Photobiomodulation Can Prevent Medication-Related Osteonecrosis of the Jaw Formation in Tooth Extraction Site of Rat Model.

Objective: This study aims to explore the preventive potential of photobiomodulation (PBM) in bisphosphonate-related osteonecrosis of the jaw (BRONJ) using a rat model. Methods: An experimental rat model was established, exposing rats to zoledronic acid (ZA), a primary risk factor for BRONJ. An 810 nm diode laser was applied with parameters of 0.33 W/cm2 power density and 10 J/cm2 energy density for 30 sec. PBM was initiated 1 day pre-extraction and continued for 2 weeks. The impact of PBM on wound healing in both soft and hard tissues was evaluated post tooth extraction. Results: ZA exposure hindered wound healing in both soft and hard tissues after tooth extraction. PBM intervention effectively mitigated the adverse effects of ZA, promoting healing processes in both tissue types. This suggests the potential of PBM as a preventive strategy for BRONJ in patients on long-term bisphosphonate treatment. Moreover, PBM exhibited enhanced wound healing in normal rats, indicating its broader applicability beyond BRONJ cases. Conclusions: PBM shows promise in preventing and improving wound healing in BRONJ and normal cases. These findings underscore the significance of optimizing PBM parameters and suggest its potential clinical relevance as a preventive intervention for BRONJ and a promoter of wound healing.

The trend of dental check-up and prevalence of dental complications following the use of bone modifying agents in patients with metastatic breast and prostate cancer: analysis of data from the Korean National Health Insurance Service.

BACKGROUND: Bone-modifying agents (BMA) are key components in the management of cancer patients with bone metastasis. Despite their clinical benefits, the use of BMA is associated with dental adverse events (AEs) including medication-related osteonecrosis of the jaw (MRONJ). This study investigated the frequency of dental surveillance before BMA treatment and the prevalence of dental AEs including MRONJ, after BMA treatment in patients with bone metastasis from breast and prostate cancer using data from the national health insurance system. METHODS: Data, including age, cancer diagnosis, administered BMA, and dental AEs during cancer treatment, of patients with bone metastasis from breast and prostate cancer who received at least one infusion of BMA between 2007 and 2019 were extracted from the Korean National Health Insurance Service (KNHIS) dataset. RESULTS: Of the 15,357 patients who received BMA, 1,706 patients (11.1%) underwent dental check-ups before BMA treatment. The proportion of patients receiving dental check-up increased from 4.4% in 2007 to 16.7% in 2019. Referral to dentists for a dental check-up was more active in clinics/primary hospitals than general/tertiary hospitals, and medical doctors and urologists actively consulted to dentists than general surgeons, regardless of the patient's health insurance status. After BMA treatment, 508 patients (3.8%) developed dental AEs, including abscess (42.9%), acute periodontitis (29.7%), acute pericoronitis (14.9%), and MRONJ (12.5% of dental AEs cases, 0.5% of total BMA treated patients). CONCLUSIONS: Considering the long treatment period in patients with metastatic cancer, coordination between dentists and oncologists is necessary to ensure appropriate dental management before the initiation of BMA.

Ozone therapy effect in medication-related osteonecrosis of the jaw as prevention or treatment: microtomographic, confocal laser microscopy and histomorphometric analysis.

OBJECTIVE: This study aimed to evaluate the efficacy of ozone therapy in the preoperative (prevention) and/or postoperative (treatment) of MRONJ. MATERIAL AND METHODS: Forty male Wistar rats were caudally treated with zoledronic acid (ZOL) and to ozone therapy before extraction (prevention, POG), after extraction (treatment, TOG), or both (prevention and treatment, TPOG), and treated with saline (SAL). The animals received intramuscular fluorochrome (calcein and alizarin), and 28 days postoperatively, they were euthanized, and the tissues were subjected to microtomographic computed tomography (microCT), LASER confocal, and histomorphometric analyses. RESULTS: Micro-CT showed a higher bone volume fraction average in all groups than that in the ZOL group (P < 0.001), the ZOL group showed high porosity (P = 0.03), and trabecular separation was greater in the TOG group than in the POG group (P < 0.05). The mineral apposition rate of the POG group was high (20.46 ± 6.31) (P < 0.001), followed by the TOG group (20.32 ± 7.4). The TOG group presented the highest mean newly formed bone area (68.322 ± 25.296) compared with the ZOL group (P < 0.05), followed by the SAL group (66.039 ± 28.379) and ZOL groups (60.856 ± 28.425). CONCLUSIONS: Ozone therapy modulated alveolar bone repair in animals treated with ZOL, mainly after surgery trauma, leading to bone formation as healing tissue. CLINICAL RELEVANCE: Osteonecrosis has been a challenge in dentistry, and owing to the lack of a consensus regarding therapy, studies presenting new therapies are important, and ozone has been one of the therapies explored empirically.

Low-level laser therapy prevents medication-related osteonecrosis of the jaw-like lesions via IL-1RA-mediated primary gingival wound healing.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a serious debilitating disease caused by anti-resorption and anti-angiogenesis drugs, significantly affecting patients' quality of life. Recent studies suggested that primary gingival wound healing may effectively prevent the development of MRONJ. This study aimed to evaluate the effects of low-level light therapy (LLLT) on promoting gingival wound healing in extraction sockets of MRONJ-like mice and preventing the occurrence of MRONJ. Furthermore, we explored underlying mechanisms. METHODS: Mice were randomly divided into the Ctrl, Zol, and Zol + LLLT groups. Administration of zoledronate and tooth extraction of bilateral maxillary second molars were used to build the MRONJ model, and LLLT was locally administered into the tooth sockets to examine the effect of LLLT. Next, to explore the function of IL-1RA, we performed LLLT with interleukin-1 receptor antagonist (IL-1RA) neutralizing antibody (named Zol + LLLT + IL-1RA NAb group) or negative control antibodies for tooth extraction in subsequent rescue animal experiments. Stereoscope observations, micro-computed tomography, and histological examination were conducted to evaluate gingival wound healing and bone regeneration in tooth sockets. The effects of LLLT on the migration capacities of zoledronate-treated epithelial cells were assessed in vitro. RESULTS: LLLT promoted primary gingival wound healing without exposed necrotic bone. Micro-computed tomography results showed higher bone volume and mineral density of the tooth sockets after LLLT. Histology analysis showed complete gingival coverage, obvious bone regeneration, and reduced soft tissue inflammation, with down-regulated pro-inflammation cytokines, like interleukin-1 beta (IL-1ß) and tumor necrosis factor-α (TNF-α), and up-regulated IL-1RA expression in the gingival tissue in the LLLT group. The rescue assay further showed that the effects of LLLT promoting gingival wound healing and preventing MRONJ might be partially abolished by IL-1RA neutralizing antibodies. In vitro studies demonstrated that LLLT accelerated zoledronate-treated epithelial cell migration. CONCLUSIONS: LLLT might promote primary gingival wound healing and contribute to subsequent bone regeneration of the tooth extractions in MRONJ-like lesions via IL-1RA-mediated pro-inflammation signaling suppression.

