Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

Connexin43 overexpression promotes bone regeneration by osteogenesis and angiogenesis in rat glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoids induced osteonecrosis of the femoral head (GIONFH) is a devastating orthopedic disease. Previous studies suggested that connexin43 is involved in the process of osteogenesis and angiogenesis. However, the role of Cx43 potentiates in the osteogenesis and angiogenesis of bone marrow-derived stromal stem cells (BMSCs) in GIONFH is still not investigated. In this study, BMSCs were isolated and transfected with green fluorescent protein or the fusion gene encoding GFP and Cx43. The osteogenic differentiation of BMSCs were detected after transfected with Cx43. In addition, the migration abilities and angiogenesis of human umbilical vein endothelial cells (HUVECs) were been detected after induced by transfected BMSCs supernatants in vitro. Finally, we established GC-ONFH rat model, then, a certain amount of transfected or controlled BMSCs were injected into the tibia of the rats. Immunohistological staining and micro-CT scanning results showed that the transplanted experiment group had significantly promoted more bone regeneration and vessel volume when compared with the effects of the negative or control groups. This study demonstrated for the first time that the Cx43 overexpression in BMSCs could promote bone regeneration as seen in the osteogenesis and angiogenesis process, suggesting that Cx43 may serve as a therapeutic gene target for GIONFH treatment.

HIF-1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid-induced osteonecrosis of the femoral head.

With the prevalence of coronavirus disease 2019, the administration of glucocorticoids (GCs) has become more widespread. Treatment with high-dose GCs leads to a variety of problems, of which steroid-induced osteonecrosis of the femoral head (SONFH) is the most concerning. Since hypoxia-inducible factor 1α (HIF-1α) is a key factor in cartilage development and homeostasis, it may play an important role in the development of SONFH. In this study, SONFH models were established using methylprednisolone (MPS) in mouse and its proliferating chondrocytes to investigate the role of HIF-1α in cartilage differentiation, extracellular matrix (ECM) homeostasis, apoptosis and glycolysis in SONFH mice. The results showed that MPS successfully induced SONFH in vivo and vitro, and MPS-treated cartilage and chondrocytes demonstrated disturbed ECM homeostasis, significantly increased chondrocyte apoptosis rate and glycolysis level. However, compared with normal mice, not only the expression of genes related to collagens and glycolysis, but also chondrocyte apoptosis did not demonstrate significant differences in mice co-treated with MPS and HIF-1α inhibitor. And the effects observed in HIF-1α activator-treated chondrocytes were similar to those induced by MPS. And HIF-1α degraded collagens in cartilage by upregulating its downstream target genes matrix metalloproteinases. The results of activator/inhibitor of endoplasmic reticulum stress (ERS) pathway revealed that the high apoptosis rate induced by MPS was related to the ERS pathway, which was also affected by HIF-1α. Furthermore, HIF-1α affected glucose metabolism in cartilage by increasing the expression of glycolysis-related genes. In conclusion, HIF-1α plays a vital role in the pathogenesis of SONFH by regulating ECM homeostasis, chondrocyte apoptosis, and glycolysis.

Association between CDK4/6 inhibitors and drug-related osteonecrosis of the jaw: A pharmacoepidemiological study using the FDA Adverse Events Reporting System.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

Palliative effect of rotating magnetic field on glucocorticoid-induced osteonecrosis of the femoral head in rats by regulating osteoblast differentiation.

With the substantial increase in the overuse of glucocorticoids (GCs) in clinical medicine, the prevalence of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) continues to rise in recent years. However, the optimal treatment for GC-ONFH remains elusive. Rotating magnetic field (RMF), considered as a non-invasive, safe and effective approach, has been proved to have multiple beneficial biological effects including improving bone diseases. To verify the effects of RMF on GC-ONFH, a lipopolysaccharide (LPS) and methylprednisolone (MPS)-induced invivo rat model, and an MPS-induced invitro cell model have been employed. The results demonstrate that RMF alleviated bone mineral loss and femoral head collapse in GC-ONFH rats. Meanwhile, RMF reduced serum lipid levels, attenuated cystic lesions, raised the expression of anti-apoptotic proteins and osteoprotegerin (OPG), while suppressed the expression of pro-apoptotic proteins and nuclear factor receptor activator-κB (RANK) in GC-ONFH rats. Besides, RMF also facilitated the generation of ALP, attenuated apoptosis and inhibits the expression of pro-apoptotic proteins, facilitated the expression of OPG, and inhibited the expression of RANK in MPS-stimulated MC3T3-E1 cells. Thus, this study indicates that RMF can improve GC-ONFH in rat and cell models, suggesting that RMF have the potential in the treatment of clinical GC-ONFH.

Proteomic profiling of extracellular vesicles derived from human serum for the discovery of biomarkers in Avascular necrosis.

