Search Results (102)

Background/Objectives: Subchondral bone marrow edema (BME) of the knee often causes persistent pain despite conservative treatment, and evidence supporting oral bisphosphonates is limited. We compared conservative treatment alone with conservative treatment plus oral alendronate. Methods: This retrospective cohort study included 82 patients with MRI-confirmed subchondral BME of the knee treated between January 2020 and January 2025. Patients received conservative treatment alone (n = 44) or conservative treatment plus alendronate 70 mg weekly for three months (n = 38). Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were assessed at baseline and three months. Radiological response was assessed on follow-up MRI as the percentage reduction in BME area. Results: Both groups improved significantly at three months. The alendronate group showed greater reductions in VAS (4.0 ± 1.4 vs. 3.2 ± 1.3 points, p = 0.009) and total WOMAC scores (25.5 ± 8.9 vs. 19.8 ± 8.6 points, p = 0.002). Median time to full weight-bearing was shorter with alendronate (7 vs. 9 weeks, p = 0.021), and complete BME regression was more frequent (42.1% vs. 18.2%, Fisher’s exact p = 0.028). After adjustment for Kellgren–Lawrence grade, alendronate was associated with a favorable radiological response (OR = 3.66, 95% CI: 1.18–11.31, p = 0.024). No serious adverse events were recorded. Conclusions: Adding oral alendronate to conservative treatment was associated with greater clinical improvement, earlier full weight-bearing, and a more favorable radiological response at three months. Prospective randomized studies are needed to confirm these findings. Full article

Bisphosphonates (BPs) and Denosumab (DMB) are antiresorptive agents (AA) commonly used in treatment of osteoporosis, multiple myeloma (8.0%), breast cancer (3.3%), prostate cancer (2.9%) and other malignancies (0.7%), bone metastases, and cancer-induced hypercalcemia. However, this therapy is associated with a significant risk of medication-related osteonecrosis of the jaw (MRONJ), particularly after tooth extraction. The aim of this narrative review was to summarize current evidence on measures aimed to reduce the risk of MRONJ after tooth extraction, and to critically discuss the strength of evidence supporting each of these measures. Articles published in the years 2013–2025 were reviewed using PubMed, Scopus, Web of Science databases. Available studies were categorized and compared with the use of selected prevention methods. The duration of the treatment, route of administration, dosage and type of AA have a significant impact on the risk of developing MRONJ. Antibiotic prophylaxis is considered in most published preventive protocols. However, the evidence supporting a single optimal regimen is limited. Patients from a high-risk group of MRONJ, demonstrating cancer, who were administered intravenous antiresorptive agents for longer than three years or zoledronic acid, or those with a history of jawbone necrosis or inflammation require prolonged antibiotic therapy (started before the procedure and continued up to 14 days after the procedure). Moreover, studies on the use of platelet-rich fibrin (PRF) and Concentrated Growth Factors (CGF) as a preventive measure have shown promising results in observational studies, along with antibiotic prophylaxis and optimal oral hygiene. Pentoxifylline with tocopherol and low-level laser therapy (LLLT) are recognized as potentially useful non-invasive preventions. However, evidence is limited due to the small sample sizes and heterogenous protocols. Vitamin D levels should be monitored, and oral supplementation should be considered if needed. AA therapy suspension prior to the surgical procedure must always be consulted with the attending physician. A multidisciplinary approach along with well-planned pre- and postoperative care is essential for safe tooth extraction in patients receiving AA therapy. Full article

Bisphosphonates (BPs) are cornerstone therapeutic agents for the management of metabolic bone disorders and skeletal complications associated with malignant tumors. However, their long-term administration is accompanied by the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). In recent years, the pathogenesis of BRONJ has remained a major focus at the intersection of osteoimmunology and oral medicine. This review systematically summarizes the latest advances in the understanding of BRONJ pathogenesis, including the direct disruption of osteoclast differentiation and bone remodeling coupling by bisphosphonates, the systemic reprogramming of immune cell subsets and inflammatory signaling pathways, the multifaceted suppression of angiogenesis and the endothelial–stromal–immune axis, and the toxic impairment of oral soft tissue repair capacity. Building upon these mechanistic insights, we further discuss the modifying and synergistic effects of local oral risk factors, microbial dysbiosis, systemic comorbidities, and genetic susceptibility on the initiation and progression of BRONJ. Furthermore, emerging therapeutic strategies targeting these pathogenic mechanisms are highlighted, including restoration of small GTPase prenylation through modulation of metabolic pathways, reconstruction of T-cell subset homeostasis via immunomodulatory approaches, enhancement of local vascularization through pro-angiogenic interventions, and preservation of soft tissue barrier integrity. Collectively, this review provides a comprehensive and multidimensional overview of the pathological landscape of BRONJ and offers a theoretical framework for clinical risk stratification and the development of personalized prevention and treatment strategies. Full article