Estudo in vivo do efeito da ozonioterapia como prevenção e/ou tratamento da osteonecrose dos maxilares induzida por medicamentos / In vivo study of the effect of ozone therapy as a prevention and/or treatment of druginduced osteonecrosis of the jaws

O ozônio tem sido utilizado no processo de reparo ósseo em condições desfavoráveis, como na osteonecrose dos maxilares induzida por medicamentos (OMIM). O objetivo deste trabalho foi avaliar a aplicação de ozonioterapia como prevenção e/ou o tratamento da OMIM. Cento e vinte ratos wistar foram distribuídos entre os grupos tratamentos: eles foram induzidos com Zoledronato e receberam ozonioterapia antes da exodontia (prevenção ­ GOP), após exodontia (tratamento ­ GOT), em ambos momentos (prevenção e tratamento ­ GOPT), um grupo não recebeu ozônio (ZOL), e outro recebeu soro fisiológico ao invés da indução (SAL). Após 14 e 28 dias pós-operatórios foram eutanasiados e as peças submetidas as análises histológicas com eosina e hematoxilina, imunoistoquímica, microtomográfica computadorizada (microCT), confocal a LASER e histomorfométrica. Em 14 dias observamos o início do reparo em GOT, assim como um epitélio presente em SAL e GOT, o mesmo ocorre em 28 dias, e uma intensa imunomarcação de osteocalcina (OC) em GOPT em 14 dias. A microCT demostrou maiores médias de BV/TV em todos grupos quando comparados a ZOL (p< 0,001), ZOL apresentou maior porosidade (p=0,03) e o espaçamento trabecular foi maior no grupo GOT quando comparado ao GOP (p< 0,05). A taxa de aposição mineral (MAR) dos grupos GOP foram maiores (21,46±14,12), seguida do grupo GOT (19,66± 13,23). GOT apresentou a maior média de %NBA (68,322±25,296), quando comparado ao grupo ZOL (p < 0,05), seguido pelo grupo SAL (66,039±28,379) e ZOL (60,856±28,425). Diante dos resultados pode-se observar que a ozonioterapia pode modular o reparo alveolar em animais induzidos com ácido zoledrônico(AU)

Ozone has been used in the bone repair process under unfavorable conditions, such as in druginduced osteonecrosis of the jaws (OMIM). The objective of this work was to evaluate the application of ozone therapy as prevention and/or treatment of OMIM. One hundred and twenty wistar rats were distributed among treatment groups: they were induced with Zoledronate and received ozone therapy before tooth extraction (prevention - GOP), after tooth extraction (treatment - GOT), at both times (prevention and treatment - GOPT), one group I did not receive ozone (ZOL), and another received saline instead of induction (SAL). After 14 and 28 days postoperatively, they were euthanized and the pieces submitted to histological analysis with eosin and hematoxylin, immunohistochemistry, computed microtomography (microCT), confocal LASER and histomorphometric analysis. In 14 days we observed the beginning of repair in GOT, as well as an epithelium present in SAL and GOT, the same occurs in 28 days, with intense immunostaining of osteocalcin (OC) in GOPT in 14 days. The microCT showed higher BV/TV means in all groups when compared to the ZOL (p< 0.001), ZOL showed greater porosity (p=0.03) and the trabecular spacing was greater in the GOT group when compared to the GOP (p< 0 .05). The mineral apposition rate (MAR) of the GOP groups were higher (21,46±14,12), followed by the GOT group (19,66± 13,23). GOT had the highest average of %NBA (68.322±25.296), when compared to the ZOL group (p < 0.05), followed by the SAL group (66.039±28.379) and ZOL (60.856±28.425). In view of the results, it can be observed that ozone therapy can modulate alveolar repair in animals induced with zoledronic acid(AU)

Estudo in vivo do efeito da ozonioterapia como prevenção e/ou tratamento da osteonecrose dos maxilares induzida por medicamentos / In vivo study of the effect of ozone therapy as a prevention and/or treatment of druginduced osteonecrosis of the jaws

O ozônio tem sido utilizado no processo de reparo ósseo em condições desfavoráveis, como na osteonecrose dos maxilares induzida por medicamentos (OMIM). O objetivo deste trabalho foi avaliar a aplicação de ozonioterapia como prevenção e/ou o tratamento da OMIM. Cento e vinte ratos wistar foram distribuídos entre os grupos tratamentos: eles foram induzidos com Zoledronato e receberam ozonioterapia antes da exodontia (prevenção ­ GOP), após exodontia (tratamento ­ GOT), em ambos momentos (prevenção e tratamento ­ GOPT), um grupo não recebeu ozônio (ZOL), e outro recebeu soro fisiológico ao invés da indução (SAL). Após 14 e 28 dias pós-operatórios foram eutanasiados e as peças submetidas as análises histológicas com eosina e hematoxilina, imunoistoquímica, microtomográfica computadorizada (microCT), confocal a LASER e histomorfométrica. Em 14 dias observamos o início do reparo em GOT, assim como um epitélio presente em SAL e GOT, o mesmo ocorre em 28 dias, e uma intensa imunomarcação de osteocalcina (OC) em GOPT em 14 dias. A microCT demostrou maiores médias de BV/TV em todos grupos quando comparados a ZOL (p< 0,05), seguido pelo grupo SAL (66,039±28,379) e ZOL (60,856±28,425). Diante dos resultados pode-se observar que a ozonioterapia pode modular o reparo alveolar em animais induzidos com ácido zoledrônico(AU)

