Radiological manifestations and clinical findings of patients with oncologic and osteoporotic medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) poses a challenging form of osteomyelitis in patients undergoing antiresorptive therapies in contrast to conventional osteomyelitis. This study aimed to compare the clinical and radiological features of MRONJ between patients receiving low-dose medications for osteoporosis and those receiving high-dose medications for oncologic purposes. The clinical, panoramic radiographic, and computed tomography data of 159 patients with MRONJ (osteoporotic group, n = 120; oncologic group, n = 39) who developed the condition after using antiresorptive medications for the management of osteoporosis or bone malignancy were analyzed. The osteoporotic group was older (75.8 vs. 60.4 years, p < 0.01) and had a longer duration of medication usage than the oncologic group (58.1 vs. 28.0 months, p < 0.01). Pus discharge and swelling were more common in the osteoporotic group (p < 0.05), whereas bone exposure was more frequent in the oncologic group (p < 0.01). The mandibular cortical index (MCI) in panoramic radiographs was higher in the osteoporotic group (p < 0.01). The mean sequestra size was larger in the oncologic group than in the osteoporotic group (15.3 vs. 10.6 mm, p < 0.05). The cured rate was significantly higher in the osteoporotic group (66.3% vs. 33.3%, p < 0.01). Oncologic MRONJ exhibited distinct clinical findings including rapid disease onset, fewer purulent signs, and lower cure rates than osteoporotic MRONJ. Radiological features such as sequestrum size on CT scan, and MCI values on panoramic radiographs, may aid in differentiating MRONJ in osteoporotic and oncologic patients.

Sclerotic bone: a sign of bone reaction in patients with medication related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction associated with antiresorptive drugs such as bisphosphonates and denosumab. When dealing with advanced and/or multiple MRONJ lesions undergoing surgical therapy, the extent of surgery is often a topic of discussion. The aim of this study was to identify the differences in bone density in and around the MRONJ lesion before and after surgical treatment to evaluate the needed surgical extend of the modelling osteotomy. In this retrospective study 26 patients with MRONJ lesions that were surgically treated in our department were observed. Length, width and bone density were measured in panoramic radiograph pre and postoperatively with the Imaging processing software Sidexis and ImageJ (Fiji). The necrotic area, the surrounding sclerotic area as well as the healthy contralateral side were observed. Measurements were performed by two independent observers. Pearson correlation was calculated to determine the interobserver variability. Bone density was significantly reduced in the necrotic bone area compared to the healthy unaffected contralateral reference side. The sclerotic bone area surrounding the necrosis showed increased bone density compared to the contralateral unaffected reference side. The density of the sclerotic bone area was increased in the previously affected MRONJ area in the postoperative panoramic radiograph. The pre and postoperative density showed no significant correlation to healing behaviour. The focus of the modelling osteotomy in surgical treatment of mature MRONJ lesions should be predominantly on the parts that appear necrotic and less dense in the panoramic radiograph as sclerotic areas might be an expression of bone reaction.

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.

Medication-related osteonecrosis of the lower jaw without osteolysis on computed tomography images.

INTRODUCTION: Surgery is the standard treatment for medication-related osteonecrosis of the jaw (MRONJ). This study reviewed patients with mandibular MRONJ who underwent surgical treatment, and in particular the characteristics of non-osteolytic MRONJ with no evidence of osteolysis on CT were described. MATERIALS AND METHODS: We conducted a retrospective study of patients with mandibular MRONJ who underwent surgery between January 2016 and September 2022. Various clinical and imaging factors regarding treatment outcomes were investigated and analyzed. Additionally, the disease course of non-osteolytic MRONJ was examined in detail. RESULTS: This study included 55 patients (66 surgeries) with a mean age of 74.7. The primary disease was osteoporosis (24 patients) and malignancy (31 patients); the type of antiresorptive agent was bisphosphonate (BP) in 21 patients and denosumab (DMB) in 26. BP was initially administered; however, it was changed to DMB in eight patients. Preoperatively, the cumulative cure rates for all 66 surgeries were 72.8% at 1 year and 77.3% at 2 years. Cure rates were significantly lower in patients with malignancy, those without osteolysis, and those who underwent sequestrum removal or marginal mandibulectomy than those with osteoporosis, osteolysis, and segmental mandibulectomy. Non-osteolytic MRONJ was observed in eight patients, all with malignancy and receiving high-dose DMB. Only two patients were cured after the initial surgery, and most patients ultimately underwent segmental mandibulectomy. CONCLUSIONS: Surgical treatment yielded good treatment outcomes in most patients with mandibular MRONJ; however, the cure rate was lower in patients with malignancy who showed no osteolysis on CT images.

