Comparison of quantitative radiomorphometric predictors of healthy and MRONJ-affected bone using panoramic radiography and cone-beam CT.

OBJECTIVES: To determine the most distinctive quantitative radiomorphometric parameter(s) for the detection of MRONJ-affected bone changes in panoramic radiography (PR) and cone-beam CT (CBCT). METHODS: PR and sagittal CBCT slices of 24 MRONJ patients and 22 healthy controls were used for the measurements of mandibular cortical thickness (MCT), fractal dimension (FD), lacunarity, mean gray value (MGV), bone area fraction (BA/TA), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular number (Tb.N). MCT was measured in the mental foramen region. While FD and lacunarity were measured on mandibular trabecular and cortical regions-of-interest (ROIs), the remaining parameters were measured on trabecular ROIs. The independent samples t-test was used to compare the measurements between the MRONJ and control groups for both imaging modalities (P = .05). RESULTS: MCT was the only parameter that differentiated MRONJ-affected bone in both PR and CBCT (P < .05). None of the remaining parameters revealed any difference for MRONJ-affected bone in CBCT (P > .05). FD, lacunarity, MGV, BA/TA, and Tb.Sp could distinguish MRONJ-affected trabecular bone in PR (P < .05). The correspondent ROI for both imaging methods that was reliable for detecting MRONJ-affected bone was the trabecular bone distal to the mental foramen above the inferior alveolar canal (ROI-3). CONCLUSIONS: MCT is a reliable parameter for the discrimination of MRONJ-affected bone in both PR and CBCT images. PR may be used to detect MRONJ-affected trabecular bone using FD, lacunarity, MGV, BA/TA, and Tb.Sp measurements as well.

Awareness, perceptions and attitudes toward medication-related osteonecrosis of the jaw among physicians who treat osteoporosis.

Osteoporosis is the most common indication for antiresorptive drugs (ARDs). Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of ARDs. Multiple risk factors can increase the risk of MRONJ, one of which is the duration of ARD intake, which is usually prolonged for osteoporosis cases. Prevention of MRONJ relies on collaborative care between treating physicians and dental practitioners. Therefore, knowledge about MRONJ and its prevention strategies is crucial for both teams. Aim: This study aimed to assess the knowledge and attitudes of physicians toward MRONJ in osteoporosis patients. Another aim was to develop recommendations for the prevention of MRONJ. Materials and methods: Through an online survey, basic information such as the practice location, training, knowledge, perceptions, and attitudes of physicians regarding ARDs and MRONJ in osteoporosis patients was collected. Statistical analysis was performed for all variables, and their correlations were explored. Results: A total of 221 physicians participated in the survey: 34.8% were rheumatologists, 25.3% were endocrinologists, 8.6% were family medicine physicians, 5.9% were orthopedists, and 5.9% were internal medicine physicians. Of them, 58.0% reported more than 6 years of experience. Only 78.7% were aware of MRONJ and recognized that bisphosphonates (BPs) can contribute to MRONJ. In contrast, 56.0% recognized denosumab as a causative factor for MRONJ. Duration of ARD therapy and pre- and post-ARD dental care were known to influence the risk of MRONJ by 62% and 65.6% of the participants, respectively. Only 41.6% and 31.2% of participants informed patients about MRONJ prior to BP and denosumab therapy, respectively. Only 25.3% and 20.8% referred patients to dentists before BP and denosumab therapy, respectively. Overall, 65.6% of the participants had a negative attitude toward MRONJ, and 34.4% had a positive attitude. A positive attitude was mostly observed among rheumatologists (55.8%) compared to other specialists (p <0.001). More years of experience were associated with a higher level of knowledge and positive attitude. Conclusion: The findings of this study identified a notable gap in the awareness, knowledge and attitudes of physicians regarding MRONJ in osteoporosis patients. Continuing education programs about ARDs and MRONJ risk are highly recommended.

Prognosis of medication-related osteonecrosis of the jaws in metastatic prostate cancer patients.