Ozone has been used in the bone repair process under unfavorable conditions, such as in druginduced osteonecrosis of the jaws (OMIM). The objective of this work was to evaluate the application of ozone therapy as prevention and/or treatment of OMIM. One hundred and twenty wistar rats were distributed among treatment groups: they were induced with Zoledronate and received ozone therapy before tooth extraction (prevention - GOP), after tooth extraction (treatment - GOT), at both times (prevention and treatment - GOPT), one group I did not receive ozone (ZOL), and another received saline instead of induction (SAL). After 14 and 28 days postoperatively, they were euthanized and the pieces submitted to histological analysis with eosin and hematoxylin, immunohistochemistry, computed microtomography (microCT), confocal LASER and histomorphometric analysis. In 14 days we observed the beginning of repair in GOT, as well as an epithelium present in SAL and GOT, the same occurs in 28 days, with intense immunostaining of osteocalcin (OC) in GOPT in 14 days. The microCT showed higher BV/TV means in all groups when compared to the ZOL (p< 0.05), followed by the SAL group (66.039±28.379) and ZOL (60.856±28.425). In view of the results, it can be observed that ozone therapy can modulate alveolar repair in animals induced with zoledronic acid(AU)

Efficacy of guided autofluorescence laser therapy in MRONJ: a systematic review.

OBJECTIVE: This review aims to explore the efficacy of fluorescence-guided excision in the treatment of necrotic bone and highlights the importance of fluorescence in distinguishing viable margins from necrotic ones for a more targeted and predictable management of MRONJ. MATERIALS AND METHODS: The review was conducted according to PRISMA guidelines using PubMed, Scopus, and Web of Science databases from January 1, 2008, to May 17, 2023. The Boolean search strategy with the following keywords "osteonecrosis" AND "fluorescence" was performed. Then, the articles were subjected to screening and eligibility phases. The papers about the use of autofluorescence-guided laser therapy in patients with jaw osteonecrosis were included. RESULTS: A total of 320 articles were initially identified through an electronic search, and ultimately, 17 papers were included in the qualitative analysis. CONCLUSIONS: In conclusion, our findings demonstrate that the VELscope system allows for clear visualization of the bone, making guided autofluorescence a precise, safe, and reliable technique.

[Therapeutic alternatives for drug-associated maxillary osteonecrosis (MRONJ): reports of two clinical cases and review of the literature]. / Alternativas terapéuticas de osteonecrosis maxilar asociada a medicamentos (ONMAM): reportes de dos casos clínicos y revisión de la literatura.

Introduction: Drug-associated Maxillary Osteonecrosis is one of the most relevant adverse effects in treatment with antiresorptive drugs such as bisphosphonates and denosumab. Oncological conditions such as multiple myeloma, breast cancer, prostate, and bone-metabolic disorders such as osteoporosis lead the indications for these antiresorptive therapies. Treatment is complex because the disease is often refractory. Pharmacological, conservative and surgical treatments are described. Objective: The aim of this study is to report two clinical cases of MRONJ treated with two different therapeutic protocols and the analysis of the available literature on these aspects based on the clinical classification defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Conclusion: Patients who develop clinical signs of great morbidity associated with MRONJ, may see their quality of life conditioned and suffer a worsening of their underlying pathology. MRONJ treatment is conditioned by the stage of the disease, its success depends on interdisciplinary management and strict medical and dental clinical follow-up, as well as rigorous monitoring to prevent or detect future recurrences early.

Introducción: La Osteonecrosis Maxilar asociada a Medicamentos (ONMAM) constituye uno de los efectos adversos más relevantes en el tratamiento con drogas antirresortivas como bifosfonatos y denosumab. Patologías oncológicas como mieloma múltiple, cáncer de mama, próstata, y alteraciones óseas-metabólicas como la osteoporosis lideran las indicaciones para estas terapias antirresortivas. El tratamiento es complejo debido a que muchas veces, la enfermedad es refractaria a la terapéutica aplicada. Se describen tratamientos farmacológicos, conservadores y quirúrgicos. Objetivo: El objetivo de este trabajo es reportar dos casos clínicos de ONMAM tratados con dos protocolos terapéuticos diferentes y el análisis de la literatura disponible en la actualidad sobre estos aspectos en base a la clasificación clínica definida por la American Association of Oral and Maxillofacial Surgeons (AAOMS). Conclusión: Los pacientes que desarrollan cuadros clínicos bucales de gran morbilidad como lo es ONMAM, pueden ver condicionada su calidad de vida y sufrir un agravamiento de su patología de base. El tratamiento de ONMAM está condicionado al estadio de la enfermedad, el éxito del mismo depende del manejo interdisciplinario y de un estricto seguimiento clínico médico y odontológico, así como también un riguroso monitoreo para evitar o detectar precozmente futuras recurrencias.

Complementarity of surgical therapy, photobiomodulation, A-PRF and L-PRF for management of medication-related osteonecrosis of the jaw (MRONJ): an animal study.

BACKGROUND: This study aimed to evaluate the complementarity of surgical therapy, photobiomodulation (PBM), advanced platelet-rich fibrin (A-PRF), and Leukocyte and platelet-rich fibrin (L-PRF) for the management of medication-related osteonecrosis of the jaw (MRONJ). METHODS: Sixty rats underwent injection of zoledronate followed by left mandibular first and second molar extractions to induce MRONJ lesions. All rats were examined for the signs of MRONJ 8 weeks post-dental extraction. Forty-nine rats with positive signs of MRONJ were appointed to seven different groups as follows: control (Ctrl); surgery alone (Surg); surgery and PBM (Surg + PBM); surgery and A-PRF insertion (Surg + APRF); surgery and L-PRF insertion (Surg + LPRF); surgery, A-PRF insertion, and PBM (Surg + APRF + PBM); surgery, L-PRF insertion, and PBM (Surg + LPRF + PBM). Euthanasia was carried out 30 days after the last treatment session. The lesions' healing was evaluated clinically, histologically, and radiographically. Data were analyzed using STATA software version 14, and the statistical significance level was set at 5% for all cases. RESULTS: According to the present study, A-PRF and L-PRF treatment resulted in significant improvements in clinical, histological, and radiographical parameters compared to the Ctrl group (P < 0.05). The PBM also decreased wound dimensions and the number of empty lacunae compared to the Ctrl group (P < 0.05). Surg + APRF + PBM and Surg + LPRF + PBM were the only groups that presented a significantly higher mean number of osteocytes (P < 0.05). No significant differences were observed between A-PRF and L-PRF treatment groups (P > 0.05). CONCLUSIONS: Surgical resection followed by applying A-PRF or L-PRF reinforced by PBM showed optimal wound healing and bone regeneration in MRONJ lesions.