Risk factors associated with prognosis of patients with medication-related osteonecrosis of the jaw.

OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive and/or antiangiogenic agents. As the treatment application for MRONJ is controversial, we aimed to identify the risk factors for poor prognosis and to help determine appropriate management. METHODS: This study included 119 patients. Relevant clinical data were obtained for all the patients. In computed tomography images, osteosclerosis, osteolysis, cortical perforation (buccal or lingual), periosteal reaction, and sequestration were evaluated. RESULTS: Multivariate analyses showed statistically significant associations between poor prognosis in patients with MRONJ and conservative treatment alone (hazard ratio [HR] 1.89), osteolysis (HR 4.67), and the absence of sequestration (HR 5.33). CONCLUSIONS: Conservative treatment alone without clear objectives needs to be avoided, and osteolytic change could be the criteria for surgical intervention. As the boundary between the lesion and vital bone is indistinct, we recommend extensive surgery in cases with unpredictable sequestration.

Spontaneous Recovery of Pathological Fracture Caused by Medication-Related Osteonecrosis of the Jaw.

Pathological fracture is one of the most serious complications in medication-related osteonecrosis of the jaw (MRONJ). This case is a report of an 87-year-old woman who had been diagnosed with pathological fracture due to MRONJ. The authors performed minimally invasive and conservative treatment, such as intraoral dressing, antibiotic therapy, and simple debridement, for patients with pathologic fractures due to MRONJ. After 1 year, the inflammatory symptoms disappeared and pathological fractures spontaneously recovered.

Pre-existing medication-related osteonecrosis of the jaw before dental extraction.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event, most commonly associated with dental extractions as a predisposing event. However, it is possible that established MRONJ may be existent before dental extractions and is mistaken for odontogenic disease. The provision of a dental extraction will lead to clinically obvious MRONJ with the cause being attributed to tooth removal. We present a case series of ten patients with pre-existing necrosis of the jaw before dental extraction.Retrospective data were collected on ten patients who presented to the oral surgery department between 2017-2021, diagnosed with pre-existing necrosis. A diagnosis of pre-existing MRONJ was made based on the identification of necrotic bone clinically, either with plain film or cone beam computed tomography (CBCT). Patients with pre-existing necrosis presented with a range of symptoms, including pain, swelling and tooth mobility. Plain film imaging revealed a variety of findings, including periapical radiolucency, periodontal ligament widening and bone loss. CBCT imaging confirmed a necrotic pattern of bone destruction confirming a diagnosis of pre-existing MRONJ.There is increasing evidence to suggest that local inflammation can be a predisposing factor for MRONJ development as opposed to surgical intervention. This case series provides early insight into the presentation of pre-existing MRONJ.

How does the clinical and tomographic appearance of MRONJ influences its treatment prognosis?

