Search Results (144)

Background and Objectives: We wished to evaluate the effect of antiresorptive agents (ARAs) on peri-implant tissues and to examine the risk factors for peri-implant medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods: The study cohort consisted of patients who underwent implant surgery or maintenance treatment between March 2012 and December 2024. The patients were divided into two groups: those in whom bisphosphonates (BPs) or denosumab (Dmab) was used to treat osteoporosis after implant treatment (the ARA group) and a control group. Peri-implant clinical parameters (implant probing depth (iPPD), implant bleeding on probing (iBoP), marginal bone loss (MBL), and mandibular cortical index (MCI)) measured at the baseline and at the final visit were statistically evaluated and compared in both groups. Risk factors were examined using a multivariate analysis of adjusted odds ratios (aORs). Results: A total of 192 implants in 61 patients (52 female, 9 male) were included in this study. The ARA group consisted of 89 implants (22 patients). A comparison of the clinical parameters showed that the ARA group had significantly higher variations in their maximum iPPD and iBoP values over time than those in the control group. Risk factors for peri-implantitis as objective variables were the use of ARAs (aOR: 3.91; 95% confidence interval [CI]: 1.29–11.9) and the change in the maximum iPPD over time (aOR: 1.86; 95% CI: 0.754–4.58). Conclusions: During long-term implant maintenance treatment, patients’ health and medication status change. Monitoring peri-implantitis, the presumed cause of peri-implant MRONJ, is essential, especially in patients who started ARA treatment after implant placement, and special attention should be paid to changes in implant pocket depth. Full article

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic mammalian target of rapamycin complex 1 (mTORC1). These complexes detect levels of various cellular nutrients, including glucose at the lysosome, and promote cellular responses to restore homeostasis. The high-glucose conditions of diabetes foster anabolic mTORC1 signaling that increases inflammation and inflammatory bone resorption in response to periodontal infections. Here, we review the structure and composition of V-ATPase, L-AMPK, mTORC1, and other elements of the energy-sensing platform. Mechanisms by which V-ATPase passes signals to the complexes are examined and recent data are reviewed. Current anti-bone resorptive therapeutics, bisphosphonates and denosumab, enhance the risk of medicine-related osteonecrosis of the jaw (MRONJ) and are not used to treat periodontal bone loss. Accumulating data suggest that it may be possible to target inflammatory bone resorption through agents that stimulate L-AMPK, including metformin and glucagon-like peptide-1 agonists. This approach may reduce inflammatory bone resorption without major effects on overall bone remodeling or increased risk of MRONJ. Full article

Background and Objectives: Bisphosphonates (BP) like zoledronic acid (ZA) and alendronic acid (AA) are used for osteoporosis (OP) or other bone-related conditions as well as to prevent the spread of metastases and in rheumatoid arthritis treatment. However, they have been associated with an increased risk of osteonecrosis of the jaw (ONJ). This systematic review aimed to assess the incidence and risk of ONJ in osteoporotic patients treated with ZA or AA and evaluate the impact of treatment duration. Material and Methods: The systematic literature review was conducted following PRISMA guidelines. The keywords “Zoledronic acid,” “Alendronic acid,” “Osteoporosis,” and “Osteonecrosis” were searched in PubMed and ScienceDirect databases. Selection criteria included studies on humans written in English, published from 2014. The systematic review protocol was registered in the PROSPERO register under the following number: CRD42024587046. Results: A total of 7 studies with 98,717 osteoporotic patients met the criteria, showing a higher ONJ incidence with ZA than AA. Six studies linked longer BP use to increased ONJ risk, which quadrupled after 5 years of AA use. A positive correlation was found between BP use (≥3 years) and ONJ in OP patients, primarily affecting females over 60. ONJ appeared after 1 year with AA, increasing over time, while ZA-related ONJ emerged as early as 5 months with a higher overall incidence. Conclusions: ZA poses a higher ONJ risk and incidence and earlier onset than AA, occurring within 5 months versus 1 year for AA. These findings emphasize the need for careful monitoring, especially in long-term BP therapy with additional risk factors. Full article