Long-Term Ligature-Induced Periodontitis Exacerbates Development of Bisphosphonate-Related Osteonecrosis of the Jaw in Mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental intraoral lesion that occurs in patients with long-term or high-dose use of anti-resorptive agents such as bisphosphonates. Tooth extraction is a known risk factor for BRONJ, and such intervention is often performed to eliminate existing pathological inflammatory conditions. Previously, we determined that ligature-induced periodontitis (LIP) is a risk factor for the development of osteonecrosis in mice, but it remains unclear whether the chronicity of LIP followed by extraction influences osteonecrosis development. In this study, we assess the effect of short-term and long-term LIP (ligature placed for 3 weeks [S-LIP] or 10 weeks [L-LIP], respectively) on osteonecrosis development in mice receiving 250 µg/kg/week zoledronic acid (ZOL). When compared to S-LIP, L-LIP caused 70% (p ≤ 0.0014) more bone loss without altering microbe composition. In the presence of ZOL, bone loss mediated by LIP was prevented and bone necrosis was induced. When the ligated tooth was extracted, histologic hallmarks of osteonecrosis including empty lacunae and necrotic bone were increased by 88% (p = 0.0374) and 114% (p = 0.0457), respectively, in L-LIP compared to S-LIP. We also observed significant increases in serum platelet factor 4 (PF4) and macrophage inflammatory factor 1 γ (MIP1γ) in mice that received ZOL treatment and had tooth extractions compared to controls, which may be systemic markers of inflammation-associated osteonecrosis development. Additionally, CD3+ T cells were identified as the major immune population in both health and disease, and we observed a 116% (p = 0.0402) increase in CD3+IL23R+ T cells in L-LIP compared to S-LIP lesions following extraction. Taken together, our study reveals that extracting a periodontally compromised tooth increases the formation of necrotic bone compared to extracting a periodontally healthy tooth and that osteonecrosis may be associated with the duration of the preexisting pathological inflammatory conditions. © 2022 American Society for Bone and Mineral Research (ASBMR).

Photodynamic therapy and photobiomodulation therapy in zoledronic acid-induced osteonecrosis in rats.

BACKGROUND: This study investigated the effect of antimicrobial photodynamic therapy (PDT), using methylene blue (MBO) and photobiomodulation therapy (PT), on the alveolar bone of rats submitted to bisphosphonate-induced osteonecrosis of the maxillaries (OMB) model using zoledronic acid (ZA). METHODS: Sixty rats divided into six groups were used: SALINE, PDT, ZA, ZA+PDT, ZA+PT, and ZA+MBO. Three weekly administrations (Days 0, 7, and 14) of ZA 0.20 mg/kg or saline solution were performed. After one month (Day 42), the exodontia of the left lower first molars were performed. An additional dose of ZA was administered at Day 49. PDT was performed on days 42, 45, 49, and 54. One month after exodontia (Day 70), the animals were euthanized to obtain samples for imaging and microscopic analysis. ANOVA/Bonferroni tests were used for statistical analysis. RESULTS: The ZA+PDT group showed a significantly lower percentage of apoptotic osteocytes than the ZA group (p < 0.001). The ZA+MBO, ZA+PT, and PDT groups significantly reduced the number of mononuclear cells compared to the ZA group (p < 0.001). The ZA+PT and ZA+PDT groups showed a significant reduction in the number of CD 68+ (p < 0.001) and CD3+ (p = 0.002) cells compared to the ZA group. The number of cells expressing INF-y had a significant reduction in the groups co-treated with PT and PDT compared to the ZA group (p < 0.001). CONCLUSIONS: We conclude that PDT and PT attenuated the severity of OMB and the inflammatory process due to a reduction of macrophages, T lymphocytes, and cytokines that stimulate the activity of these cells.

Efficacy of complementary treatment with autologous platelet concentrates and/or mesenchymal stem cells in chemical osteonecrosis of the jaw. Systematic review of the literature.

The aim of this systematic review was to establish the current status of the subject and find out what scientific evidence we have on the use of autologous plasma concentrates (APCs) and mesenchymal stem cells (MSCs) as complementary therapies at the management of Medication-related Osteonecrosis of the jaw (MRONJ). We performed a literature search of articles published between December 2019 to January 2020 in electronic databases, in accordance to PRISMA system. The variables analyzed were: the number of patients, age, sex, medical history, origin of MRONJ, imaging studies, treatment performed, and evolution of MRONJ. The articles included in the review were grouped into two groups (Group A "Therapy with APCs" and Group B "Therapy with APCs and MSCs"). Newcastle-Ottawa scale (NOS) was used to assess the quality of the articles. Fisher's exact test was used to evaluate eventual differences between groups. Of the 306 patients who were included, 297 belonged to Group A and 9 to Group B. In our sample, women predominated against men and no significant differences in age were observed. Osteoporosis was the most frequent underlying disease in both groups. The most common origin of MRONJ was oral surgery in group A. Conservative surgery was performed in all patients, but complementary treatment was applied in different ways in each group. The resolution of the pathology was achieved in 90% of cases in both groups without significant differences between them. The mean score of the reviewed studies at NOS was 4. There are currently no published scientific data that can sufficiently support the use of APCs and MSCs for the treatment of established MRONJs.

[A Case Report of Kampo Medicine Improving the Symptoms of Antiresorptive Agent-related Osteonecrosis of the Jaw (ARONJ)].

A 56-year-old woman visited an oral surgery clinic in October X with sudden pain in the left mandible. She was diagnosed with left mandibular osteomyelitis based on head computed tomography examination findings. The pain did not reduce even with amoxicillin and loxoprofen sodium hydrate. The patient was then referred to our clinic for treatment. Hainosankyuto (7.5 g/d), loxoprofen sodium hydrate (180 mg/d), and mecobalamin (1500 µg/d) alleviated the pain. However, numbness and tingling pain in the left part of the chin increased. Pregabalin 50 mg/d was then prescribed and then increased from 50 to 100 mg/d. The patient was diagnosed with antiresorptive agent-related osteonecrosis of the jaw (ARONJ). As the pain was exacerbated by discontinuation of the hainosankyuto, it was used continuously. The patient experienced no pain, even after discontinuing the mecobalamin and pregabalin. Platycodon root in hainosankyuto promotes drainage. The patient did not show any significant swelling because she took hainosankyuto during the early stages of inflammation. In addition, the pain resolved even when only hainosankyuto was used, possibly due to the analgesic effect of platycodon root, glycyrrhiza root, and peony root. Hainosankyuto may be an effective adjunctive treatment for patients with ARONJ whose pain is difficult to control with general treatment.