OBJECTIVES: To identify clinical and tomographic prognostic factors for conservative and surgical treatment of medication-related osteonecrosis of the jaws (MRONJ). METHODS: A retrospective search identified patients treated with antiresorptive drugs (ARDs), diagnosed with Stage 1, 2 or 3 MRONJ, and having CBCT scans previous to conservative or surgical treatment. Following data collection, imaging assessment of the following parameters on each MRONJ site was performed: involvement of teeth and/or implants, presence of osteosclerosis, osteolysis, sequestrum formation, periosteal reaction, and pathological fractures. For statistical analysis, patients and lesions were divided into conservative and surgical treatment. Comparisons were made between successful and unsuccessful outcomes. Significance was set at p ≤ 0.05. RESULTS: 115 ARD-treated patients who developed 143 osteonecrosis lesions were selected. 40 patients and 58 lesions received conservative treatment, of which 14 patients (35%) and 25 lesions (43%) healed. Additionally, 75 patients and 85 lesions underwent surgery, with 48 patients (64%) and 55 lesions (65%) that healed. Clinical and tomographic risk factors for conservative treatment were MRONJ staging, tooth involvement, extensive osteosclerosis, and deep sequestrum formation (p < 0.05). Complementarily, poor prognostic indicators for surgical therapy were a short bisphosphonate (BP) holiday, MRONJ staging, absence of sequestrum formation, and presence of periosteal reaction (p < 0.05). CONCLUSIONS: Lesions at Stage 3 MRONJ, with tooth involvement, or sequestrum formation showed poor outcomes when conservative treatment is chosen. Alternatively, surgical treatment is most effective when BPs are discontinued, in Stage 1 lesions, in the presence of sequestrum formation, and absence of periosteal reaction.

Three-dimensional clinical assessment for MRONJ risk in oncologic patients following tooth extractions.

OBJECTIVES: To identify clinical and local radiographic predictors for medication-related osteonecrosis of the jaws (MRONJ) by the assessment of pre-operative CBCT images of oncologic patients treated with anti-resorptive drugs (ARDs) undergoing tooth extractions. METHODS: This retrospective, longitudinal, case-control study included clinical and imaging data of 97 patients, divided into study and control group. Patients in the study group (n = 47; 87 tooth extractions) had received at least one dose of ARD, undergone tooth extraction(s), and had a pre-operative CBCT. An age-, gender-, and tooth extraction-matched control group (n = 50; 106 tooth extractions) was selected. Three calibrated, blinded, and independent examiners evaluated each tooth extraction site. Statistical analysis used χ2/Fisher's exact/Mann-Whitney U test to contrast control and study group, ARD type used, and sites with or without MRONJ development. p-value ≤ 0.05 was considered significant. RESULTS: From the study group, 15 patients (32%) and 33 sites (38%) developed MRONJ after tooth extraction. When controls were compared to study sites, the latter showed significantly more thickening of the lamina dura, widened periodontal ligament space, osteosclerosis, osteolysis, and sequestrum formation. In the study group, MRONJ risk significantly increased in patients who had multiple tooth extractions, were smokers, and had shorter drug holidays. Periosteal reaction and sequestrum formation may indicate latent MRONJ lesions. Additionally, patients given bisphosphonates showed considerably more osteosclerosis than those given denosumab. CONCLUSIONS: Periosteal reaction and sequestrum formation are suspected to be pre-clinical MRONJ lesions. Furthermore, ARD induced bony changes and radiographic variations between ARD types were seen.

Osteonecrosis maxilar relacionada con la medicación: el papel del radiólogo / Medication-related osteonecrosis of the jaw: the radiologist's role

En las últimas décadas se ha descrito ampliamente y se ha llegado a conocer en profundidad un temido efecto adverso de los bisfosfonatos, la osteonecrosis maxilar, que consiste en la destrucción ósea de parte del hueso maxilar como consecuencia del consumo de estos fármacos antirresortivos. En los últimos años han salido a la luz nuevos fármacos que también pueden ocasionar osteonecrosis maxilar, como algunos anticuerpos monoclonales o fármacos antiangiogénicos. Es por esto por lo que el término de “osteonecrosis maxilar por bisfosfonatos” ha quedado obsoleto, prefiriéndose el término de “osteonecrosis maxilar relacionada con la medicación”. El objetivo de esta revisión es describir las características radiológicas de la osteonecrosis maxilar relacionada con la medicación que, aunque son inespecíficas, es importante que el radiólogo las reconozca en el marco clínico adecuado.(AU)