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a severe complication associated with bisphosphonate therapy commonly used in patients with osteoporosis and malignancies. Methods: This retrospective study evaluates the risk factors and clinical outcomes of BRONJ patients treated at the Oral and Maxillofacial Surgery Clinic in Iaşi, Romania, with the goal of optimizing preventive and therapeutic strategies. Data from 72 BRONJ patients treated between January 2013 and December 2023 were analyzed. Results: The majority (83.3%) of patients had underlying malignancies, predominantly breast and prostate cancers. The mandible was most affected, with tooth extraction identified as the primary triggering event. Systemic comorbidities, notably arterial hypertension, diabetes mellitus, and concurrent chemotherapy, were significantly associated with increased BRONJ severity. Surgical intervention was frequently required, with sequestrectomy being the predominant procedure, reflecting advanced disease at the time of diagnosis. Conclusions: The findings underline the critical importance of early identification, preventive dental management, and a collaborative multidisciplinary approach to improve patient prognosis. Full article

Background: Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a severe complication associated with bisphosphonate therapy, commonly used in the treatment of osteoporosis and metastatic bone diseases. Low-Level Laser Therapy (LLLT) has been proposed as a potential treatment modality for BRONJ, with its anti-inflammatory, analgesic, and regenerative effects being of particular interest. This systematic review aims to critically assess the current evidence regarding the efficacy of LLLT in the management of BRONJ. Methods: This review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of electronic databases, including PubMed, Scopus, and Web of Science, was performed to identify relevant studies published up to September 2024. The systematic review protocol has been registered on the International Prospective Register of Systematic Reviews (PROSPERO) with the number 423003. All studies considered are observational. Studies were included if they investigated the application of LLLT in BRONJ treatment, reporting clinical outcomes such as pain reduction, lesion healing, and quality of life. The quality of the studies was assessed using the Cochrane Risk of Bias tool, and the data were synthesized descriptively. Results: A total of four studies met the inclusion criteria. The findings indicate that LLLT, particularly when used in conjunction with surgical debridement and pharmacological therapy, significantly may reduce pain and promote soft tissue healing in patients with BRONJ. However, the heterogeneity of study designs, laser parameters, and outcome measures limits the generalizability of these results. Furthermore, most studies were small-scale, with moderate to high risk of bias. Conclusions: The current evidence suggests that LLLT may be a beneficial adjunctive therapy in the treatment of BRONJ. However, conclusions are limited by the lack of randomized controlled trials and methodological heterogeneity, particularly for pain management and soft tissue regeneration. However, further high-quality randomized controlled trials with standardized laser protocols are necessary to establish its efficacy and optimize clinical application. Therefore, one of the limitations of this literature review with meta-analysis is that only four studies were considered and, moreover, they were observational. The results of the meta-analysis showed that there is not enough evidence to declare a statistical correlation; this result will surely be due to the small number of studies and heterogeneity. Full article

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the side effects of bisphosphonate (BP) administration. Despite some preventive measures having been suggested, a definitive and effective treatment strategy for BRONJ remains to be established. Recent evidence has indicated that BPs dramatically impair the function of orofacial bone marrow stromal cells (BMSCs), which may contribute to the development of osteonecrosis. Thus, we hypothesized that recovery-impaired function of BMSCs at lesion sites could be beneficial in treating BRONJ. N6-methyladenosine (m6A) modification is the most common epigenetic modification and has been demonstrated to play a vital role in the modulation of BMSCs’ function. We detected the role of m6A modification in regulating the function of orofacial BMSCs under BP stimulation, and found that BPs led to a reduction in the global m6A methylation level, SAM level, and METTL3 expression in BMSCs during the osteogenic differentiation period. Meanwhile, betaine, a methyl group donor, effectively reversed the BP-decreased global m6A methylation level and SAM level in BMSCs, as well as rescuing the differentiation ability of impaired BMSCs. In the last part, we built a BRONJ rat model and supplemented rats with betaine via drinking water. The results showed that betaine successfully attenuated bone lesions and promoted wound healing in BP-injected rats, thereby providing new insight into future clinical treatment for BRONJ. Full article