Treatment of medication-related osteonecrosis of the jaw (MRONJ). A systematic review.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a severe drug-related side effect mostly seen in the maxillofacial region of patients under current or previous treatment with antiresorptive and/or angiogenic agents. There is a wide range of treatment options explained in literature for the management of this condition, from conservative treatments to surgical procedures of various levels of invasiveness, which are sometimes supplemented with adjunctive therapies. The present systematic review aimed at evaluating the treatment options of MRONJ in terms of successful outcomes. MATERIALS AND METHODS: Medline, Scopus, and Cochrane databases were searched. The search was limited to clinical studies involving human subjects with at least 3 cases. There was no other limitation for language, publication date, and study design for the articles to be included. A hand search of the bibliographies of identified articles was also performed. The evaluation criterion was an improvement in the healing of the treated site after treatment procedures. RESULTS: After evaluation of the full text of the articles, 118 articles were selected for evaluation (15 platelet concentrates, 4 teriparatide, 10 laser therapy, 3 hyperbaric oxygen, 2 ozone applications, 9 conservative protocols, and 75 surgical interventions articles). The evaluated articles reported positive improvements in healing/staging of the osteonecrosis sites. CONCLUSIONS: Due to the low evidence level and the limited sample size of the studies included, the results of this review must be cautiously interpreted. However, they can be suggestive for evaluating the possible benefits of these treatment options in MRONJ management. Further prospective comparative studies with a large sample size are urgently needed to confirm the results.

Caracterización clínico-terapéutica de pacientes diagnosticados con Osteonecrosis en los maxilares relacionada con medicación / Clinical and therapeutic characterization of patients diagnosed with medication-related osteonecrosis of the jaws

Introducción: La osteonecrosis en los maxilares por medicación es una afección asociada al tratamiento con bifosfonatos, antireabsortivos y antiangiogénicos. Objetivo: Caracterizar clínica y terapéuticamente los pacientes diagnosticados de Osteonecrosis en los Maxilares relacionada con medicación. Material y Método: Se realizó una serie de casos de 19 pacientes, la totalidad de los diagnosticados con la entidad en el Servicio de Cirugía Maxilofacial. Facultad de Estomatología Raúl González Sánchez, enero 2018-enero 2019. Se identificó severidad, factores de riesgo y se estandarizó tratamiento que incluyó la curación con aceite ozonizado y la aplicación de láser infrarrojo. Se evaluó el tratamiento a los 90 días. Se operacionalizaron las variables: sexo, tipo de medicación, vía y tiempo de administración, localización y evaluación al tratamiento. Resultados: La edad promedio de los pacientes fue 69±8,5 años, un 52,63 por ciento fueron masculinos, el zolendronato fue el agente mas asociado en el 78,95 por ciento de los casos, la enfermedad periodontal fue el factor local preponderante (57,89 por ciento), la localización mandibular postero lateral y el estadio evolutivo 2 predominaron en el 63,16 por ciento y 52,63 por ciento de las lesiones. El 78,94 por ciento de los casos presentó evolución satisfactoria a los 90 días. Conclusiones: La medicación con bifosfosfonatos parenterales predominantemente con el zolendronato, fue la causa principal de las osteonecrosis, las cuales prevalecieron en el sector postero lateral de mandíbula y con el estadio 2. La variante de tratamiento de curación con aceite ozonizado e irradiación con láser fue la más implementada. Los valores de lesiones resueltas y mejoradas a los 90 días fueron satisfactorios(AU)

Introduction: Medication-related osteonecrosis of the jaws is an affection associated with the treatment with bisphosphonates, antiresorptive agents or antiangiogenic medications. Objective: To perform a clinical and therapeutic characterization of patients with the diagnosis of medication-related osteonecrosis of the jaws. Material and Method: A case series of a total of 19 patients with the diagnosis of medication-related osteonecrosis of the jaws was carried out in the Department of Dental and Maxillofacial Surgery of ¨Raúl González Sánchez¨ Dental School of Havana from January 2018 to January 2019. The severity and risk factors were identified and the treatment including the healing with ozone oil and the application of infrared laser was standardized. The patients were evaluated in the 90 days after treatment. The operationalization of variables included: sex, type of medications, ways and time of administration, localization, and evaluation of treatment. Results: The average age of patients was 69±8,5 years and 52,63 percent of them were male. Zolendronate was the most associated agent in 78,95 percent of cases. Periodontal disease was the most identified local factor (57, 89 percent). The posterolateral area of the mandible and stage 2 disease evolution predominated in 63,16 percent and 52, 63 percent of lesions, respectively. Also 78, 94 percent of cases had a satisfactory evolution in the 90 days after treatment. Conclusions: The administration of intravenous bisphosphonates, particularly Zolendronate, was the main cause of osteonecrosis. These lesions were mainly located in the posterior lateral area of the mandible and presented stage 2 disease evolution. Healing with ozone oil and application of infrared laser was the most implemented alternative treatment. The values of resolved and improved lesions were satisfactory in the 90 days after treatment(AU)

