Search Results (444)

Adjuvant endocrine therapy for early breast cancer significantly reduces recurrence but increases bone fragility. Given limited data on denosumab (60 mg every 6 months) in premenopausal patients receiving endocrine therapy for early breast cancer, we conducted a retrospective real-world study at the Gemelli Hospital (September 2018–January 2025). A descriptive analysis was performed. The primary endpoint was to assess efficacy, evaluated by changes in bone mineral density via dual-energy X-ray absorptiometry and by monitoring bone turnover markers, particularly serum C-terminal telopeptide of type I collagen. Safety was evaluated based on adverse endocrine therapy events (osteoporotic fractures) and adverse denosumab events (osteonecrosis of the jaw). Sixty-nine patients were eligible for the study. Endocrine therapy included ovarian function suppression with exemestane (89.8%) or tamoxifen (10.1%). Baseline spinal osteoporosis decreased from 20.3% to 5.8%, osteopenia from 39.1% to 34.8%, with normal T-scores rising from 17.4% to 34.8%. Femoral improvements were similar. Serum C-terminal telopeptide of type I collagen levels (evaluated in 35.8%) showed stable reduction in 97%. Denosumab adherence was 89.9%. One osteonecrosis of the jaw case occurred (1.4%); no fractures were reported. Denosumab demonstrated efficacy in improving bone density and reducing bone turnover, with excellent adherence and favorable safety. Longer follow-up is needed to assess post-discontinuation effects. Full article

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

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a common condition in hip surgery, which is characterized by the death of bone cells due to disruption of the blood supply and ultimately irreversible destruction of the hip joint. As a result of the COVID-19 pandemic, a significant increase in the incidence of ONFH has been identified. To better understand the pathogenesis of ONFH in the context of COVID-19, our research aimed to determine pathomorphological changes in articular tissues specific to post-COVID-19 ONFH. Methods: Using morphological, morphometric, and statistical methods, the femoral heads after hip arthroplasty were retrospectively studied in patients with post-COVID-19 ONFH (n = 41) compared to a non-COVID-19 group of patients (n = 47). Results: Our results revealed that the key morphofunctional biomarkers of post-COVID-19 ONFH were clusters of mast cells, extensive areas of fibrosis, numerous arterial and venous thrombi, and giant cell granulomas. The potential relationship of those morphological features with the action of the SARS-CoV-2 coronavirus was discussed. Conclusions: Mast cells have been proposed as the leading players that may trigger the main molecular and cellular mechanisms in the development of post-COVID-19 ONFH and can be considered a diagnostic sign of the disease. 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/Objectives: Prolonged use of denosumab in patients with metastatic breast cancer has raised concerns about the development of medication-related osteonecrosis of the jaw (MRONJ). However, the threshold at which the risk increases remains unclear. Methods: This retrospective cohort study analyzed patients with breast cancer and bone metastases who received denosumab between May 2012 and August 2024. Associations between cumulative denosumab administration and MRONJ were evaluated using univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff for cumulative doses. Results: MRONJ developed in 101 patients (31.2%). Multivariate analysis identified cumulative denosumab administration (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03–1.06; p < 0.001) and a history of tooth extraction (OR: 4.40, 95% CI: 2.23–8.71; p < 0.001) as independent risk factors for MRONJ. ROC analysis determined an optimal cutoff of 32 cumulative doses, with an area under the curve of 0.83 (95% CI: 0.78–0.88; p < 0.0001). Conclusions: Cumulative denosumab administration and history of tooth extraction were independent risk factors for MRONJ in patients with breast cancer and bone metastases. The risk of MRONJ increased after 32 cumulative doses, providing a clinically actionable threshold for risk assessment and patient monitoring. 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

Secondary osteonecrosis (ON) is a common complication in paediatric cancer survivors. Combining multipotent mesenchymal stromal cells (MSCs) with core decompression surgery halts disease progression and stimulates bone regeneration. However, the success of advanced therapy medicinal products (ATMPs) requires versatile “off-the-shelf” tissue engineering products (TEPs). This study evaluated the safety and efficacy of TEPs loaded with allogeneic MSCs from Wharton’s jelly (WJ-MSCs) in a large-animal model of bone regeneration to support a paediatric investigational plan for ON patients. WJ-MSC-laden fibrin-based hydrogels combined with a synthetic bone substitute (PRO-DENSE^TM) were tested in 16 juvenile sheep (8 males and 8 females) distributed in four experimental groups. Each animal received four cylindrical bone defects in the femoral and tibial epiphyses and was assessed at 6 and 12 weeks. Safety was confirmed, and bone regeneration was observed across all groups. A combination of WJ-MSCs with PRO-DENSE^TM led to improved histological scores, osteogenesis, and construct integration. Trabecular bone volume also increased more in cellular groups over time. However, effects were inconsistent across groups, reflecting the variability seen in clinical trials and highlighting the significant impact of factors such as immunogenetic compatibility, MSC batch potency, and interaction with the recipient’s microenvironment on the therapeutic effectiveness and successful clinical translation of allogeneic ATMPs. Full article