Background: In 2020, the definition of Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) was revised. The current definition is Medication-Related Osteonecrosis of the Jaws (MRONJ), to underline the fact that not only bisphosphonates are implicated in the onset of the disease. This study aims to investigate the efficacy of marginal resection using a piezoelectric device in patients with BRONJ. Methods: A retrospective study was conducted on subjects treated at the Dental Clinic University Hospital of Padua (Italy) from January 2017 to April 2024. Only patients diagnosed with BRONJ stages 1 and 2, who underwent marginal resection of the maxillae using a piezoelectric instrument were included. Patients who had received radiotherapy to the head and neck region, those with MRONJ, and those with primary tumors of the maxillary bones were excluded. Marginal resection was considered an effective treatment when complete epithelialization of the surgical site was achieved, with no signs or symptoms of disease, and the condition remained stable one-year post-operation. Results: In total, 21 patients (17 females and 4 males) were selected. A single resection was performed for each patient, resulting in a total of 21 surgeries: 14 in the mandible and 7 in the maxilla. At one-year post-surgery, 20 patients showed no signs or symptoms of the disease. One patient experienced two recurrences, both of which were subsequently treated. Conclusions: marginal resection using a piezoelectric device is an effective procedure for the treatment of BRONJ, although it remains a relatively invasive and destructive therapeutic approach. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition often associated with bisphosphonate use, leading to impaired bone healing and difficult clinical management. Given the lack of predictable therapeutic options, this study investigated the effects of systemic ozone therapy on MRONJ healing. This study aimed to analyze the effects of systemic ozone therapy on oral hard and soft tissue healing in senescent rats with medication-related osteonecrosis of the jaw (MRONJ) induced by antiresorptive therapy. Methods: Twenty-eight senescent Wistar rats, aged eighteen months and weighing ~350 g, were used for this study. The animals were divided into four groups. The negative control (SAL) group received saline applications, while the control-treated (SAL+OZ) group received saline applications and ozone therapy (0.7 mg/kg). The MRONJ (ZOL) group received Zoledronate, an intravenous antiresorptive drug (100 μg/kg), and the MRONJ-treated (ZOL+OZ) group received zoledronate application and was treated with systemic ozone therapy (0.7 mg/kg). All rats underwent molar extraction in the third week of the experiment and were euthanized in the seventh week of the experiment. The mandibles were resected, reduced, and prepared for microtomographic analysis, histopathological/histometric analysis, and immunohistochemistry. Results: The ZOL group presented characteristics of vitreous, non-vital, and dense bone, poor vascularization, and high values of inflammation markers compatible with MRONJ. In contrast, the ZOL+OZ group exhibited improvement in alveolar bone and soft tissue healing, a decrease in nonvital bone area, and modulation of local inflammation. Conclusions: It can be concluded that Ozone therapy improved oral hard and soft tissue healing of MRONJ in senescent female rats subjected to antiresorptive drugs and might be considered for future clinical applications. Full article

Background: Medication-related osteonecrosis of the jaw (MRONJ) is drug-induced bone destruction that is exposed for a minimum of 6 to 8 weeks in patients who have not received head and neck radiotherapy and who have not been diagnosed with facial bone metastases. MRONJ treatment outcomes are unpredictable. Therefore, alternative treatment methods are being explored, such as blood-derived platelet-rich preparations enriched with growth factors, including advanced platelet-rich fibrin (A-PRF). The presence of growth factors may enhance healing and reduce post-procedure complications. There are no studies examining the effect of A-PRF on the healing of patients with MRONJ. The aim of this study was to retrospectively evaluate treatment outcomes of patients with MRONJ surgically treated without and with the use of A-PRF. Materials and methods: This retrospective study included 28 patients who suffered from osteomyelitis due to MRONJ and underwent surgical treatment between 2019 and 2024. The patients were divided into two groups: the first group received surgical treatment without A-PRF, and the second group received surgical treatment with the application of A-PRF. This study analyzed demographic and clinical data, as well as treatment outcomes. Results: The patients were aged from 43 to 82 years. The most common cause of MRONJ was the administration of zoledronic acid for oncological reasons (22 patients, 78.6%), given intravenously. In 20 patients (71.4%), the antiresorptive treatment lasted longer than three years. The obtained healing distribution was binomial (presence or absence of healing). Estimation of the probability of healing using the maximum likelihood method provided a result of approximately 64%. The probability of ten or more healed patients in the A-PRF group was 41%. A-PRF helps with a probability of 59%, and without A-PRF, it was lower. Concomitantly, the differences between the group with A-PRF and without A-PRF were not statistically significant. Conclusions: The patients with MRONJ should have regular check-ups with radiological examinations at least every six months to detect possible recurrence. Treatment for MRONJ is long and difficult. Treatment of non-advanced lesions, without additional risk factors (such as treatment with zoledronate intravenously for oncological purposes for 3 years), showed a better prognosis. Sometimes, in addition to surgery, it is necessary to consider alternative methods. A-PRF may enhance MRONJ healing. However, there is no evidence of a significant effect of A-PRF on the healing of MRONJ. Full article