Effectiveness of surgery and hyperbaric oxygen for antiresorptive agent-related osteonecrosis of the jaw: A subgroup analysis by disease stage.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an adverse event induced by antiresorptive agents (ARAs). The purpose of this study was to evaluate variables, mainly surgery and hyperbaric oxygen (HBO) therapy, associated with treatment outcomes in patients with a diagnosis of ARONJ at a single center. We enrolled consecutive patients who presented to our hospital for the management of stage 2 or 3 ARONJ between January 2003 and December 2019. The relationship between potentially predictive factors and outcome variables was examined using statistical analyses, along with a subgroup analysis based on disease stage. Of 252 patients included in this study, 206 had stage 2 ARONJ and 46 had stage 3 ARONJ. There were 119 patients with osteoporosis and 133 with malignant disease. In total, 139 patients were healed, and the healing rate of patients with stage 3 ARONJ was lower than that of patients with stage 2 ARONJ. With regard to the combination of surgery and HBO therapy, most patients underwent HBO before and after surgery. In the univariable analysis, surgery showed a therapeutic effect in both stage 2 and 3 ARONJ, whereas HBO showed a therapeutic effect in stage 2 ARONJ. In the multivariable analysis for stage 2 ARONJ, extensive surgery showed a stronger association with healing than conservative surgery, whereas ≥46 sessions of HBO therapy was less associated with healing than was non-HBO therapy. Our findings suggest that extensive surgery is highly effective against ARONJ regardless of disease stage if there is a sequestrum separation and systemic tolerance, whereas HBO therapy before and after surgical approach can be effective. Further studies are needed to identify treatment strategies for patients with treatment-refractory ARONJ who may be forced to undergo long-term HBO therapy with the expectation of sequestrum separation.

Ozonotherapy for Treatment of Radiation Therapy-induced Jaw Osteonecrosis and Bisphosphonates: Case Report / Ozonioterapia para o Tratamento de Osteonecrose em Mandíbula Induzida pela Radioterapia Associada com Bisfosfonato: Relato de Caso / Ozonoterapia para el Tratamiento de la Osteonecrosis de la Mordaza Inducida por Terapia de Radiación y Bisfosfonatos: Relato de Caso

Introduction: The inhibition of osteoclastic activity, associated with different treatment modalities in patients with head and neck cancer, make bones unable to respond to repair processes related to physiological traumas or infection and may result in bone necrosis. The present study aims to report a clinical case of osteoradionecrosis in mandible, and how its sequels were controlled by ozonotherapy. Case report: A 73-year-old female patient with infiltrative ductal breast carcinoma with mandibular metastasis was submitted to chemo and radiotherapy at head and neck region associated with bisphosphonate. Three years later, she was diagnosed with hemimandibular osteoradionecrosis that exhibited communication with oral cavity and with a chronic, suppurative and persistent associated infection. It was applied adjuvant therapy with ozone through the cutaneous fistula and the exposed and necrotic bone. Additionally, non-vital bone debridement was proceeded in two surgical steps. The patient is after a 1-year follow-up non-symptomatic. Conclusion: It is supposed that ozonotherapy, due to its antibacterial and immunoregulatory mechanism of action, was an important therapeutic agent for improving the patient's quality of life.

Introdução: A inibição da atividade osteoclástica, associada a diversas modalidades de tratamento utilizadas em pacientes com câncer de cabeça e pescoço, torna o osso incapaz de responder aos processos de reparo relacionados a traumas fisiológicos ou à infecção, e pode resultar em necrose óssea. O presente estudo tem como objetivo relatar um caso clínico de osteonecrose em mandíbula como consequência do uso de bisfosfonato associado à quimioterapia e à radioterapia para tratamento de câncer de mama com metástase para mandíbula, tendo suas sequelas controladas por meio do uso da ozonioterapia. Relato do caso: Paciente do sexo feminino, 73 anos, com história de carcinoma ductal infiltrante de mama com metástase óssea em mandíbula, a qual foi submetida ao tratamento de quimioterapia e radioterapia em região de cabeça e pescoço; três anos depois, foi diagnosticada com osteonecrose da hemimandíbula direita com exposição completa para a cavidade bucal e infecção crônica, supurativa e persistente. Foi realizada terapia adjuvante com aplicação de ozônio nas fístulas cutâneas e no remanescente ósseo exposto e necrosado, além do desbridamento dos sequestros ósseos em duas etapas cirúrgicas. Paciente encontra-se em acompanhamento há 1 ano, sem sintomatologia associada. Conclusão: Observou-se que a ozonioterapia, em razão da sua ação antibacteriana e cicatrizante, foi um importante agente terapêutico para a melhora da qualidade de vida da paciente.

Introducción: La inhibición de la actividad osteoclástica, asociada con las diversas modalidades de tratamiento utilizadas por los pacientes con cáncer de cabeza y cuello, hace que el hueso no pueda responder a los procesos de reparación relacionados con traumas o infecciones fisiológicas y puede provocar necrosis ósea. El presente estudio tiene como objetivo informar un caso clínico de osteonecrosis mandibular como consecuencia del uso de bisfosfonato asociado con quimioterapia y radioterapia para tartar el cáncer de mama con mandíbula metastásica, controlando sus secuelas mediante el uso de la terapia con ozono. Relato del caso: Paciente de 73 años con antecedentes de carcinoma ductal mamario infiltrante con metástasis en la mandíbula ósea fue sometida a quimioterapia y radioterapia en la región de la cabeza y el cuello. Tres años después, le diagnostica con osteonecrosis hemimandibular derecha con exposición completa a la cavidad oral e infección crónica, supurativa y persistente. La terapia adyuvante se realizó con la aplicación de ozono en las fístulas cutáneas y en el remanente óseo expuesto y necrótico, además del desbridamiento de los secuestros óseos en dos etapas quirúrgicas. El paciente ha estado bajo seguimiento durante 1 años in síntomas asociados. Conclusión: Debido a su acción antibacteriana y curativa, la ozonioterapia fue un importante agente terapéutico para mejorar la calidad de vida del paciente.

Efetividade da terapia fotodinâmica antimicrobiana utilizando butil azul de toluidina e laser de baixa potência na prevenção da osteonecrose dos maxilares associada à terapia medicamentosa / Effectiveness of antimicrobial photodynamic therapy using butyl toluidine blue and low-level laser in preventing the occurrence of medicationrelated osteonecrosis of the jaws

