Tratamento cirúrgico para osteonecrose dos maxilares induzida por bisfosfonatos: relatos de casos / Surgical treatment for bisphosphonate-induced maxillary osteonecrosis: case reports

Introdução: os bisfosfonatos são um grupo de medicamentos utilizados no tratamento de doenças osteolíticas, tais como mieloma múltiplo, osteoporose e doença de Paget. Uma complicação tardia dessa medicação é a osteonecrose em ossos maxilares. Esta é definida como desenvolvimento de osso necrótico na cavidade bucal de paciente em tratamento atual ou prévio com bisfosfonato, após sofrer algum procedimento cirúrgico bucal invasivo, sem ter realizado radioterapia. Objetivo: descrever, por meio de relatos de casos, a opção de técnica cirúrgica para tratamento da osteonecrose por bisfosfonatos. Materiais e método: em todos os casos relatados, a terapêutica cirúrgica contou com osteotomia e remoção cirúrgica do sequestro ósseo, debridamento, irrigação com soro fisiológico e sutura contínua simples. Resultados: o controle clínico pós-operatório evidenciou boa cicatrização, melhora considerável da lesão e reepitelização significativa, em curto e longo período. Conclusão: os pacientes devem passar por um criterioso exame odontológico, antes do uso desses medicamentos. Nenhum tratamento cirúrgico invasivo deve ser realizado durante a terapia com esses fármacos. (AU)

Introduction: Bisphosphonates are a group of medications used to treat osteolytic diseases such as multiple myeloma, osteoporosis, and Paget's disease. A late complication of this medication is osteonecrosis in the maxillary bones. It is defined as the development of necrotic bone in the oral cavity of a patient under current or with previous treatment with bisphosphonate and subjected to some invasive oral surgical procedure without radiotherapy. Objective: This study aimed to describe, through case reports, the option of a surgical technique for the treatment of osteonecrosis with bisphosphonates. Materials and Method: In all cases reported, surgical therapy included osteotomy and surgical removal of bone sequestration, debridement, irrigation with saline solution, and simple continuous suture. Results: The postoperative clinical control revealed satisfactory healing, considerable lesion improvement, and significant short- and long-term re-epithelialization. Conclusion: Patients should be subjected to a careful dental examination before using these medications. No invasive surgical treatment should be performed during therapy with these drugs. (AU)

Treatment of bisphosphonate-related osteonecrosis using platelet-rich plasma: microtomographic, microscopic, and immunohistochemical analyses

Abstract The present study aimed to investigate the use of platelet-rich plasma (PRP) on tooth extraction sites in rats treated with bisphosphonates. Thirty Albinus Wistar male rats were administered 0.035 mg/kg zoledronic acid intravenously for 8 weeks, divided into four administrations with a 2-week interval between each application, after which their upper right central incisors were extracted to induce the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The samples were divided into the following two groups: Group 1 (G1) underwent marginal resection of BRONJ followed by the use of PRP, while Group 2 (G2) underwent resection of BRONJ but without the use of PRP. The treatment groups were evaluated after 14, 28, and 42 days. Clinical, microtomographic, microscopic, and immunohistochemical (IHC) evaluations were performed. Microtomography results revealed no significant difference between the groups (p <0.05) in any time period. Histomorphometric analysis showed increased bone formation over time for both groups (p < 0.001). G1 demonstrated a greater amount of new bone formation than G2 at 28 and 42 days (p < 0.001), with G1 presenting greater vascularization and a slightly higher VEGF expression. For both groups, RANKL/OPG expression levels were sufficient as a parameter for indicating the rate of bone remodeling in a previously treated area of osteonecrosis groups. Taken together, our findings indicated that the use of PRP improves the resolution process of BRONJ.