In recent decades, the dreaded adverse effect of bisphosphonates, osteonecrosis of the jaw, has been widely reported and described in detail. Osteonecrosis of the jaw consists of the destruction of part of the maxilla as a consequence of these antiresorptive drugs. In recent years, new drugs that can also cause osteonecrosis of the jaw (e.g., some monoclonal antibodies or antiangiogenic drugs) have come on the market. For this reason, the term “bisphosphonate-related osteonecrosis of the jaw” has been replaced with “medication-related osteonecrosis of the jaw (MRONJ). This review aims to describe the radiologic characteristics of MRONJ that, although nonspecific, radiologists need to recognize in the appropriate clinical context.(AU)

Medication-related osteonecrosis of the jaw using periodontitis-induced rat before tooth extraction.

OBJECTIVE: This study aimed to investigate the occurrence of medication-related osteonecrosis of the jaw (MRONJ) after tooth extraction due to periodontitis in ovariectomized rats. METHODS: Twenty-four osteoporosis-induced rats were administered with zoledronic acid (ZA; ZA group) or saline (CONT group). In both groups, tooth extraction was performed after inducing periodontitis, and all animals were sacrificed 8-week after tooth extraction. RESULTS: Micro-CT of the tibia showed that the bone volume fraction, bone surface density, trabecular number, and bone mineral density were significantly higher in the ZA group than in the CONT group. Histologically, the proliferative zone on the growth plate was thicker in the ZA group than in the CONT group. Micro-CT of the extraction sites revealed that the bone volume fraction was significantly higher in the ZA group than in the CONT group. Radiologically, the ZA group showed partial healing and delayed healing. Histological analysis revealed normal bone healing status with completely healed epithelium in the extraction sites of the CONT group, whereas abnormal empty osteocytes in the necrotic bone and inflammatory infiltration were observed in the ZA group. CONCLUSION: The incidence of MRONJ increased in the rats administered with ZA.

Medication-related osteonecrosis of the jaw without osteolysis on computed tomography: a retrospective and observational study.

Medication-related osteonecrosis of the jaw (MRONJ) is a refractory osteonecrosis caused by antiresorptive agents such as bisphosphonate and denosumab (DMB). In MRONJ surgery, computed tomography (CT) is generally used to determine the extent of bone resection. However, in some recent MRONJ cases, no abnormal findings were detected on CT. Therefore, we aimed to clarify the characteristics of MRONJ without osteolysis. This retrospective and observational study included 18 patients diagnosed with MRONJ between October 2020 and October 2022 at Department of Dentistry and Oral Surgery, Kansai Medical University Medical Center. In four of 18 patients with MRONJ, no abnormal findings such as osteolysis, separation of sequestrum, and periosteal reaction were observed on CT images at the first visit. All four patients with non-osteolytic MRONJ had malignant tumors and received high-dose DMB, and in the four patients there were no preceding dental infections such as apical lesions or periodontal disease and the trigger of MRONJ was unknown. Surgery was performed in three of the four patients. The extent of bone resection was determined using magnetic resonance imaging and intraoperative gross findings. In the future, it is necessary to establish a method for diagnosing non osteolytic MRONJ and determining the extent of bone resection.

Maximum and mean standardized uptake values of medication-related osteonecrosis of the jaw with bone SPECT/CT: comparison of mandibular pathologies, control and temporomandibular joints.