O presente estudo teve como objetivo avaliar a efetividade e a segurança do emprego de múltiplas sessões de aPDT, utilizando o butil azul de toluidina (BuAT) e a irradiação com laser de baixa potência (LBP), no sítio de extração dental de ratas com os principais fatores de risco para a ocorrência da osteonecrose dos maxilares associada à terapia medicamentosa (ONM-M). Vinte e oito ratas senescentes foram distribuídas em quatro grupos experimentais: VEI, VEI-aPDT, ZOL e ZOL-aPDT. O protocolo de tratamento teve duração de 7 semanas. Um dia antes do início deste protocolo foi instalada uma ligadura de algodão ao redor do primeiro molar inferior esquerdo para indução da periodontite experimental (PE). Nos grupos VEI e VEI-aPDT, as ratas receberam injeções intraperitoneais de 0,45ml de solução de cloreto de sódio 0,9% (veículo) a cada três dias. Nos grupos ZOL e ZOL-aPDT, as ratas receberam 0,45ml do veículo acrescido de 100µg/Kg do zoledronato a cada três dias. Após três semanas do início do protocolo de tratamento a ligadura foi removida e foi realizada a exodontia do primeiro molar inferior esquerdo. Nos grupos VEI e ZOL não foi efetuado nenhum tratamento local no sítio de extração dental. Nos grupos VEI-aPDT e ZOL-aPDT foram realizadas sessões de aPDT aos 0, 2, e 4 dias pós exodontia. Para a aPDT depositouse sobre o sítio de extração dental 300µl de BuAT (concentração: 0,5mg/ml; tempo de pré-irradiação, 60s) em seguida foi realizada a irradiação com laser de baixa potência (laser: InGaAIP; 660nm; 35mW; 74,2J/cm²; 60s) emissor: InGaAlP; comprimento de onda: 660 nm, laser visível - vermelho; potência: 35 mW; densidade energética por ponto: 74,2 J/cm2 ; tempo de aplicação: 60s). Decorridos 28 dias pós-operatórios foi realizada a eutanásia. As hemimandíbulas foram devidamente processadas para assegurar que no sítio de extração dental fossem efetuadas: 1) análise clínica; 2) análise histológica da reparação tecidual; 3) análise histométrica da Porcentagem de Tecido Ósseo Neoformado (PTOnf); 4) análise histométrica da Porcentagem de Tecido Ósseo Não Vital (PTOnv) e; análise imunoistoquímica de células TRAPpositivas. Os dados foram submetidos à análise estatística com nível de significância de 5%. Os grupos ZOL e ZOL-aPDT apresentaram menor quantidade de células TRAP-positivas quando comparados com os grupos VEI e VEI-aPDT. O grupo ZOL apresentou grande comprometimento do processo de reparação tecidual, condizentes com um quadro de ONM-M. Os grupos VEI, VEI-aPDT e ZOL-aPDT apresentaram um processo de reparação tecidual favorável do sítio de extração dental. No grupo ZOL a PTOnf no sítio de extração dental se mostrou menor que nos grupos VEI, VEI-aPDT e ZOL-aPDT. No grupo ZOL a PTOnv se mostrou maior que nos grupos VEI, VEIaPDT e ZOL-aPDT. No grupo ZOL-aPDT a PTOnv se apresentou maior que nos grupos VEI e VEI-aPDT. O emprego de múltiplas sessões de aPDT, utilizando o BuAT e LBP, no sítio de extração dental de ratas senescentes tratadas com alta dose de zoledronato se mostrou uma estratégia terapêutica segurança e efetiva para evitar a ocorrência da ONM-M pós exodontia(AU)

The present study aimed to evaluate the effectiveness and safety of using multiple aPDT sessions, using butyl toluidine blue (BuTB) and low-level laser irradiation (LLL), at the dental extraction site of rats with the main risk factors for the occurrence of medication-related osteonecrosis of the jaws (MRONJ). Twenty-eight senescent rats were distributed in four experimental groups: VEH, VEH-aPDT, ZOL and ZOL-aPDT. The treatment protocol lasted 7 weeks. One day before the beginning of this protocol, a cotton ligature was installed around the mandibular first molar left to induce experimental periodontitis (EP). In the VEH and VEH-aPDT groups, the rats received intraperitoneal injections of 0.45 ml of 0.9% sodium chloride solution (vehicle) every three days. In the ZOL and ZOL-aPDT groups, the rats received 0.45 ml of the vehicle plus 100 µg / Kg of zoledronate every three days. Three weeks after the beginning of the treatment protocol, the ligature was removed and extraction of the mandibular first molar left was performed. In the VEH and ZOL groups, no local treatment was performed at the tooth extraction site. In the VEH-aPDT and ZOL-aPDT groups, aPDT sessions were performed at 0, 2, and 4 days after extraction. For aPDT, 300µl of BuTB was deposited on the dental extraction site (0.5mg / ml; pre-irradiation time, 60s), followed by irradiation with low-level laser (laser: InGaAIP; 660nm; 35mW; 74.2J / cm²; 60s). After 28 postoperative days, euthanasia was performed. The hemimandibles were properly processed to ensure that at the tooth extraction site: 1) clinical analysis; 2) histological analysis of tissue repair; 3) histometric analysis of the Percentage of Neoformed Bone Tissue (PNFBT); 4) histometric analysis of the Percentage of NonVital Bone Tissue (PNVBT) and; immunohistochemical analysis of TRAP-positive cells. The data were submitted to statistical analysis with a 5% significance level. The ZOL and ZOL-aPDT groups showed less TRAP-positive cells when compared with the VEH and VEH-aPDT groups. The ZOL group showed great compromise in the tissue repair process, consistent with MRONJ. The groups VEH, VEH-aPDT and ZOL-aPDT presented a favorable tissue repair process at the dental extraction site. In the ZOL group, the PNFBT at the tooth extraction site was lower than in the VEH, VEH-aPDT and ZOL-aPDT groups. In the ZOL group, PNVBT was higher than in the VEH, VEHaPDT and ZOL-aPDT groups. In the ZOL-aPDT group, PNVBT was higher than in the VEH and VEH-aPDT groups. The use of multiple aPDT sessions, using BuTB and LLL, at the dental extraction site of senescent rats treated with a high dose of zoledronate proved to be a safe and effective therapeutic strategy to prevent the occurrence of MRONJ after tooth extraction(AU)

Avaliação da ozonioterapia no tratamento da osteonecrose induzida por zoledronato em ratas senis / Evaluation of ozone therapy in the treatment of zoledronate-induced osteonecrosis in senile rats