Background/Objectives: Osteonecrosis of the jaw, a non-healing wound, is a side effect in patients treated with nitrogen-containing bisphosphonates (e.g., zoledronate) after some oral procedures. Considering zoledronate toxicity in surgical wounds and the capacity of calcium phosphate synthetic compounds to adsorb it, the aim of this work was to demonstrate and elucidate the mechanism underlying this adsorption. Methods: Four different calcium phosphate synthetic bone substitutes were used in this study: AdBone^® BCP (0.5–1 mm), Guidor^® easy-graft (0.5–1 mm), Maxresorb^® (0.5–1 mm) and Maxresorb^® (0.8–1.5 mm). The materials were incubated in aqueous zoledronate solutions. Samples of the solutions obtained after 1, 2, 3, 6, 24, 48, 72 and 120 h of conditioning were then analyzed by spectrophotometry to measure their absorbance and subsequently characterized by micro-elemental analysis. Results: All four materials demonstrated time-dependent zoledronate adsorption. AdBone^® BCP achieved the most rapid and sustained sequestration, reaching 80% reduction at 24 h and stabilizing at 85% from 72 h onwards without re-release. Maxresorb^® formulations showed comparable kinetics through 72 h (70–75%) but exhibited partial re-release at 120 h. Guidor^® easy-graft showed negligible adsorption through the first 24 h, consistent with the physical barrier effect of its PLGA coating. Spectrophotometric findings were independently confirmed by elemental analysis. Conclusions: This work confirms zoledronate adsorption by calcium phosphate synthetic biomaterials. Among the tested materials, AdBone^® BCP demonstrated the most favorable adsorption profile, with kinetics well matched to the critical window of alveolar wound healing. These findings support the use of biphasic calcium phosphate bone substitutes as a local strategy to reduce free zoledronate bioavailability at the surgical site, potentially lowering the risk of MRONJ in patients undergoing dentoalveolar procedures under bisphosphonate therapy. Full article

Background and Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive therapy. Although several local and systemic risk factors have been documented, the role of metabolic biomarkers and their relationship with clinical characteristics remains insufficiently investigated. The aim of the present study was to evaluate the relationships between antiresorptive therapy, serum vitamin D levels, demographic characteristics, and lesion location in patients diagnosed with MRONJ. Materials and Methods: This retrospective study included 72 patients diagnosed with MRONJ, divided into three groups according to the antiresorptive therapy administered: zoledronic acid (n = 30), denosumab (n = 22), and oral bisphosphonates (n = 20). Clinical and demographic data, including age, sex, smoking status, serum vitamin D levels, number of extracted teeth, lesion location (mandibular versus maxillary), and associated comorbidities, were obtained from medical records. Statistical analysis was performed using Welch’s ANOVA, Welch’s t-test, chi-square, Fisher’s exact, and Pearson and Spearman correlation analyses. Results: No significant differences in serum vitamin D levels were observed among the three antiresorptive therapy groups. However, patients with mandibular MRONJ had significantly lower serum vitamin D levels than those with maxillary involvement (p = 0.046). Lower serum vitamin D levels were independently associated with mandibular MRONJ after multivariable adjustment. Female sex and thyroid disease were more frequent in the oral bisphosphonate group. Additionally, patient age was moderately positively correlated with the number of extracted teeth (r = 0.440, p < 0.001). Conclusions: This retrospective study identified a possible association between lower serum vitamin D levels and mandibular MRONJ. Given the observational design of the study, these findings should be interpreted with caution and require confirmation in larger prospective studies. Full article