Medication-related osteonecrosis of the jaw, osteoradionecrosis, and osteomyelitis: A comparative histopathological study

Abstract It is largely known that some oral diseases can be diagnosed based upon their clinical manifestation combined with the patient's medical history and generally not depending on examination. This is the case of some bone diseases such as osteoradionecrosis of the jaw (ORNJ), osteomyelitis of the jaw (OMJ), and medication-related osteonecrosis of the jaw (MRONJ). The present study aimed to analyze the histopathological features of these specific bone diseases in order to evaluate similarities and differences. Forty-four bone specimens resected from each bone disease (22 cases of ORNJ, 6 cases of OMJ, and 16 cases of MRONJ) were analyzed by two experienced oral pathologists without prior knowledge of the diagnosis, considering bone tissue condition, inflammation, vascularization, and the presence of microorganisms. In addition, the examiners formulated a diagnostic hypothesis for each specimen. Many histopathological similarities were found among the diseases, especially considering the presence of necrotic bone, inflammation, and microorganisms. Statistically significant differences were detected in empty bone lacunae, which was decreased in ORN (p = 0.042), and considering neutrophil count, which was low in the MRONJ group (p ≤ 0.001). The Kappa coefficient was calculated and agreement was detected based on the histopathological parameters, but not for diagnostic suggestion (p=0.23). In conclusion, histopathological aspects of ORNJ, OMJ, and MRONJ do not permit a conclusive diagnosis, emphasizing the necessity of a detailed clinical report.

Effects of Zoledronic Acid in Experimental Periapical Lesions in Rats: An Imaging and Histological Analysis

Abstract The aim of this study was to assess the imaging and histological features of experimental periapical lesions, including the adjacent alveolar bone, in rats under zoledronic acid treatment. The study used 40 male Wistar rats distributed into 8 groups of 5 animals each: G1: induction of periapical lesion (PL) and weekly intraperitoneal administration (WIPA) of saline solution (0.9% NaCl) for 4 weeks; G2: PL induction and WIPA of zoledronic acid (0.15 mg/kg/week) for 4 weeks; G3: PL induction and WIPA of saline solution for 8 weeks; G4: PL induction and WIPA of zoledronic acid for 8 weeks; G5:WIPA of saline solution for 4 weeks and subsequent PL induction; G6: WIPA of zoledronic acid for 4 weeks and subsequent PL induction; G7: WIPA of saline solution for 8 weeks and subsequent PL induction; G8: WIPA of zoledronic acid for 8 weeks and subsequent PL induction. The administration of zoledronic acid or saline solution continued after PL induction until the euthanasia. Thus, cone beam computed tomography and histological analysis were performed. Statistical analyzes were performed by ANOVA and Kruskal-Wallis test. Groups treated with zoledronic acid showed significantly smaller size of PL than the groups treated with 0.9% NaCl (p<0.05). PLs were formed by chronic inflammation ranging from mild to moderate, with no difference between groups. In all specimens, no mandibular necrosis was observed. In conclusion, the presence of PLs apparently does not represent an important risk factor for the development of bisphosphonate-related osteonecrosis of the jaws.

Resumo O objetivo deste estudo foi avaliar as características histológicas e de imagem de lesões periapicais experimentais, incluindo o osso alveolar adjacente, em ratos sob tratamento com ácido zoledrônico. O estudo utilizou 40 ratos Wistar, machos, distribuídos em 8 grupos de animais cada: G1: indução de lesão periapical (LP) e administração intraperitoneal semanal (AIS) de solução salina (NaCl 0.9%) por 4 semanas; G2: indução de LP e AIS de ácido zoledrônico (0,15 mg/kg/week) por 4 semanas; G3: indução de LP e AIS de solução salina por 8 semanas; G4: indução de LP e AIS de ácido zoledrônico por 8 semanas; G5- AIS de solução salina por 4 semanas e subsequente indução de LP; G6- AIS de ácido zoledrônico por 4 semanas e subsequente indução de LP; G7: AIS de solução salina por 8 semanas e subsequente indução de LP; G8: AIS de ácido zoledrônico por 8 semanas e subsequente indução de LP. A administração de ácido zoledrônico ou solução salina continuou após indução de LP até a eutanásia. Após isso, tomografia computadorizada de feixe cônico e análise histológica foram realizadas. Análises estatísticas foram realizadas por ANOVA e teste de Kruskal-Wallis. Os grupos tratados com ácido zoledrônico mostraram LPs significativamente menores que os grupos tratados com NaCl 0.9% (p <0.05). LPs eram formadas por inflamação crônica variando de leve a moderada, sem diferença entre os grupos. Em todos os espécimes, necrose mandibular não foi observada. Em conclusão, a presença de LPs aparentemente não representa um fator de risco importante para o desenvolvimento de osteonecrose relacionada ao uso de bisfosfonatos.