A ozonioterapia vem se demonstrando uma ferramenta promissora na prevenção de infecções e no auxílio da reparação tecidual, conciliando com os desafios no tratamento da osteonecrose dos maxilares induzida por medicamentos (ONM-M), este projeto objetiva analisar os efeitos da ozonioterapia, em 55 ratas senis (18 meses), entre 300-350g, induzidas a osteonecrose via medicamentosa (Zoledronato 100µg/kg), após exodontia do primeiro molar inferior. Os animais foram divididos em 4 grupos equitativos (10 ratas por grupo), o primeiro grupo SAL, recebeu aplicações de soro fisiológico por 7 semanas, grupo SAL + OZ recebeu aplicações de soro fisiológico por 7 semanas e o tratamento com a ozonioterapia (0,7mg/kg) a cada 2 dias por 28 dias, o grupo ZOL recebeu aplicações de zoledronato (100µg/kg) por 7 semanas e por último o grupo ZOL + OZ recebeu também aplicações de zoledronato no mesmo protocolo e foi tratado com a ozonioterapia (0,7mg/kg) a cada 2 dias por 28 dias. Todos as ratas receberam a antibioticoterapia (Cristacilina® 0,1ml/kg por dia) iniciando 3 dias antes do procedimento de extração, se estendendo até 4 dias de pós-operatório, passaram pela extração do molar na terceira semana de experimento e foram submetidas a eutanásia na sétima semana de experimento. Após a eutanásia as mandíbulas foram ressecadas, reduzidas e preparadas para as análises microtomográficas (caracterização óssea do osso senil (MCT0) e após terapia com zoledronato (MCT1ZOL) contra seu par controle (MCT1SAL), parâmetros volumétricos (Bv,Bv.Tv,Tb.Th,Tb.N,Tb.Sp,Po.Tot) dos grupos experimentais), histométricas (porcentagem de osso neoformado e porcentagem de osso não vital) e imunoistoquímicas (expressão de TNFa, IL-1b, VEGF, OCN e TRAP). Os resultados da caracterização óssea não apresentaram diferença quando comparado os grupos experimentais (p> 0,05), possivelmente devido ao pouco tempo decorrido na terapia com zoledronato. Os demais resultados comparando os grupos experimentais mostrou com diferenças estatisticamente significativas (p< 0,05) uma característica de osso vítreo, denso, sem vitalidade, pobre em vascularização, com elevados valores para marcadores de inflamação, traduzindo isso em osteonecrose dos maxilares relacionada com a medicação, destoando principalmente do grupo controle SAL, que apresentou melhora na reparação alveolar e características de osso vital e vascularizado. A ozonioterapia (ZOL+OZ, SAL+OZ) apresentou valores significantes estatisticamente quando comparado ao grupo sem tratamento, traduzindo em melhora na vascularização do tecido ósseo, em melhora reparacional do alvéolo, modulação da inflamação local e o aparecimento/manutenção de células osteoblásticas ativas (p< 0,05). Mostrando-se uma terapia viável no controle/tratamento da osteonecrose dos maxilares relacionado com medicamentos(AU)

Ozone therapy has been shown to be a promising tool in the prevention of infections and in the aid of tissue repair, reconciling with the challenges in the treatment of medication-induced jaw osteonecrosis (ONM-M), this project aims to analyze the effects of ozone therapy in 55 rats senile (18 months), between 300-350g, induced to osteonecrosis via medication (Zoledronate 100µg / kg), after extraction of the lower first molar. The animals were divided into 4 equitable groups (ten rats per group), the first SAL group, received saline applications for 7 weeks, SAL + OZ group received saline applications for 7 weeks and ozone therapy (0, 7mg / kg) every 2 days for 28 days, the ZOL group received applications of zoledronate (100µg / kg) for 7 weeks and lastly the ZOL + OZ group also received applications of zoledronate in the same protocol and was treated with ozone therapy (0.7mg / kg) every 2 days for 28 days. All rats received antibiotic therapy (Cristacilina® 0.1ml / kg per day) starting 3 days before the extraction procedure, extending up to 4 days after the operation, underwent molar extraction in the third week of the experiment and were submitted to euthanasia in the seventh week of experiment. After euthanasia, the mandibles were resected, reduced and prepared for microtomographic analysis (bone characterization of senile bone (MCT0) and after therapy with zoledronate (MCT1ZOL) against its control pair (MCT1SAL), volumetric parameters (Bv, Bv.Tv, Tb .Th, Tb.N, Tb.Sp, Po.Tot) of the experimental groups), histometric (percentage of newly formed bone and percentage of non-vital bone) and immunohistochemistry (expression of TNFa, IL-1b, VEGF, OCN and TRAP) . The results of bone characterization did not show any difference when comparing the experimental groups (P> 0.05), possibly due to the short time elapsed in zoledronate therapy. The other results comparing the experimental groups showed with statistically significant differences (P < 0.05) a characteristic of vitreous bone, dense, without vitality, poor in vascularization, with high values for inflammation markers, translating this into a related jaw osteonecrosis with medication, disagreeing mainly with the SAL control group, which showed improvement in alveolar repair and characteristics of a vital and vascularized bone. Ozone therapy (ZOL + OZ, SAL + OZ) showed statistically significant values when compared to the untreated group, translating into an improvement in bone tissue vascularization, a reparational improvement of the alveolus, modulation of local inflammation and the appearance/maintenance of cells active osteoblasts (P < 0.05). Showing to be a viable therapy in the control/treatment of osteonecrosis of the jaws related to drugs(AU)

Treatment of BRONJ with ozone/oxygen therapy and debridement with piezoelectric surgery.

OBJECTIVE: Bisphosphonate related osteonecrosis of the jaw (BRONJ) is progressive bone destruction in the maxillofacial region of patients under current or previous treatment with Bisphosphonates. The present case series study aimed to evaluate if ozone/oxygen therapy and debridement with piezoelectric surgery may improve the treatment of BRONJ. PATIENTS AND METHODS: The treatment modality of the patients included ozone/oxygen mixture from medical oxygen. The protocol for ozone/oxygen mixture therapy appointments was set as twice a week for 10 weeks, for a total of 20 applications for each patient. The evaluation of the lesions was based on the clinical and radiologic parameters. The primary outcome was the necrotic lesion reduction during ozone/oxygen therapy sessions and up to the end of follow up periods. The healing of the lesion was taken as a positive result. The level of significance was taken as p <0.05. RESULTS: A total of 14 patients affected by osteonecrosis were included. The mean follow-up of the patients was 14.3 months. The overall success rate after treatment was 64.2%. CONCLUSIONS: According to the results, ozone/oxygen therapy and debridement with Piezoelectric surgery for BRONJ treatment is a safe procedure with successful outcomes.