This study evaluated the structural, electronic, pharmacokinetic, and receptor-binding properties of three bisphosphonate derivatives, alendronate, risedronate, and zoledronate, to investigate their therapeutic relevance in osteoporosis and breast cancer. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level showed that risedronate exhibited the highest kinetic stability (ΔE = 6.7468 eV), whereas zoledronate displayed greater chemical reactivity (ΔE = 2.9669 eV) and the strongest nonlinear optical response (β = 1.20 × 10⁻³⁰ esu). ADMET analysis indicated acceptable safety profiles for all compounds, although high polarity and low lipophilicity may limit oral bioavailability. Molecular docking against 11 breast cancer- and bone metabolism-related targets revealed favorable binding affinities, particularly for zoledronate and risedronate. Zoledronate showed strong interactions with ESR2, VEGFR/KDR, GGPS1, and FPPS, whereas risedronate exhibited notable affinity for BRCA2 and MMP9. Bioinformatics analyses identified significant dysregulation of GGPS1, FDPS, TNFSF11, ESR1, MMP9, and BRCA2 in breast cancer tissues, while survival analysis linked elevated FDPS, MMP9, and BRCA2 expression to poor prognosis. Network analyses highlighted pathways related to mevalonate metabolism, hormone signaling, angiogenesis, extracellular matrix remodeling, and the RANK/RANKL/OPG axis. These findings support the potential repurposing of bisphosphonates, particularly zoledronate, for breast cancer-associated bone disease. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication of bisphosphonate therapy, whose risk is currently assessed through qualitative staging systems that do not integrate pharmacological determinants of cumulative drug exposure. The aim of this study is to present the Bisphosphonate Accumulation Index (BAI), a pharmacologically derived, dimensionless scalar quantifying cumulative exposure to bone-targeted antiresorptive agents by integrating relative potency, administered dose, dosing frequency, route-specific bioavailability, and treatment duration, for use as a pre-procedural assessment tool in patients receiving bisphosphonates. Methods: The BAI combines five pharmacologically grounded parameters from peer-reviewed literature: (1) relative antiresorptive potency referenced to etidronate; (2) dose per administration (mg); (3) monthly dosing frequency; (4) bioavailability route; and (5) years of treatment within the preceding 10-year window. The model includes nine bisphosphonates registered in Italy. Results: The BAI spans approximately five orders of magnitude (from <1000 for short-term oral therapy to >120,000 for monthly intravenous zoledronic acid). Four analyses support the model: sensitivity analysis identifies relative potency as the main source of variance; ecological calibration against nine MRONJ incidence data points yielded r = 0.911 (p = 0.0006, R² = 0.829), indicating that the BAI accounts for approximately 83% of the population-level variance in published incidence rates across heterogeneous regimens (ecological correlation; this does not establish individual-level predictive validity); Monte Carlo simulation on 10,000 patients generated a plausible exposure-strata distribution (6.1% low, 66.6% moderate, 27.3% high); and concordance analysis with a DDD-based metric showed discordance in 7/8 regimens. Conclusions: The BAI is a transparent, reproducible, pharmacologically grounded metric of cumulative antiresorptive exposure addressing the quantitative gap identified in the AAOMS 2022 Position Paper. The BAI measures pharmacological exposure, which is a necessary but insufficient component of MRONJ risk; clinical modifiers such as corticosteroid co-administration, diabetes, renal function, and procedure type are not integrated and must be evaluated independently. The provisional exposure strata reported here (<1000, 1000–10,000, >10,000) are hypothesis-generating and intended solely to guide the design of validation studies; they should not be used as clinical decision rules until prospective patient-level validation has been completed. Full article