OBJECTIVES: The aim of this study was to find out the prognosis of medication-related osteonecrosis of the jaws (MRONJ) in prostate cancer patients who received two different types of antiresorptive agents for bone metastasis. MATERIALS AND METHODS: We retrospectively surveyed a cohort of 95 metastatic prostate cancer patients with 122 MRONJ lesions treated in a single medical center. Treatment outcomes and prognostic factors were investigated. The cumulative complete response rate was calculated with the Kaplan-Meier method, and significance was examined with the log-rank and Breslow tests. Cox regression was used for the univariate and multivariate analyses of prognostic factors. RESULTS: The cumulative complete response rate of all patients at 12 months was 37.8%, and that of patients treated with zoledronic acid and denosumab was 22.9% and 70.5%, respectively. Denosumab, pretreatment C-terminal telopeptide of collagen I (CTX) level > 150 pg/ml, and anemia were identified as independent prognostic factors in a multivariate analysis with adjusted hazard ratios of 3.18 (95% confidence interval [CI], 1.24-8.11), 3.24 (95% CI, 1.39-7.53), and 0.42 (95% CI, 0.19-0.93), respectively. CONCLUSION: A higher pretreatment level of CTX, using denosumab as the antiresorptive agent and without anemia, indicates a better treatment outcome of MRONJ in prostate cancer patients.

Osteonecrosis of the Jaws in Patients with Hereditary Thrombophilia/Hypofibrinolysis-From Pathophysiology to Therapeutic Implications.

Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone's venous outflow that occurs in individuals with hereditary thrombophilia and/or hypofibrinolysis has a less known impact on jaw health and healing capability. Our research provides the most comprehensive, up-to-date and systematized information on the prevalence and significance of hereditary thrombophilia and/or hypofibrinolysis states in ONJ. We found that hereditary prothrombotic abnormalities are common in patients with ONJ refractory to conventional medical and dental treatments. Thrombophilia traits usually coexist with hypofibrinolysis traits. We also found that frequently acquired prothrombotic abnormalities coexist with hereditary ones and enhance their negative effect on the bone. Therefore, we recommend a personalized therapeutic approach that addresses, in particular, the modifiable risk factors of ONJ. Patients will have clear benefits, as they will be relieved of persistent pain and repeated dental procedures.

Pain characteristics in medication-related osteonecrosis of the jaws.

PURPOSE: To characterise pain from medication-related osteonecrosis of the jaws (MRONJ) and the effects of antimicrobial treatment on it. METHODS: Data from files of patients diagnosed with MRONJ according to the position paper of the American Association of Oral and Maxillofacial Surgeons (2014) and Multinational Association of Supportive Care in Cancer and American Society of Clinical Oncology (2019) were collected retrospectively, including gender, age, primary disease, bone-modifying agents (BMAs)/anti-angiogenics, administration route, involved jaw, location, and exposure size. The patients were treated according to the abovementioned position papers' recommendations, i.e. all patients who suffered from pain were staged as 2 or 3 and treated with systemic amoxicillin, or doxycycline or clindamycin in case of sensitivity, and local antiseptic and hygiene instructions. RESULTS: Data from 77 MRONJ patients (aged 65.09 ± 11.9 years old) were analysed. Most (90.1%) received bisphosphonates for cancer (79%) and osteoporosis (17%). A total of 67.5% experienced pain; 36.5% had moderate-to-severe pain. Female gender was significantly associated with the presence of pain (p = 0.002). Osteonecrosis lesions after dento-alveolar surgery had a higher risk of pain development than spontaneous lesions (p = 0.045). Medical and oncologic background, type of pharmacotherapy, lesion size, and location were not associated with pain levels. Worse initial pain was significantly associated with better relief following MRONJ treatment (p = 0.045). Meaningful pain reduction (≥ 50%) was significantly correlated with initial pain severity (p = 0.0128, OR = 4.75). CONCLUSIONS: Pain from infection and inflammation often accompanies MRONJ. The presence of pain is correlated with longer BMAs pre-therapy and if surgery preceded the MRONJ. Persistency of the mild pain together with a resistance to common antimicrobial treatment, although not complete, is a feature that MRONJ pain shares with neuropathic-"like" pain, and requires further study and consideration during treatment.