Desarrollo de un modelo experimental de osteonecrosis de maxilar asociada al tratamiento crónico con aminobisfosfonatos / Experimental model of osteonecrosis of the jaw associated to chronic treatment with aminobisphosphonates

La osteonecrosis de maxilar asociada a aminobisfosfonatos (BRONJ) constituye un efecto secundario del tratamiento crónico con los más potentes. Un modelo experimental permitiría determinar la patogenia de dicha alteración. La oveja presenta características orales y del metabolismo óseo similar al humano y permite realizar manipulaciones bucales. Se evaluaron cambios clínicos, remodelación ósea y masa ósea maxilar en ovejas hembras adultas tratadas con zolendronato (ZOL), durante 22 meses y utilizando dosis equivalente al tratamiento de neoplasias. Seis ovariectomizadas (OVX) recibieron ZOL; 5 OVX y 4 SHAM (control) recibieron solución fisiológica. Al inicio, 4 y 22 meses se evaluó calcemia, fosfatemia, crosslaps (CTX) y fosfatasa alcalina ósea. Al final, se evaluó contenido mineral óseo de la hemimandíbula superior (CMO: mg/cm2). Al final del estudio, CTX disminuyó significativamente en ZOL (p<0,05) sin diferencias entre SHAM y OVX. En maxilar, los contenidos de Ca y P (g/g tejido) y CMO (g/cm2 ) disminuyeron en OVX vs. SHAM (p<0,05) y solo Ca y CMO respecto de ZOL (p<0,05). ZOL incrementó el contenido de Ca y CMO, mientras que el de P permaneció significativamente disminuido respecto de SHAM. La sobrevida en SHAM y OVX fue del 100% y en ZOL 77% (2 muertes); 2 ovejas del grupo ZOL presentaron necrosis de maxilar. Conclusiones: fue posible obtener desarrollo de BRONJ por tratamiento crónico con ZOL, el cual redujo notablemente la resorción y, según la relación Ca/P, posiblemente haya afectado la mineralización ósea. (AU)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of chronic treatment with the most powerful aminobisphosphonates (BPs). An experimental animal model would allow to determine the pathogenesis of this complication. Ewes exhibit similar oral cavity characteristics and bone metabolism as humans, and they are suitable for oral cavity interventions. We examined herein the clinical manifestations, bone remodeling status, and maxillary bone mass in adult female ewes treated with zoledronate (ZOL) for 22 months. Six ovariectomized (OVX) ewes received ZOL; and 5 OVX and 4 SHAM animals received saline solution. At the start of the experiment, and at the 4 and 22 month-time points serum Ca, P, crosslaps (CTX), and bone alkaline phosphatase were measured. Bone mineral content (BMC) of the superior hemimandible was measured at the end of the experiment. At this time point, CTX was significantly decreased only in the ZOL group (p<0.05). Ca and P content (g/g tissue) and BMC in the mandible were significantly decreased in the OVX group compared to SHAM animals (p<0.05) and only Ca content and BMC were decreased when compared to ZOL (p<0.05). ZOL treatment increased the Ca content and BMC, whereas the P content remained low compared to the SHAM group (p<0.05). All ewes from the SHAM and OVX groups and 77% of the animals from the ZOL group survived until the end of the experiment, whereas two ewes of ZOL group exhibited BRONJ. Conclusion: under our experimental conditions, it was possible to induce BRONJ by the chronic ZOL administration, which in turn induced a high reduction in bone resorption as well as possibly impaired bone mineralization, based on the Ca/P ratio in the mandible. (AU)

Medication-related osteonecrosis of the jaw. Introduction of a new modified experimental model