Medication-related osteonecrosis of the jaw (MRONJ) represents a major clinical challenge for oral and maxillofacial surgery departments as well as dental practices. With increasing life expectancy and the more frequent use of medications associated with osteonecrosis, the incidence of MRONJ continues to rise. To date, there are no uniform treatment standards with scientifically proven effectiveness for this condition. To evaluate the impact of platelet-rich fibrin (PRF) on the outcomes of MRONJ treatment and to identify factors that may influence the effectiveness of PRF therapy, we conducted a comparative prospective study including 22 patients divided into two groups: patients treated with PRF and patients treated without PRF. PRF was prepared according to the PRF Duo Quattro Process protocol for PRF (Nice, France). The study was registered at ClinicalTrials.gov (NCT07464678). The following parameters were assessed: age, smoking status, gender, lesion location, body mass index (BMI), C-reactive protein (CRP) concentration, pain intensity, presence or absence of fistulas, soft tissue healing and radiological findings. Patients were evaluated preoperatively and postoperatively at 14 days, 6 weeks, and 6 months. The study demonstrated a reduction in pain after surgery among patients treated with PRF. In addition, the use of PRF resulted in improved healing outcomes in patients with elevated CRP. Higher BMI was associated with poorer therapeutic response to PRF. Improvements in soft tissue healing and disease stage were observed in the PRF group; however, these differences did not reach statistical significance. All findings should be interpreted with caution due to the limited sample size. There is still no standardized treatment for MRONJ. The use of platelet-rich fibrin as an inexpensive and safe adjunctive therapy may provide clinical benefits for patients, particularly through a significant reduction in pain. Further large-scale, multicenter studies are required to confirm these findings. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a clinically significant side effect related to antiresorptive therapies, such as denosumab and bisphosphonates. MRONJ may develop following oral surgical procedures or spontaneously. Although the pathophysiological processes underlying MRONJ are not well clarified, infections, commonly occurring after oral surgery, seem to have an important contribution in its development. Consequently, the role of the oral microbiota warrants investigation. This study investigates the possible contribution of the salivary microbiota to the onset of osteonecrosis in subjects treated with zoledronate or denosumab. Methods: Three groups of subjects were analyzed: patients treated with zoledronate or denosumab who had developed MRONJ (cases); those who did not (controls) and healthy subjects. Oral microbioma was evaluated through next-generation sequencing. Results: A total of 55 individuals were enrolled: 16 healthy subjects (29.1%), 21 controls (38.2%), and 18 cases (32.7%). Differences in the abundance of certain bacterial taxa were observed both among the three groups and in pairwise comparisons. Furthermore, a cut-off value of 5.51% for Streptococcus spp. was identified as being associated with the development of MRONJ. Conclusions: For the first time, this preliminary study highlights differences in the salivary microbiota among healthy subjects, controls, and cases, suggesting a potential cut-off value for Streptococcus spp. Despite the limited sample size, these findings provide initial insights. Further studies in larger cohorts are warranted. Full article

Glucocorticoids (GCs) are widely used for their potent anti-inflammatory and immunosuppressive effects, but their use is strongly associated with negative impacts on bone health. Rapid bone loss and an increased risk of fragility fractures are characteristics of glucocorticoid-induced osteoporosis (GIOP), the most common type of secondary osteoporosis. While oral GCs are a well-known cause of GIOP, growing evidence suggests that non-oral routes of administration may also negatively affect the skeleton. This review summarizes current knowledge on the pathophysiology of GIOP, highlighting the complex relationship between direct and indirect mechanisms. It examines the effects of various routes of GC administration—oral, intravenous, inhaled, topical, and epidural—on bone mineral density, microarchitecture, and fracture. While parenteral GCs may have fewer systemic effects than oral therapy, long-term exposure or high cumulative doses may still cause clinically significant skeletal deterioration. This review also discusses current methods for assessing, preventing, and treating the fracture risk associated with GIOP. These strategies include lifestyle modifications, calcium and vitamin D supplements, and medications such as denosumab, bisphosphonates, and anabolic agents. Reducing the incidence of glucocorticoid-associated fractures and improving prevention and treatment requires an understanding of how GCs impact bone. Full article

Segmental mandibular resection may be indicated as a treatment in, for example, advanced stages of oral squamous cell carcinoma (OSCC). Osseous reconstruction of these defects is a fundamental part of static and dynamic masticatory rehabilitation, particularly when dental implants are required. The Segmental Mandibular Defect Reconstruction (SMDR) Registry aims to generate real-world evidence on SMDR through an international, prospective, multicentre case series designed as a registry. While OSCC is a common indication for segmental mandibular resection, the SMDR Registry also aims to capture outcomes for rarer mandibular conditions and the increasing number of collateral damage cases resulting from systemic medication therapies (antiresorptive drugs, immunotherapeutics) or irradiation, which may likewise lead to medication-related osteonecrosis of the mandible (MRONJ) or osteo(radio)necrosis with tumour-like segmental resection of the mandible, highlighting the value of an international database for these less frequent pathologies. Primary objectives are to describe the patient population and current treatment modalities, describe the outcomes and adverse events (AEs) for different treatment modalities, and identify potential predictors for successful autologous reconstruction of SMDs. Approximately 300 patients with a mandibular lesion resulting from bisphosphonate- and immunomodulatory drug-induced osteonecrosis of the mandible, ameloblastoma or osteosarcoma of the mandible, oral metastases related mandibular lesions indicated for segmental resection, or OSCC undergoing SMDR or intending to undergo one- or two-stage reconstruction will be prospectively recruited over a 36-month period. Baseline information, treatment details, and outcome measures will be documented. All treatments will be per the usual practice at participating sites. Outcome measures include clinical, patient-reported, and radiological outcomes; AEs related to the condition and/or treatment with a possible influence on the outcome will be recorded. Full article