Quality of life in cancer patients with or without medication-related osteonecrosis of the jaw.

PURPOSE: Cancer and its therapies can have a significant impact on general and oral health and, therefore, cause a reduction in patients' quality of life (QoL). The study aimed to evaluate the QoL of cancer patients who use antiresorptive and anti-angiogenic medications with or without the development of medication-related osteonecrosis of the jaws (MRONJ). METHODS: Sixty-two patients diagnosed with cancer under antiresorptive therapy answered three instruments from the European Organization for Cancer Research and Treatment (EORTC). The first questionnaire (QLQ-C30) aimed to measure the overall QoL, the second (QLQ-ELD14) is a complementary module for elderly patients, and the third (QLQ-OH15) aimed to assess oral health related to QoL. RESULTS: The mean age of the patients was 62.19 years, and 12.9% developed MRONJ. There was no significant difference between sex and MRONJ. Among the QLQ-C30 scales, the item "role functioning (RF2)" presented a significant result (p = 0.019). Those patients without MRONJ had a better function performance both in their daily chores and in their free time. Age was not associated to MRONJ, although some concerns are common to the elderly and cancer patients. QoL related to oral health presented a significant result (p = 0.048) showing that MRONJ has a negative impact on patients' QoL. CONCLUSION: Our results showed that MRONJ has a significant impact on the general and oral QoL of cancer patients, and therefore prevention and awareness must be a priority.

Prognosis of medication-related osteonecrosis of the jaws in cancer patients using antiresorptive agent zoledronic acid.

BACKGROUND/PURPOSE: Anti-resorptive agents are commonly used in cancer patients with bone metastasis or multiple myeloma (MM). An adverse event termed medication-related osteonecrosis of the jaws (MRONJ) was discovered in patients using these agents but relatively little attention has been paid to its prognosis. Our aims were to find out the treatment outcomes and prognostic indicators of MRONJ in cancer patients who received zoledronic acid as antiresorptive therapy. METHODS: We retrospectively surveyed a cohort of 133 cancer patients who received zoledronic acid. A total of 150 MRONJ lesions were included for investigation. Cumulative complete response rate after treatment was calculated with the Kaplan-Meier method, and significance was examined with the log-rank tests. Cox regression was used for univariate and multivariate analyses of prognostic factors. RESULTS: The cumulative complete response rate of all patients at 24 months was 53.2%, and those of patients with MM, breast cancer and prostate cancer were 27.8%, 60.7% and 68.0%, respectively. Having MM was identified as an independent prognostic factor in a multivariate analysis with adjusted hazard ratios of 0.28 (95% confidence interval, 0.09-0.83). CONCLUSION: For cancer patients with ONJ related to zoledronic acid, patients with MM endure a worse treatment outcome.

Medication-related osteonecrosis of the jaw (MRONJ) and eNOS Polymorphisms in multiple myeloma patients: a single center experience.