ABSTRACT PURPOSE : To evaluate a modified experimental model for medication-related osteonecrosis of the jaw (MRONJ) through the upper right central incisor extraction followed by intravenous bisphosphonate administration. METHODS: Forty five rats underwent the upper right central incisor tooth extraction were divided in 2 groups: Group I - experimental group, 30 rats received an intravenous administration protocol of zoledronic acid 35μg/kg into the tail vein every two weeks, totalizing four administrations, during eight weeks of administration, previously the extraction, and Group II - control group, 15 rats didn't received any medication before extraction. The groups were subdivided in postoperative periods: 14/28/42 days. Clinical analysis and microtomography were performed to verify the presence of osteonecrosis. In addition, descritive histological analysis of hematoxylin-eosin stained sections was performed to evaluate the presence of osteonecrosis or necrotic foci. RESULTS: Twelve (40%) rats, from experimental group, showed clinical signs of MRONJ (p=0.005), however, all samples showed imaginologic findings like osteolysis and loss of integrity of the cellular walls (p≤0.001). Microscopic evaluation revealed osteonecrosis areas with microbial colonies and inflammatory infiltrate (p≤0.001). In the control group, all animals presented the chronology of a normal wound healing. CONCLUSIONS: The presence of medication-related osteonecrosis of the jaw after maxillary central incisor extraction in rats. This new experimental model may be considered an option for the study of MRONJ.

Quantitative ultrasound at the hand phalanges in patients with bisphosphonate-related osteonecrosis of the jaws

Patients with bisphosphonate-related osteonecrosis of the jaws (BRONJ) who received intravenous or oral bisphosphonates (BP) were selected for determination of their bone microarchitecture as a risk predictor of BRONJ development. The diagnosis of BRONJ was made based on clinical and radiographic findings. The control group consisted of healthy patients. All patients underwent quantitative and qualitative ultrasound measurements of bone at the hand phalanges carried out using the DBM Sonic BP. Ultrasound bone profile index (UBPI), amplitude-dependent speed of sound (AD-SoS), bone biophysics profile (BBP), and bone transmission time (BTT) were measured. The BRONJ group consisted of 17 patients (62 ± 4.24; range: 45-82); 10 (58.8%) were male and seven (41.1%) were female, of whom 11 (64.7%) suffered from multiple myeloma, three (17.6%) from osteoporosis, one (5.8%) from prostate cancer, one (5.8%) from kidney cancer, and one (5.8%) from leukemia. Fourteen (82.3%) of them received intravenous BP whereas three (17.6%) received oral BP. Nine (9/17; 52.9%) patients developed bone exposure: two in the maxilla and seven in the mandible. Regarding quantitative parameters, Ad-SoS was low in the BRONJ group, but not significant. The UBPI score was significantly reduced in BRONJ patients with exposed bone when compared to controls (0.47 ± 0.12 vs. 0.70 ± 0.15; p = 0.004). The present study demonstrated that quantitative ultrasound was able to show bone microarchitecture alterations in BRONJ patients, and suggests that these analyses may be an important tool for early detection of bone degeneration associated with BRONJ.

Osteonecrosis mandibular y maxilar secundaria a bifosfonatos: presentación de tres nuevos casos / Mandibular and maxilar osteonecrosis secondary to bisphosphonates: introduction of three new cases

El empleo de los bifosfonatos supone en la actualidad una herramienta de especial relevancia para el manejo terapéutico de diversas patologías, en tanto que forman parte del tratamiento estándar. Sin embargo, y de un modo casi paralelo, se han documentado un amplio número de casos en los que el paciente, secuencialmente a su tratamiento con bifosfonatos, ha desarrollado un cuadro de necrosis avascular en región maxilar y/o mandibular. Cuadro éste, de complejo abordaje, que tiende a comprometer y mermar la calidad de vida de nuestros pacientes. No obstante, la posible aparición de esta complicación, no debe por otra parte, implicar reticencias en cuanto a su uso en la terapéutica, sino más bien constituir un aspecto a vigilar durante el tiempo de terapia. El objetivo de este trabajo es alertar sobre las posibles complicaciones en pacientes que reciben terapia con bifosfonatos a través de la revisión de la literatura y la presentación de tres nuevos casos clínicos.

The use of bisphosphonates is now particularly important in the therapeutic management of various pathologies, as an integral part of standard therapy. However, in an almost parallel form, a large number of cases have been documented in which the patient following treatment with bisphosphonates, developed a vascular necrosis event in the maxillary and/or mandibular region. This is an event of complex approach which tends to compromise and undermine the quality of life for our patients. However the possible occurrence of this complication should not on the other hand, imply misgivings about their use in therapy, but rather constitute an event to be monitored during the time of therapy.The aim of this paper is to advise about possible complications in patients receiving bisphosphonate therapy through literature review and the presentation of these three new clinical cases.