OBJECTIVE: Recently, single-photon emission CT/CT (SPECT/CT) plays an important role in assessing patients with medication-related osteonecrosis of the jaw (MRONJ). The aim of this study was to investigate maximum and mean standardized uptake values (SUVs) of MRONJ with bone SPECT/CT, especially comparison of mandibular pathologies, control and temporomandibular joints. METHODS: 61 mandibular patients with MRONJ who underwent bone SPECT/CT were included in this study. The maximum and mean SUVs of the lesion, right and left sides of the lesion, opposite side of the lesion as control, right and left temporomandibular joints were analyzed using a workstation and software. The SUVs of MRONJ were analyzed using one-way analysis of variance with Tukey's honestly significant difference test. Patient characteristics with MRONJ and SUVs were analyzed using Mann-Whitney U test. P-values less than 0.05 were considered to indicate statistical significance. RESULTS: The maximum and mean SUVs for opposite side of the lesions (4.4 ± 2.0 and 1.8 ± 0.7) were significantly lower than those for mandibular lesions (18.3 ± 8.1 and 6.3 ± 2.8), right side of the lesions (8.1 ± 3.9 and 2.9 ± 1.3) and left side of the lesions (8.1 ± 3.9 and 2.8 ± 1.4), respectively. The maximum and mean SUVs for right and left sides of the lesions, and opposite side of the lesions, right and left temporomandibular joints were not significant difference. Furthermore, the maximum SUVs of the mandibular lesions were a significant difference for age and staging. CONCLUSIONS: The maximum and mean SUVs with SPECT/CT can be useful in the quantitative management of MRONJ patients.

Radiologic findings of osteonecrosis, osteoradionecrosis, osteomyelitis and jaw metastatic disease with cone beam CT.

PURPOSE: The purpose of this study was to assess CBCT scans of patients with medication related osteonecrosis of the jaws (MRONJ), osteoradionecrosis (ORN), osteomyelitis (OM) and jaw metastatic disease (JM), evaluate the presence and extent of radiologic findings, identify radiologic parameters that may distinguish the four entities and last, introduce a new modified radiographic index (CRIm), in order to contribute to the diagnosis of these conditions. METHODS: Τwo major databases were retrospectively searched for fully documented and diagnosed CBCT scans of MRONJ, ORN, OM and JM from 2006 to 2019. 335 CBCT scans met the inclusion criteria and were assessed under standardized viewing conditions blindly by 2 observers. The CRIm index proposed in this study evaluates: lytic changes, sclerosis, periosteal bone formation, sequestration, non-healing extraction sockets and other findings which included: sinus implication, inferior alveolar canal implication and jaw fracture. Lytic changes, sclerosis, periosteal bone formation, sequestration and non-healing extraction sockets were scored as: absent (0), localized/single (1) and extensive/multiple (2). Each one of other findings were scored individually as: absent (0) and present (1). For statistical analysis t-test, Pearson's r correlation coefficient, one-way ANOVA and Bonferonni were performed. RESULTS: Extensive lytic changes were the most common finding, especially for ORN, where it occurred in all CBCT scans (100%). The mean value of the CRIm index differs significantly between CBCT scans with MRONJ and JM, as well as between those with OM and JM (Bonferroni p < 0.001). CONCLUSIONS: The new modified Composite Radiographic Index introduced in this study, appears to have improved an objective approach to the previously used Composite Radiographic Index by means of cumulative radiologic features. Τhe predominance of certain radiologic features in one or more of these entities may lead the diagnostician towards the correct diagnosis.

Treatment outcomes and time to healing of medication-related osteonecrosis of the jaw based on image findings.