BACKGROUND: Multiple myeloma (MM) constitutes approximately 10% of hematological malignancies. Bisphosphonates have established themselves in solid organ metastasis and multiple myeloma lytic bone lesions by inhibiting osteoclast activation. Medication-related osteonecrosis of the jaw (MRONJ) emerges as an important complication. Investigating host-based factors, and developing personal risk factors gain importance in the development mechanism of MRONJ. We aimed to reveal the different genotype polymorphisms, and clinical effects of eNOS in patients with a diagnosis of MRONJ in MM patients. METHODS: Medical records and blood samples were collected from 60 MRONJ patients with MM and 60 healthy controls. Inclusion criteria was having an exposed maxillofacial bone for more than eight weeks, a history of bisphosphonates, and no history of radiation therapy for the jaws. eNOS G894T and intron 4 VNTR were calculated by polymerase chain reaction and/or restriction fragment length polymorphism. RESULTS: eNOS G894T and VNTR genotypes and alleles were compared statistically with the healthy control group. There was no significant difference between the two groups. In comparison between G894T and clinical parameters, aphthous stomatitis was more common in TT genotype, while DMFT > 3 was more common in TG-GG genotype (p = 0.035, 0.023). CONCLUSIONS: eNOS induces osteogenesis in bone metabolism, with its regulatory effects on bone remodeling and also NO induced angiogenesis takes place indirectly with its protective effect on endothelial functions. We see that these polymorphisms affecting the entire process of bone remodeling and angiogenesis, especially mucosal damage, which is the triggering factor of MRONJ pathology, have been revealed in the MM patient group. Considering the MRONJ initiating factors, it is necessary to emphasize the importance of our study results. It should be seen as an important step for new studies towards MRONJ and its treatment.

Complementarity of Photo-Biomodulation, Surgical Treatment, and Antibiotherapy for Medication-Related Osteonecrosis of the Jaws (MRONJ).

Background and Objectives: Antiresorptive or anti-angiogenic agents may induce medication-related osteonecrosis of the jaws (MRONJ), which represents a challenge for clinicians. The aim of this study is to design and apply a composed and stage-approach therapy combining antibiotherapy, surgical treatment, and photo-biomodulation (PBM) for the prevention or treatment of MRONJ lesions. Materials and Methods: The proposed treatment protocol was carried out in the Department of Oral & Maxillofacial Surgery of the "Victor Babes" University of Medicine and Farmacy of Timisoara, in 2018-2020. A total of 241 patients who were previously exposed to antiresorptive or anti-angiogenic therapy, as well as patients already diagnosed with MRONJ at different stages of the disease were treated. A preventive protocol was applied for patients in an "at risk" stage. Patients in more advanced stages received a complex treatment. Results: The healing proved to be complete, with spontaneous bone coverage in all the n = 84 cases placed in an "at risk" stage. For the n = 49 patients belonging to stage 0, pain reductions and decreases of mucosal inflammations were also obtained in all cases. For the n = 108 patients proposed for surgery (i.e., in stages 1, 2, or 3 of MRONJ), a total healing rate of 91.66% was obtained after the first surgery, while considering the downscaling to stage 1 as a treatment "success", only one "failure" was reported. This brings the overall "success" rate to 96.68% for a complete healing, and to 99.59% when downscaling to stage 1 is included in the healing rate. Conclusions: Therefore, the clinical outcome of the present study indicates that patients with MRONJ in almost all stages of the disease can benefit from such a proposed association of methods, with superior clinical results compared to classical therapies.

Medication-related osteonecrosis and osteoradionecrosis of the jaws: Update and current management.

Medication related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis of the jaws (ORNJ) are two different diseases of quite similar appearance. MRONJ is mainly due to antiresorptive or antiangiogenic drug therapy and ORNJ to radiotherapy. The present work aimed at presenting and comparing the current knowledge on MRONJ and ORNJ. They both present as an exposure of necrotic bone and differ in some clinical or radiological characteristics, clinical course and mostly in treatment. They share similar risk factors. A tooth extraction is more frequently found as a triggering factor in MRONJ. The frequency of a maxillary localisation seems higher for MRONJ. On computed tomographic images, a periosteal reaction seems characteristic of MRONJ. More frequent pathological fractures seem to occur in ORNJ. It is mandatory, for ORNJ diagnosis, to exclude a residual or recurrent tumour using histological examination. Both MRONJ and ORNJ are challenging to treat and cannot be managed similarly. For both, it would still be worth to optimise awareness within the medical community, patients' oral hygiene and dental cares to improve their prevention and make their incidences decrease. Conservative therapy is more frequently achieved for MRONJ than ORNJ and surgical resection is more often performed for ORNJ. For both diseases, the last treatment possible in refractory cases is a surgical extensive resection with free flap reconstruction. A MRONJ classification is widely used today, whereas no consensus exists to date for ORNJ classification. We propose a classification that could play this role.

Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw.

Treatment strategies of medication-related osteonecrosis of the jaw (MRONJ) are controversial. Recently, surgical treatment has been reported as superior to nonsurgical treatment, but the contribution discontinued antiresorptive agent use during MRONJ treatment remains unclear. This study aimed to evaluate the efficacy of drug holidays and treatment strategies in MRONJ cases. Four-hundred and twenty-seven patients with MRONJ treated at nine hospitals from 2009 to 2017 were included in this multicenter retrospective study. Multivariate Cox regression analysis showed that the primary disease (osteoporosis or malignant tumor), diabetes, serum albumin, and treatment method (surgical or nonsurgical) were significantly correlated with the cure rate. The cumulative 1-year cure rates in the surgical and nonsurgical treatment groups were 64.7% and 18.2%, respectively. However, discontinuing antiresorptive agents did not influence the treatment outcome in the cohort overall, or in 230 patients after performing propensity score matching among the discontinuation and continuation groups. When stratifying by treatment method, antiresorptive agent discontinuation significantly increased the cure rate in patients with osteoporosis who underwent nonsurgical treatment. In patients with malignant tumors undergoing nonsurgical therapy, discontinuing the antiresorptive agent was associated with a better treatment outcome, but not with statistical significance. In contrast, drug holidays showed no effect on improving outcomes in patients with both osteoporosis and malignant tumors who underwent surgical therapy. Thus, regardless of the primary disease, discontinuing antiresorptive agents during treatment for MRONJ may not be necessary and may be helpful in some cases. Future prospective trials should examine this question further.

Changes in peripheral monocyte populations 48-72 hours after subcutaneous denosumab administration in women with osteoporosis.

OBJECTIVES: To examine the effect of denosumab administration in the peripheral blood white cell population, to further elucidate a plausible pathophysiological link between denosumab and osteonecrosis of the jaw. METHODS: Thirty women with osteoporosis, after denosumab treatment were included. Peripheral blood samples were obtained prior to and 48-72 hours following denosumab administration. Flow cytometry gated at the monocyte population for CD14/CD23/CD123/CD16 stainings were performed. RESULTS: We were able to record a number of changes in the monocyte populations between baseline and after denosumab administration. Most importantly, in the monocyte populations we were able to detect statistically significant increased populations of CD14+/CD23+ (p=0.044), CD14-/CD23+ (p=0.044), CD14+/CD123+ (p=0.011), CD14+/CD123- (p=0.011) and CD14-/CD16+ (p=0.028). In contrast, statistically significant decreased populations of CD14-/CD123+ (p=0.034), CD14+/CD16+ (p=0.037) and CD14+/CD16- (p=0.014) were detected. CONCLUSIONS: Our results provide evidence supporting the hypothesis that denosumab administration modifies the monocyte mediated immune response in a manner similar to that of bisphosphonates. This may partly explain the trivial immunity changes recorded with denosumab.

Clinical significance of periosteal reaction as a predictive factor for treatment outcome of medication-related osteonecrosis of the jaw.

Regarding treatment strategies for medication-related osteonecrosis of the jaw (MRONJ), surgical therapy has recently been reported to be more effective than conservative therapy. However, some patients did not achieve complete healing, even when extensive surgery was performed. Periosteal reaction in MRONJ patients is often observed by the CT examination. Tssshe purpose of this study was to investigate the relationship between periosteal reaction and treatment outcome of MRONJ. A total of 164 surgeries in 136 patients with MRONJ at two hospitals were included in the study. Correlations between various clinical and radiographic factors and treatment outcome were examined with Cox regression analysis. The results showed that the presence of periosteal reaction, as well as primary disease involving malignant tumor, were independent risk factors related to poor outcome. Furthermore, we examined factors related to the occurrence of the periosteal reaction and found that 4 variables were significantly correlated with periosteal reaction by multivariate analysis: gender (female), site (lower jaw), primary disease (malignant tumor), and osteosclerosis (severe). The present study clarified that the cure rate after surgical treatment decreased in cases with periosteal reaction, suggesting that it is necessary to review the treatment method.