Background: The present case report study aims to describe, from both clinical and histological aspects, the bone healing pattern in a patient under oral bisphosphonates therapy. Case Presentation: an 82-year-old female patient has been under oral nitrogen bisphosphonates therapy for two years. She underwent a tooth extraction. After four months, two bone biopsies were harvested, during standard implant drilling procedures. The first one corresponded to the healed alveolar socket of the previously extracted tooth (specimen A), while the second one corresponded to the bone ridge that was edentulous before starting the bisphosphonates therapy (specimen B). Morphometric and histologic analyses were performed. Results: In both, the bone resulted vital and no evidence of empty lacunae was detected. A reduction in the haversian canal diameter was observed in specimen B. The present case report highlights histological findings suggesting that patients undergoing oral bisphosphonates therapy may be eligible for surgical therapy. A pre-operative careful anamnesis and the observance of international guidelines for treating patients taking bisphosphonates are mandatory. Conclusions: These preliminary results will be used to plan a large clinical study in order to better understand the influence of bisphosphonates on the bone healing process. Full article

Diabetes is a significant risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ), a severe oral complication with limited treatment options. Salivary testing offers a noninvasive approach for monitoring BRONJ risk; however, few studies have investigated salivary biomarkers in BRONJ. This study screened salivary biomarkers that reflect the progression of BRONJ under diabetic conditions. A diabetic BRONJ rat model was established to screen for diabetes-related biochemical biomarkers in saliva. Streptozotocin (STZ) administration elevated blood glucose and glycated albumin levels and altered lipid and renal function markers, confirming diabetes induction. Subsequent zoledronic acid (ZA) administration and extraction of the maxillary first molar delayed epithelialization, inflammatory cell infiltration, bone exposure, and necrosis in extraction sockets, indicating successful establishment of a diabetic BRONJ model. This model showed reductions in submandibular and sublingual gland size, as well as in acinar cell number. Although salivary secretion volume was reduced, saliva samples were successfully collected from all groups. Screening identified elevated urea nitrogen (UN) and total ketone bodies (T-KB) in the STZ + ZA group. These findings suggest that salivary UN and T-KB may reflect disease progression and serve as potential biomarkers for predicting BRONJ risk under diabetic conditions. Full article

Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress. Full article

Objectives: This study aimed to evaluate dentists’ knowledge in Split-Dalmatia County regarding bisphosphonates and their oral side effects. Methods: An anonymous, 20-item questionnaire assessing demographics, knowledge of indications, mechanisms of action, and complications of bisphosphonates was electronically distributed via email to dentists in Split-Dalmatia County between March and April 2025. Descriptive statistical analysis was performed, and the results are presented as absolute numbers and percentages. The Chi-square test was used to compare proportions between groups, with a significance level set at p < 0.05. Results: A total of 172 dentists from Split-Dalmatia County participated (response rate was 71.36%). The mean total knowledge score was 7.3 ± 1.4 out of 9 items. The results indicated that most respondents correctly answered questions about indications for bisphosphonate use (95.9%), mechanism of action (93.6%), and the most common complication—osteonecrosis of the jaw (92.4%). The lowest correct response rate (38.4%) was for procedures before invasive dental treatments. Only 18.6% of participants answered all nine knowledge questions correctly. No significant differences in knowledge were found based on gender, age, year of graduation, or educational level. Nearly all dentists (95.3%) expressed interest in further education on this topic. Conclusions: Although dentists demonstrated satisfactory general knowledge regarding bisphosphonates, important gaps remain, particularly in practical application, including recommendations for managing patients on bisphosphonates undergoing invasive dental procedures. Given the rising use of bisphosphonates and the potential severity of their side effects, additional education is warranted to enhance prevention, promote early detection, and ensure appropriate clinical management of related complications. Full article