OBJECTIVES: This study aimed to evaluate the prognostic treatment outcome of non-operative management of medication-related osteonecrosis of the jaw (MRONJ), particularly regarding the relationship between image findings and treatment outcomes. METHODS: This single-center, retrospective observational study included patients with MRONJ who were conservatively treated between 2010 and 2020. All patients were evaluated in terms of MRONJ treatment outcomes, time to healing, and prognostic factors, including sex, age, underlying disease, antiresorptive drug type, discontinuation of antiresorptive treatment, chemotherapy, corticosteroid treatment, diabetes mellitus, location of MRONJ, clinical stage of MRONJ, and computed tomography image findings. RESULTS: The complete healing rate among the patients was 68.5%. Cox proportional hazards regression analysis revealed that "Sequestrum formation" on the internal texture (hazard ratio = 3.66; 95% confidence interval, 1.30-10.29; P =.014) and chemotherapy (hazard ratio = 0.41; 95% confidence interval, 0.18-0.95; P =.037) were significantly associated with treatment outcome. The median time to healing in patients with "Sequestrum formation" on the internal texture (4.4 months) was significantly shorter than the median time to healing in those marked with "Sclerosis" or "Normal" (35.5 months; P <.001) and "Lytic changes with sclerosis" (14.5 months; P =.015). CONCLUSIONS: The image findings on the internal texture of the lesions at the initial examination and chemotherapy were associated with the treatment outcomes of nonoperative management of MRONJ. The image findings of "Sequestrum formation" were associated with lesions taking a short time to heal and better outcomes, whereas "Sclerosis" and "Normal" were associated with lesions with longer healing times.

Chronic Periodontal Infection and Not Iatrogenic Interference Is the Trigger of Medication-Related Osteonecrosis of the Jaw: Insights from a Large Animal Study (PerioBRONJ Pig Model).

Background and Objectives: Antiresorptive drugs are widely used in osteology and oncology. An important adverse effect of these drugs is medication-induced osteonecrosis of the jaw (MRONJ). There is scientific uncertainty about the underlying pathomechanism of MRONJ. A promising theory suspects infectious stimuli and local acidification with adverse effects on osteoclastic activity as crucial steps of MRONJ etiology. Clinical evidence showing a direct association between MRONJ and oral infections, such as periodontitis, without preceding surgical interventions is limited. Large animal models investigating the relationship between periodontitis and MRONJ have not been implemented. It is unclear whether the presence of infectious processes without surgical manipulation can trigger MRONJ. The following research question was formulated: is there a link between chronic oral infectious processes (periodontitis) and the occurrence of MRONJ in the absence of oral surgical procedures? Materials and Methods: A minipig large animal model for bisphosphonate-related ONJ (BRONJ) using 16 Göttingen minipigs divided into 2 groups (intervention/control) was designed and implemented. The intervention group included animals receiving i.v. bisphosphonates (zoledronate, n = 8, 0.05 mg/kg/week: ZOL group). The control group received no antiresorptive drug (n = 8: NON-ZOL group). Periodontitis lesions were induced by established procedures after 3 months of pretreatment (for the maxilla: the creation of an artificial gingival crevice and placement of a periodontal silk suture; for the mandible: the placement of a periodontal silk suture only). The outcomes were evaluated clinically and radiologically for 3 months postoperatively. After euthanasia a detailed histological evaluation was performed. Results: Periodontitis lesions could be induced successfully in all animals (both ZOL and NON-ZOL animals). MRONJ lesions of various stages developed around all periodontitis induction sites in the ZOL animals. The presence of MRONJ and periodontitis was proven clinically, radiologically and histologically. Conclusions: The results of this study provide further evidence that the infectious processes without prior dentoalveolar surgical interventions can trigger MRONJ. Therefore, iatrogenic disruption of the oral mucosa cannot be the decisive step in the pathogenesis of MRONJ.

Anti-angiogenic drug aggravates the degree of anti-resorptive drug-based medication-related osteonecrosis of the jaw by impairing the proliferation and migration function of gingival fibroblasts.