Microbial diversity in infections of patients with medication-related osteonecrosis of the jaw.

OBJECTIVES: A central role of infections in the treatment of MRONJ patients is widely accepted. An investigation of the MRONJ lesions' biofilms as potential pathogens seems logical. MATERIALS AND METHODS: We investigated the clinical data of our MRONJ patients who received surgery in advanced stage of the disease. Special attention was granted to the local colonizers harvested from osseous MRONJ specimens and submucosal putrid infections. RESULTS: Eleven out of 71 patients presented a spontaneous onset of the disease and for 60 out of 71 patients a trigger was detected. Breast cancer (29.6%) and prostate cancer (22.5%) were the most frequent underlying disease for prescription of an antiresorptive therapy, mostly zoledronate. Submucosal soft tissue biofilms significantly differed from biofilms harvested from the MRONJ lesions bottom, yet the most frequent bacteria were equally present in both groups: Streptococcus species (spp.), Prevotella spp., Actinomyces spp., Veillonella spp., and Parvimonas micra. The cephalosporins, cefuroxime and cefotaxime, and ß-lactam antibiotics with ß-lactamase inhibitor revealed the greatest susceptibility for the detected bacteria. CONCLUSION: The bacteria from the submucosal areas and the bottom of the infected bone presented comparable susceptibility to the common antibiotics regimes. Streptococcus spp., Prevotella spp., and Veillonella spp. present a high abundance in MRONJ lesions beside Actinomyces spp. The MRONJ lesions bottom is in many cases not infected by Actinomyces spp. CLINICAL RELEVANCE: The removal of the necrotic bone reduces the variety of bacteria found in MRONJ lesions, in particular at the bottom of the lesion.

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study.

OBJECTIVE: This study was intended to investigate the effects of icariin on the healing of tooth extraction sites under the systemic administration of zoledronic and dexamethasone. METHOD: Thirty female rats underwent bilateral ovariectomy and were randomly assigned to 5 groups: SS group received a weekly injection of saline, while ZD, ZD + LICA, ZD + MICA, and ZD + HICA groups received zoledronic with dexamethasone for 8 weeks. One week later, mandibular first molars were extracted in all groups. Then, 30, 60, and 120 mg/kg icariin were intragastrically given to ZD + LICA, ZD + MICA, and ZD + HICA groups daily for 10 weeks, while saline was given to SS group and ZD group. Blood samples and mandibles were harvested for examinations after 10 weeks. RESULTS: Significantly smaller wound area was noted in SS and ZD + HICA groups, but the incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) was not significantly different. Groups injected with zoledronic and dexamethasone had higher C-terminal cross-linked telopeptide of type 1 collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP 5b), and the number of osteoclast cells, with less vascular endothelial growth factor (VEGF) and osteocalcin (OCN). In contrast, CTX-1, TRACP 5b, and the number of osteoclast cells declined after using icariin and promoted VEGF and OCN were noted and the effects were in a dosage-dependent manner. CONCLUSION: Concurrent use of zoledronic and dexamethasone inhibits the expression of VEGF, OCN, and wound healing and increases the number of osteoclast cells, serum CTX-1, and TRACP-5b after discontinuation for 10 weeks. Icariin weakens those effects in a dose-dependent manner but does not influence the onset of BRONJ.

The effect of antiresorptive drugs on implant therapy: Systematic review and meta-analysis.