Bisphosphonates (BPs) are drugs used to cure metabolic diseases like osteoporosis and oncological conditions, such as multiple myeloma and bone metastases. The pharmacological activity of these compounds is mediated by their capacity to induce a systemic osteoclast depletion, finally resulting in reduced bone resorption. In spite of their efficacy, the clinical application of BPs is sometimes associated with a frightening side effect known as osteonecrosis of the jaw (ONJ). In principle, a therapeutic approach able to elicit the local re-activation of osteoclast production could counteract the onset of ONJ and promote the healing of its lesions. Using a vitamin D3-dependent model of osteoclast differentiation, it has been previously demonstrated that when used at supra-physiological concentrations, magnesium strongly favors the process under consideration, and its effect is furtherly enhanced by the presence of a BP called zoledronate. Here, we show that similar results can be obtained in a RANKL-dependent model of osteoclast differentiation, suggesting that a topical therapy based on magnesium may be also suitable for ONJ determined by denosumab in light of the ability of this monoclonal antibody to target RANKL. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a multifactorial condition defined as an adverse drug reaction that results in progressive jawbone destruction and necrosis in individuals treated with certain medications, occurring without a history of prior radiotherapy. These drugs are mainly bisphosphonates, denosumab, and other bone-modifying agents, anti-angiogenic agents such as anti-endothelial growth factor, tyrosine kinase inhibitors, and proteins classified as mammalian targets of rapamycin. The diagnosis of MRONJ is based on clinical (exposed jawbone, fistula with pus, hyperplasia of the mucosa overlying the necrotic bone tissue) and radiological evaluation. We report four cases of clinical and radiological evidence of osteonecrosis of the jaw that are unrelated to the use of antiresorptive or anti-angiogenic agents. In two instances, histological and microbiological evidence was also found (high concentration of Actinomyces, the microbe most commonly found in oral sites affected by MRONJ). These atypical cases are reported to highlight the possibility that other, previously undocumented, drugs may also contribute to the development of ONJ Full article

Osteonecrosis of the jaw (ONJ), including the maxilla and mandible, is considered a challenging therapeutic problem, mainly due to the lack of understanding of its pathogenesis. It is well known that ONJ is a severe side effect caused by certain medications used to treat bone metastasis and osteoporosis, such as bisphosphonates, which inhibit bone resorption. Other therapeutics with similar side effects are, for instance, receptor activators of nuclear factor kappa-B ligand (RANK-L) inhibitor (denosumab), tyrosine kinase inhibitors (sunitinib), and antiangiogenics (bevacizumab). The conservative or surgical treatment of these medication-related osteonecroses of the jaw (MRONJs) is generally effortful and still not entirely effective. Therefore, the research seeks alternative treatment options like tissue engineering and stem cell therapy, which predominantly represent mesenchymal stem cells (MSCs) and their derivatives, such as extracellular vesicles. Moreover, it was published that novel stem cell therapy could even prevent the onset of MRONJ. On the other hand, the administration of stem cells may also be accompanied by some other health risks, such as an increased chance of cancer metastasis occurrence in cancer patients. The current review paper summarizes the most recent progress in stem-cell-based and stem-cell-free treatment options for the ONJ. Similarly, we discuss this novel approach’s future perspectives and possible obstacles. Full article

