features between ORN, SOM, and BIONJ: necrotic bone with empty haversian systems and Volkmann canals However, marrow fibrosis is a distinctive histologic feature in ORN along with nonviable periosteum, consistent with the hypocellular-hypovascular-hypoxic mechanism involved in this disease In contrast, histopathologic evidence in this series did show viable periosteum, which indicates that bisphosphonates are not directly toxic to osteoblasts but that osteoblasts are ultimately impaired due to the decreased osteoclastic function.4 Unlike in BIONJ, there is no osteoclastic impairment in ORN but rather direct injury to all cells in the field of radiation The radiation directly damages the blood supply, the periosteum, the overlying mucosa, and the overlying skin Infection is not considered a part of the primary mechanism of BIONJ Microorganisms exhibit an opportunistic role when the bone becomes exposed The bone develops necrosis in the case of BIONJ because of the inhibitory action of the drug on the farnesyl synthase enzyme,10-12,15 which results in bone exposure, and after exposure, the necrotic exposed bone becomes colonized by microorganisms In contrast, histopathologic findings in SOM specimens suggest that microorganisms induce an inflammatory response within the marrow space and cause blood vessel thrombosis as the main mechanism of disease.4 Unlike in SOM, the microorganisms seen in this series were found exclusively on the bony surface, supporting the opportunistic role of microorganisms as described in the literature.4 The most common isolated microorganisms in cases of superinfection include Actinomyces spp, Eikenella spp, and Moraxella spp Actinomyces spp were isolated in cases The administration of clindamycin is not recommended because of its low effectiveness against ORIGINAL ARTICLE Franco-Pretto et al 415 the microorganisms isolated in BIONJ cases.16 Actinomyces spp are weakly sensitive to clindamycin, which explains why the drug was not effective in treating the superinfection in cases The current antibiotic therapy recommendation includes penicillin VK, 500 mg every hours daily, as empiric treatment and doxycycline, 100 mg daily, as a second option Antibiotic therapy should be extended at least 14 days or until infection signs disappear.16-18 Marx has observed that penicillin VK is well tolerated for long-term formulation in this group of patients and in those with bacterial sclerosing osteomyelitis.17 Interestingly, case of this series was refractory to doxycycline treatment and required surgical management The mandible is the most affected bone in the maxillofacial region, at a 2:1 proportion compared with the maxilla according to several publications.19-21 Zones with anatomic prominences such as torus and exostoses are predisposed to develop the condition because of a greater propensity to experience direct trauma Other anatomic zones with higher risk include the internal oblique line and mylohyoid groove.22-25 Other risk factors associated with developing the condition include dentoalveolar surgical procedures such as dental extractions and dental implant placement.26-30 Patients with cancer who have periodontal disease and odontogenic infection have a 7-fold higher risk to develop BIONJ when treated with intravenous bisphosphonates.26-28 Previous reports have clearly established other risk factors associated with the development of BIONJ: potency of bisphosphonate, drug half-life, dose, route, and total period of administration.26,29 In the case of oral bisphosphonates, there is a directly proportional relation between the severity of the clinical picture and the period of administration Because of its low gastrointestinal absorption, bioavailability ranges between 0.70% and 0.59% Thus, it is necessary to administer bisphosphonates for a long period, which can result in a total osteoclastic depletion capable of promoting BIONJ Previous studies have included patients who received oral bisphosphonate treatment for more than years.16 There is no clear correlation between BIONJ severity and intravenous-route bisphosphonates When the drug is administered using the intravenous route, 60% of the administered drug is absorbed by bone, and the rest is excreted in urine This results in a fast depletion of functional osteoclasts and those precursors located in the bone marrow.16 In the case of zoledronic acid, the literature reports a mean of 9.3 months of administration for the promotion BIONJ, without difference in case severity between shorter and longer periods of administration.20 All patients of this case series had a history of intravenous bisphosphonate therapy The ORAL AND MAXILLOFACIAL SURGERY 416 Franco-Pretto et al second patient in this study developed BIONJ without surgical intervention after 12 months of zoledronic acid intravenous therapy Another condition related to increasing severity of BIONJ cases is the presence of multiple myeloma Because of the replacement of the normal bone marrow cellular population by abnormal cells, the action of bisphosphonates in this group of patients results in an earlier and more severe clinical presentation of BIONJ.26 Clinical findings in the second case in this article support this conclusion The AAOMS developed a BIONJ staging system that takes into consideration symptoms, imaging findings, and the presence of bone exposure.2 The system has been useful in the diagnosis and management of this group of patients However, there is no unified method that can aid in establishing the risk of developing BIONJ Marx et al.,16 in a series of 30 patients with BIONJ, found a correlation between serum levels of CTX (c-terminal-telopeptide) and occurrence of the disease The CTX test measures concentration of crossed peptide links that result from collagen type I degradation during bone reabsorption Flichy-Fernández et al.31 did not find significant differences between CTX values and doses and periods of administration of oral bisphosphonates Although the present series included