OBJECTIVES: A considerable portion of the adult population has received and/or is receiving treatment with antiresorptive drugs (ARDs). It is thus relevant to assess possible side effects of ARD intake in connection to various aspects of implant therapy. The aim of this study was to answer the focused question "In patients with systemic intake of ARDs, what is the outcome and complication rate of implant therapy including associated bone grafting procedures comparing to patients without systemic intake of ARDs?" MATERIALS AND METHODS: Original studies fulfilled predefined inclusion criteria (e.g., case series, cohort studies, case-control studies, and controlled and/or randomized controlled clinical trials; retro- or prospective design; and ≥10 patients with systemic intake of ARDs). Various patient-, medication-, and intervention-related parameters [i.e., implant loss, grafting procedure complication/failure, peri-implant marginal bone levels/loss, medication-related osteonecrosis of the jaws (MRONJ), and peri-implantitis] were extracted, and meta-analyses and quality assessment were performed. RESULTS: Twenty-four studies with bisphosphonate (BP) intake (mainly low dose for osteoporosis treatment) and seven studies on hormone replacement therapy (HRT), including ≥10 patients, and controls not taking the medication were identified. Furthermore, seven studies on MRONJ associated with implants were included. Meta-analyses based on four studies reporting on patient level and eight studies reporting on implant level showed no significant differences in terms of implant loss between patients on BPs (mainly low dose for osteoporosis treatment) and controls. Furthermore, low-dose BP intake did not compromise peri-implant marginal bone levels. Based on two studies, no negative effect of HRT was observed on the implant level, while HRT appeared to exert a marginally significant negative effect regarding implant survival on the patient level and regarding peri-implant marginal bone levels. Based on six studies reporting single-patient data, MRONJ in patients on BP for osteoporosis appeared in 70% of the cases >36 months after start of drug intake, while in patients with cancer, MRONJ appeared in 64% of the cases ≤36 months after first BP intake. CONCLUSION: Low-dose oral BP intake for osteoporosis treatment, in general, does not compromise implant therapy, that is, patients on ARDs do not lose more implants nor get more implant-related complications/failures comparing to implant patients without BP intake. There is almost no information available on the possible effect on implant therapy of high-dose BPs or other widely used ARDs (e.g., denosumab), or on the success or safety of bone grafting procedures. Patients with high-dose ARD intake for management of malignancies, patients on oral BP over a longer period of time, and patients with comorbidities should be considered as high-risk patients for MRONJ.

Drugs and diseases: Summary and consensus statements of group 1. The 5th EAO Consensus Conference 2018.

OBJECTIVES: The task of this working group was to update the knowledge about the use of drugs and biologicals affecting healing of soft tissue and bone during implant treatment or procedures associated with it. Moreover, the impact of titanium particles and biocorrosion on complications and implant survival has been analysed. MATERIALS AND METHODS: The literature in the areas of interest (platelet concentrates, antiresorptive drugs as well as implant-host interaction) was screened using systematic reviews for the former two areas, whereas a narrative critical review was performed for the latter topic. Two manuscripts on platelet concentrates, one manuscript on antiresorptive drugs and one manuscript on the effects of biocorrosion, were presented for group analysis with subsequent discussion in the plenum and final consensus approval. RESULTS: Results and conclusions of the individual reviews of the three topics are presented in the respective papers. Conclusions of the group on strengths and weaknesses of available evidence as well as consensus statements and directions for further research are provided in this study. The following papers were subject to group discussions and formed the basis for the consensus statements: Stähli A, Strauss FJ, Gruber R. () The use of platelet-rich-plasma to enhance the outcomes of implant-related therapies: a systematic review Strauss FJ, Stähli A, Gruber R. (2018) The use of platelet-rich-fibrin to enhance the outcomes of implant-related therapies: a systematic review Mombelli A, Hashim D, Cionca N. () What is the impact of titanium particles and bio-corrosion on implant survival and complications? A critical review Stavropoulos A, Bertl K, Pietschmann P, Pandis N, Morten Schiødt, Klinge B. () The effect of antiresorptive drugs on implant therapy: a systematic review.

Issues with the surgical treatment of antiresorptive agent-related osteonecrosis of the jaws.