On 24 February 2024, Italian physicians, dentists and oral care specialists, students, nurses, psychologists, dental hygienists, and other professionals met (live or online) to discuss controversial issues about medication-related osteonecrosis of the jaw (MRONJ). One section hosted international experts who gave lectures about MRONJ experiences in North America, Europe, and Italy. A second section summarized the principal points of an Italian MRONJ position paper published in February 2024 by experts from the Italian Societies of Oral Pathology and Medicine (SIPMO) and Maxillofacial Surgery (SICMF). The following section collates expert opinions about open issues and required fields of research: different definitions of MRONJ and impact on staging; the assessment of individual MRONJ risk before the start of antiresorptive therapy; surgery and implantology in patients at risk for MRONJ; cancer patients without metastases and prevention of cancer-treatment-induced bone Loss (CTIBL); the role of dental hygiene professionals; combined (medical and surgical) and surgical therapy for MRONJ in-patients and out-patients; and legal aspects and claims related to MRONJ diagnosis and treatment. Scientific contributions from hospitals and universities all over Italy were presented in specific sessions (epidemiology; case series; special case reports; prevention experiences; MRONJ treatment). Conclusions: the conference confirmed the importance of the adequate imaging study of bone in the diagnosis and staging of MRONJ cases, the role of surgery in MRONJ treatment, and the value of oral hygiene in the MRONJ prevention. Full article

This review systematically examines the oral complications associated with conventional and novel anti-cancer therapies. It highlights that while molecularly targeted agents including monoclonal antibodies targeting the vascular endothelial growth factor and its receptor, the epidermal growth factor receptor, tyrosine kinase inhibitors, and immune checkpoint inhibitors tend to exhibit a lower overall toxicity profile compared to traditional cytotoxic chemotherapeutics, they are nonetheless linked to significant oral adverse events. These complications encompass inflammatory mucosal reactions known as mucositis, salivary gland dysfunction leading to a sensation of dryness in the mouth, taste alterations referred to as dysgeusia, and, critically, medication-related osteonecrosis of the jaw. In particular, bone-modifying agents such as bisphosphonates and denosumab disrupt bone remodeling and the formation of new blood vessels, thereby increasing the susceptibility to osteonecrosis of the jaw, especially following invasive dental procedures. The review delineates the multifactorial pathogenesis underlying these toxicities, which involves direct cell toxicity, impaired wound healing, and secondary infections. Furthermore, it emphasizes the importance of pre-treatment dental evaluation and preventive strategies including patient education, prophylactic dental care, and the integration of adjunctive therapies such as laser therapy and autologous platelet concentrates to mitigate these adverse effects. The analysis advocates for interdisciplinary collaboration between oncologists and dental professionals to optimize management protocols, enhance treatment adherence, and ultimately improve the quality of life for oncology patients undergoing anti-cancer therapy. Full article

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event. Herein, we conducted a quantitative structure–activity relationship analysis using the U.S. Food and Drug Administration Adverse Drug Reaction Database System (FAERS) and machine learning to construct a drug prediction model for MRONJ induction based solely on chemical structure information. Methods: A total of 4815 drugs from FAERS were evaluated, including 70 and 139 MRONJ-positive and MRONJ-negative drugs, respectively, identified based on reporting odds ratios, Fisher’s exact tests, and ≥100 total adverse event reports. Then, we calculated 326 chemical structure descriptors for each drug and compared three supervised learning algorithms (random forest, gradient boosting, and artificial neural networks). We also compared the number of chemical structure descriptors (5, 6, 7, 8, 9, 10, 20, and 30 descriptors). Results: We indicated that the MRONJ prediction model using an artificial neural network algorithm and eight descriptors achieved the highest validation receiver operating characteristic curve value of 0.778. Notably, the total polar surface area (ASA_P) was among the top-ranking descriptors, and MRONJ-positive drugs such as bisphosphonates and anticancer drugs showed high values. Our final model demonstrated a balanced accuracy of 0.693 and a specificity of 0.852. Conclusions: In this study, our MRONJ-inducing drug prediction model identified drugs with polar surface area properties as potential causes of MRONJ. This study demonstrates a promising approach for predicting MRONJ risk, which could enhance drug safety assessment and streamline drug screening in clinical and preclinical settings. Full article