cases, the relevant histopathologic features described herein, along with the effects of bisphosphonates on bone metabolism, may explain the physiopathology of this disease, which is different from other necrotizing and inflammatory conditions such as ORN and SOM It is important that every patient undergoing bisphosphonate treatment is previously submitted for oral examination to treat all dental needs before beginning bisphosphonate therapy CONCLUSION Further study with larger series should be accomplished to completely understand the pathophysiology of the disease Future research should focus on histopathologic differences between BIONJ, SOM, and ORN that could confirm separate mechanisms for each disease, to improve prevention and treatment protocols based on current evidence REFERENCES Sawatari Y, Marx RE Bisphosphonates and bisphosphonate induced osteonecrosis Oral Maxillofac Surg Clin N Am 2007;19: 487-498 Ruggiero S, Dodson T, Assael L, Landesberg R, Marx RE, Bhoomi M American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jawsd2009 update J Oral Maxillofac Surg 2009;67:2-12 OOOO October 2014 Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws J Oral Maxillofac Surg 2007;65:369-376 Marx RE, Tursun R Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease Int J Oral Maxillofac Surg 2012;41:283-289 Favia G, Pilolli GP, Maiorano E Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy Bone 2009;45:406-413 Hansen T, Kunkel M, Weber A, James Kirkpatrick C Osteonecrosis of the jaws in patients treated with bisphosphonatesd histomorphologic analysis in comparison with infected osteoradionecrosis J Oral Pathol Med 2006;35:155-160 Bittner T, Lorbeer N, Reuther T, Böhm H, Kübler AC, MüllerRichter UD Hemimandibulectomy after bisphosphonate treatment for complex regional pain syndrome: a case report and review on the prevention and treatment of bisphosphonate-related osteonecrosis of the jaw Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2012;113:41-47 Bedogni A, Blandamura S, Lokmic Z, et al Bisphosphonateassociated jawbone osteonecrosis: a correlation between imaging techniques and histopathology Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:358-364 Marx RE Osteoradionecrosis: a new concept of its pathophysiology J Oral Maxillofac Surg 1983;41:283-288 10 Martin J, Gill V Bisphosphonatesdmechanism of action Experimental and clinical pharmacology Austi Preser 2000;23:130-139 11 Rogers M, Frith J, Luckman S, et al Molecular mechanisms of action of bisphosphonates Bone 1999;24:738-798 12 Russel R, Croucher P, Roger M Bisphosphonates: pharmacology, mechanisms of action and clinical uses Osteoporos Int 1999;9:566-580 13 Russell RG, Watts NB, Ebetino FH, Rogers MJ Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy Osteoporos Int 2008;19: 733-759 14 Weinstein RS, Roberson PK, Manolagas SC Giant osteoclast formation and long-term oral bisphosphonate therapy N Engl J Med 2009;360:53-62 15 Assael L Bisphosphonates and oral health: primer and an update for the practicing surgeon Oral Maxillofacial Surg Clin N Am 2011;23:443-453 16 Marx RE, Cillo J, Ulloa J Oral bisphosphonateeinduced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention and treatment J Oral Maxillofac Surg 2007;65: 2397-2410 17 Marx RE, Carlson ER, Smith BR, Toraya N Isolation of Actinomyces species and Eikenella corrodens from patients with chronic diffuse sclerosing osteomyelitis J Oral Maxillofac Surg 1994;52:26-33 18 Marx RE, ed Oral and Intravenous Bisphosphonate-Induced Osteonecrosis of the Jaws: History, Etiology, Prevention, and Treatment Hanover Park, IL: Quintessence Publishing; 2006 19 Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff S Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases J Oral Maxillofac Surg 2004;62:527-534 20 Marx RE, Sawatari Y, Fortin M, Broumand V Bisphosphonateinduced exposed bone (osteonecrosisyosteopetrosis) of the jaws: risk factors, recognition, prevention and treatment J Oral Maxillofac Surg 2005;63:1567-1575 21 Ruggiero SL, Fantasia J, Carlson E Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for OOOO Volume 118, Number 22 23 24 25 26 27 diagnosis, staging and management Oral Surg Oral Med Oral Path Oral Radiol Endod 2006;102:433-441 Ruggiero S, Gralow J, Marx RE, et al Practical guidelines for the prevention, diagnosis and treatment of osteonecrosis of the jaw in patients with cancer J Oncol Pract 2006;2:7-14 Freitas M, Cedrún J, Fernández J, García A, Fernández J, Diz P Oral bisphosphonate-related osteonecrosis of the jaws: clinical characteristics of a series of 20 cases in Spain Med Oral Patol Oral Cir Bucal 2012;17:e751-e758 Barasch A, Cunha-Cruz J, Curro FA, et al Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN J Dent Res 2011;90:439-444 Otto S, Abu-Id MH, Fedele S, et al Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: not just a sporadic coincidenceda multi-centre study J Craniomaxillofac Surg 2011;39:272-277 Badros A, Weikel D, Salama A, et al Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors J Clin Oncol 2006;24:945-952 Jadu F, Lee L, Pharoah M, Reece D, Wang L A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients Ann Oncol 2007;18:2015-2019 ORIGINAL ARTICLE Franco-Pretto et al 417 28 Hoff AO, Toth BB, Altundag K, et al Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates J Bone Miner Res 2008;23: 826-836 29 Bamias A, Kastritis E, Bamia C, et al Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors J Clin Oncol 2005;23:8580-8587 30 Gutta R, Louis PJ Bisphosphonates and osteonecrosis of the jaws: science and rationale Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:186-193 31 Flichy-Fernández AJ, Alegre-Domingo T, González-Lemonnier S, et al Study of serum CTX in 50 oral surgical patients treated with oral bisphosphonates Med Oral Patol Oral Cir Bucal 2012;17: E367-E370 Reprint requests: Elias Franco Pretto Universidad Militar Nueva Granada Department of Oral and Maxillofacial Surgery Bogota, DC Colombia elias.pretto@gmail.com; elias.pretto@outlook.com