Antiresorptive agent-related osteonecrosis of the jaw is a rare but significant complication in patients using antiresorptive agents such as bisphosphonates and denosumab. Although the disease is well recognized, and many studies have been performed on the management of this condition, the treatment of severe osteonecrosis is still a challenge. Most recent studies have shown an advantage of surgical treatment over conservative treatment for stage 2/3 patients, but there is no consensus on the appropriate surgical procedures for antiresorptive agent-related osteonecrosis of the jaw. Furthermore, patients with severe systemic conditions may not be appropriate for extensive surgical treatment, and the treatment protocol for such patients has not been established. In this review, issues regarding the current surgical treatment for antiresorptive agent-related osteonecrosis of the jaws are discussed, with an emphasis on the clinical aspects.

Medication-related osteonecrosis of the jaw: Surgical or non-surgical treatment?

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (bisphosphonates and denosumab) and anti-angiogenic therapy used in the management of oncologic and, less frequently, osteoporotic patients. While there is good international agreement on the diagnostic and staging criteria of MRONJ and the cessation of antiresorptive/anti-angiogenic treatments, the gold standard of treatment is still controversial, in particular between non-surgical and surgical approaches. The former usually includes antiseptic mouth rinse, cyclic antibiotic therapy, low-level laser therapy and periodic dental checks; the latter consists of surgical necrotic bone removal. The purpose of this retrospective study was to describe the therapeutic approaches and outcomes of 131 lesions from 106 MRONJ patients treated at the Policlinic of Bari. Non-surgical treatments were chosen for 24 lesions that occurred in 21 patients who, due to comorbidities and/or the impossibility of stopping oncologic therapies, could not undergo surgical treatment. As to the outcome, all the surgically treated lesions (107) showed complete healing, with the exception of 13.5% of the lesions, all of which were stage III, which did not completely heal but showed reduction to stage I. The 24 non-surgically treated lesions never completely healed and, rather, generally remained stable. Only two cases exhibited a reduction in staging. Based on our observations, MRONJ occurring both in neoplastic and non-neoplastic patients benefits more from a surgical treatment approach, whenever deemed possible, as non-surgical treatments do not seem to allow complete healing of the lesions.

Increased CD14+ and decreased CD14- populations of monocytes 48 h after zolendronic acid infusion in breast cancer patients.

It has been proposed that bisphosphonates cause osteonecrosis of the jaws through impairment of the monocyte population function and proliferation. Such changes have been confirmed in jaw tissues, ex vivo. In this clinical study, we report for the first time a similar pattern of changes in peripheral blood monocytes. INTRODUCTION: The aim of this study is to examine the effect of zolendronic acid administration in the peripheral blood white cell population, seeking a plausible pathophysiological link between bisphosphonates and osteonecrosis of the jaw. METHODS: Twenty-four breast cancer patients, under zolendronic acid treatment for bone metastasis, were included. Peripheral blood samples were obtained prior to and 48 h following zolendronic acid administration. Flow cytometry gated at leukocyte, monocyte, and the granulocyte populations for the CD4/CD8/CD3, CD3/CD16+56/CD45/CD19, CD14/CD123, and CD14/23 stainings were performed. RESULTS: We were able to record a number of changes in the white cell populations after 48 h of zolendronic acid administration. Most importantly, in the monocyte populations, we were able to detect statistically significant increased populations of CD14+/CD23+ (p = 0.038), CD14+/CD23- (p = 0.028), CD14+/CD123+ (p = 0.070, trend), and CD14+/CD123- (p = 0.043). In contrast, statistically significant decreased populations of CD14-/CD23+ (p = 0.037) and CD14-/CD123+ (p = 0.003) were detected. CONCLUSIONS: Our results provide evidence supporting the hypothesis that bisphosphonate administration modifies the monocyte-mediated immune response. An increase of CD14+ peripheral blood monocyte (PBMC) populations along with a decrease of CD14- PBMC populations has been recorded. The latter finding is in accordance with limited-currently existing-evidence and warrants further elucidation.