BACKGROUND: Long-term use of anti-resorptive or anti-angiogenic drugs in cancer patients with odontogenic infections may lead to medication-related osteonecrosis of the jaw (MRONJ). This study investigated whether anti-angiogenic agents aggravate MRONJ occurrence in anti-resorptive-treated patients. METHODS: The clinical stage and jawbone exposure of MRONJ patients caused by different drug regimens were analyzed to ascertain the aggravation effect of anti-angiogenic drugs on anti-resorptive drug-based MRONJ. Next, a periodontitis mice model was established, and tooth extraction was performed after administering anti-resorptive and/or anti-angiogenic drugs; the imaging and histological change of the extraction socket were observed. Moreover, the cell function of gingival fibroblasts was analyzed after the treatment with anti-resorptive and/or anti-angiogenic drugs in order to evaluate their effect on the gingival tissue healing of the extraction socket. RESULTS: Patients treated with anti-angiogenic and anti-resorptive drugs had an advanced clinical stage and a bigger proportion of necrotic jawbone exposure compared to patients treated with anti-resorptive drugs alone. In vivo study further indicated a greater loss of mucosa tissue coverage above the tooth extraction in mice treated with sunitinib (Suti) + zoledronate (Zole) group (7/10) vs. Zole group (3/10) and Suti group (1/10). Micro-computed tomography (CT) and histological data showed that the new bone formation in the extraction socket was lower in Suti + Zole and Zole groups vs. Suti and control groups. In vitro data showed that the anti-angiogenic drugs had a stronger inhibitory ability on the proliferation and migration function of gingival fibroblasts than anti-resorptive drugs, and the inhibitory effect was obviously enhanced after combining zoledronate and sunitinib. CONCLUSION: Our findings provided support for a synergistic contribution of anti-angiogenic drugs to anti-resorptive drugs-based MRONJ. Importantly, the present study revealed that anti-angiogenic drugs alone do not induce severe MRONJ but aggravate the degree of MRONJ via the enhanced inhibitory function of gingival fibroblasts based on anti-resorptive drugs.

Successful New Dental Implant Installation in a Healed Site of Medication-Related Osteonecrosis of the Jaw: A Case Report.

The purpose of this case report was to present a rare clinical case of successful new dental implant installation in the site of previously healed medication-related osteonecrosis of the jaw (MRONJ). An 80-year-old female patient with history of oral bisphosphonate (BP) therapy presented with pain and swelling of gingiva in the right posterior mandible. One of the 3 implants placed 15 years ago in the right mandibular posterior area was removed 6 months before the visit to our hospital, which led to worsening of the symptoms. After clinical and radiographic examination, the patient was diagnosed with stage 2 MRONJ. Along with antibiotic therapy, the patient underwent surgical intervention via sequestrectomy and removal of the remaining 2 implants. Adequate soft and hard tissue healing without any complications and signs of recurrence was confirmed, and implant installation with simultaneous bone grafting and prosthesis fabrication were done in the explantation sites of MRONJ. By the 7-year follow-up, no implant failure has been observed, and installation of implants was successful in the previously healed MRONJ site. Dental implant installation is possible in a patient with history of failed implant due to MRONJ. However, a careful treatment planning is needed before implantation in a previously healed site of MRONJ to reduce the potential risks of MRONJ recurrence and implant failure.

Involvement of Impaired Angiogenesis and Myelosuppression in Antiresorptive-agent Related Osteonecrosis of the Jaw Mouse Model.

OBJECTIVE: To explore the involvement of bone marrow cells and angiogenesis in the pathogenesis of antiresorptive agent-related osteonecrosis of the jaw (ARONJ). METHODS: We performed micro-computed tomography (CT) and histological analyses in an ARONJ mouse model generated using bisphosphonate (BP) and cyclophosphamide (CY). RESULTS: Micro-CT analysis showed that BP and CY inhibited osteoneogenesis in the extraction socket. Histological analysis at 3 days after tooth extraction showed inhibition of vascular endothelial cell and mesenchymal stem cell mobilization into the extraction socket. When neovascularization of the extraction fossa was observed from as early as 1 day after extraction, it occurred predominantly in the area adjacent to the extraction fossa and close to the bone marrow cavity. In addition, the extraction fossa communicated with the adjacent bone marrow via the vasculature. Histological evaluation of the alveolar bone marrow around the extraction socket showed a decrease in bone marrow cells in the BP + CY group. CONCLUSION: Both inhibition of angiogenesis and suppression of bone marrow cell mobilization are involved in the pathogenesis of ARONJ.