Background: Oral ulceration with bone sequestration (OUBS) is an uncommon clinical lesion characterized by painful mucosal ulceration associated with exposed and necrotic bone in the oral cavity, often without known factors inducing osteonecrosis. Despite its potential for diagnostic confusion with more serious lesions, such as medication-related osteonecrosis, OUBS remains poorly understood and underreported. Objectives: To systematically review the literature on OUBS and identify its main clinical and radiographic characteristics to assist in early diagnosis and appropriate management. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted in the PubMed, Scopus, and Web of Science databases on 27 January 2024, to identify case reports, case series, and observational studies that described OUBS. Data extraction focused on demographic information, lesion location, clinical features, radiographic findings, possible etiological factors, management, and outcomes. The Joanna Briggs Institute (JBI) critical appraisal tools were utilized to assess the quality of the case reports and series. Data were synthesized narratively due to heterogeneity among studies. Results: Fifty-seven patients from 22 studies were included. The male-to-female ratio was 2.5:1, with most cases (71.9%) occurring in males. The mean age was 50.22 ± 11.49 years, with the highest incidence in patients aged 50–59 years (64.9%). Most cases were localized to the mandible (94.7%). Clinically, lesions were shallow ulcers (mean size: 0.75 ± 0.85 cm). Pain was the most common symptom (88.9%). Radiographs revealed no significant maxillary abnormalities, but some cases showed radiopaque areas in the mandible. Surgical interventions were most common (40.4%), with complete healing in 67.7% of cases within 4 weeks. Limitations include the predominance of case reports and series, which limits the strength of evidence. Conclusions: Recognizing OUBS can prevent misdiagnosis and unnecessary interventions. Further studies are needed to clarify its etiology and natural history. Registration: This review was registered on the PROSPERO database (registration number CRD42024541416). Full article

(1) Background: Osteonecrosis of the femoral head (ONFH), caused by insufficient blood supply, leads to bone tissue death. Current treatments lack effective bone regeneration materials to reverse disease progression. This study introduces an injectable and self-setting 3D porous bioceramic scaffold (Mg@Ca), combining MgO + SiO₂ mixtures with α-hemihydrate calcium sulfate, designed to promote bone repair through in situ pore formation and osteoinduction. (2) Methods: In vitro experiments evaluated human bone marrow mesenchymal stem cell (h-BMSC) proliferation, differentiation, and osteogenic marker expression in Mg@Ca medium. Transcriptome sequencing identified bone development-related pathways. In vivo efficacy was assessed in a rabbit model of ONFH to evaluate bone repair. (3) Results: The Mg@Ca scaffold demonstrated excellent biocompatibility and supported h-BMSC proliferation and differentiation, with significant up-regulation of COL1A1 and BGLAP. Transcriptome analysis revealed activation of the PI3K-Akt signaling pathway, critical for osteogenesis. In vivo results confirmed enhanced trabecular density and bone volume compared to controls, indicating effective bone repair and regeneration. (4) Conclusions: The Mg@Ca scaffold offers a promising therapeutic approach for ONFH, providing a minimally invasive solution for bone defect repair while stimulating natural bone regeneration. Its injectable and self-setting properties ensure precise filling of bone defects, making it suitable for clinical applications. Full article

Radical chemoradiotherapy has been used as a frontline treatment for squamous cell cancer of the anus for the last 30–40 years. Considerable acute and chronic adverse effects have been observed following radiotherapy using 2D and 3D techniques. A case of very late-onset severe chronic toxicity in a patient 26 years after radiotherapy is presented. The patient underwent radical chemoradiotherapy for squamous anal cancer stage T3N3M0 in 1998. In the anal region, cumulative doses up to 77.6 Gy (including electron boost) were administered. Durable complete regression of the disease was achieved. Fourteen years after treatment, the patient developed vast fibroatrophy of the anus and perineum, progressing within the subsequent four years to necrosis and sphincter loss. Twenty years after treatment, the asymptomatic osteonecrotic foci in the left femur appeared on MRI scans. Despite two courses of hyperbaric oxygen treatment, the fibroatrophy and subsequent necrosis of soft tissues remained progressive, but the osteonecrosis was stable. Twenty-six years after treatment, the progressive changes induced symptomatic osteomyelitis of the ischium and pubic bone. The patient now requires permanent supportive treatment. The presented case is exceptional in the very late-onset typical chronic adverse effects developing after non-conformal radiotherapy administered at high doses as part of contemporary treatment protocols. There is little evidence regarding the late onset of chronic adverse effects, since the follow-up period is usually shorter than that of the case presented. Moreover, a significant portion of patients do not survive to reach the late-onset period of adverse effects. The presented case shows that there may be long-term survivors of anal cancer in the population who were treated with outdated techniques and who still carry a risk of late-onset severe, progressive adverse effects. 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