BACKGROUND: Avascular necrosis (AVN) is a medical condition characterized by the destruction of bone tissue due to a diminished blood supply. When the rate of tissue destruction surpasses the rate of regeneration, effective treatment becomes challenging, leading to escalating pain, arthritis, and bone fragility as the disease advances. A timely diagnosis is imperative to prevent and initiate proactive treatment for osteonecrosis. We explored the potential of differentially expressed proteins in serum-derived extracellular vesicles (EVs) as biomarkers for AVN of the femoral head in humans. We analyzed the genetic material contained in serum-derived exosomes from patients for early diagnosis, treatment, and prognosis of avascular necrosis. METHODS: EVs were isolated from the serum of both patients with AVN and a control group of healthy individuals. Proteomic analyses were conducted to compare the expression patterns of these proteins by proteomic analysis using LC-MS/MS. RESULTS: Our results show that the levels of IGHV3-23, FN1, VWF, FGB, PRG4, FCGBP, and ZSWIM9 were upregulated in the EVs of patients with AVN compared with those of healthy controls. ELISA results showed that VWF and PRG4 were significantly upregulated in the patients with AVN. CONCLUSIONS: These findings suggest that these EV proteins could serve as promising biomarkers for the early detection and diagnosis of AVN. Early diagnosis is paramount for effective treatment, and the identification of new osteonecrosis biomarkers is essential to facilitate swift diagnosis and proactive intervention. Our study provides novel insights into the identification of AVN-related biomarkers that can enhance clinical management and treatment outcomes.

Key insights into antiresorptive drug use and osteonecrosis in osteoporotic patients undergoing tooth extractions: A clinical and CBCT assessment.

This study investigates the effects of antiresorptive drugs and risk factors for medication-related osteonecrosis of the jaws in osteoporotic patients undergoing tooth extraction. Among the findings, antiresorptive-treated patients had thicker lamina dura and longer healing times. Additionally, corticosteroid intake and multi-rooted teeth carried a higher osteonecrosis risk. Bone sequestrum indicated osteonecrosis. PURPOSE: To describe the effects of antiresorptive drugs (ARD) in the maxilla and mandible and risk factors for medication-related osteonecrosis of the jaws (MRONJ) in osteoporotic patients undergoing tooth extractions using clinical data and cone beam computed tomography (CBCT). METHODS: This retrospective cohort study collected clinical and CBCT data from 176 patients. The study group (n = 78; 224 extractions) received ARD treatment, underwent tooth extraction, and had a pre-operative CBCT. Additionally, age-, sex-, and tooth-matched controls were selected (n = 98; 227 extractions). Radiographic examinations were performed independently by three calibrated examiners. Statistical analysis included Chi-square, Fisher's exact, Mann-Whitney U, and t-tests to contrast clinical and radiographic data between study and control, MRONJ + and MRONJ - , and bisphosphonate and denosumab patients/sites. Significance was set at p ≤ 0.05. RESULTS: From the study group, 4 patients (5%) and 5 sites (2%) developed MRONJ after tooth extraction. ARD-treated patients exhibited significantly more thickening of the lamina dura and a longer average mucosal healing time (4.4 weeks) than controls (2.6 weeks). In the study group, MRONJ risk significantly increased with corticosteroid intake and in multi-rooted teeth. No significant differences between bisphosphonates and denosumab use were seen in the tomographic features (p > 0.05). Lastly, bone sequestrum was exclusively observed in osteoporotic patients, who exhibited post-operative exposed bone or histological evidence of osteonecrosis. CONCLUSION: Osteoporotic patients under ARD may exhibit thickening of the lamina dura and prolonged post-operative healing. Among these patients, multi-rooted teeth are at higher risk for MRONJ than single-rooted teeth. Sequester formation is a radiographic indicator of osteonecrosis.

miR-486-5p Attenuates Steroid-Induced Adipogenesis and Osteonecrosis of the Femoral Head Via TBX2/P21 Axis.

Enhanced adipogenic differentiation of mesenchymal stem cells (MSCs) is considered as a major risk factor for steroid-induced osteonecrosis of the femoral head (SOFNH). The role of microRNAs during this process has sparked interest. miR-486-5p expression was down-regulated significantly in femoral head bone tissues of both SONFH patients and rat models. The purpose of this study was to reveal the role of miR-486-5p on MSCs adipogenesis and SONFH progression. The present study showed that miR-486-5p could significantly inhibit adipogenesis of 3T3-L1 cells by suppressing mitotic clonal expansion (MCE). And upregulated expression of P21, which was caused by miR-486-5p mediated TBX2 decrease, was responsible for inhibited MCE. Further, miR-486-5p was demonstrated to effectively inhibit steroid-induced fat formation in the femoral head and prevented SONFH progression in a rat model. Considering the potent effects of miR-486-5p on attenuating adipogenesis, it seems to be a promising target for the treatment of SONFH.

Preventive Effects of Dental Pulp Stem Cell-conditioned Media on Anti-RANKL Antibody-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw is a serious disease occurring in patients with cancer and osteoporosis, who are undergoing treatment with antiresorptive agents (ARAs) such as bisphosphonate (BP) or denosumab, an antibody targeting receptor activator of NF-κB ligand. Recently, stem cell-based therapy has been shown to be effective in preventing the development of bisphosphonate-related osteonecrosis of the jaw. However, studies on denosumab-related osteonecrosis of the jaw (DRONJ) remain limited. Here, the efficacy of treatment with dental pulp stem cell conditioned media (DPSC-CM) in preventing DRONJ in a murine model was evaluated. Local administration of DPSC-CM into the extraction socket of a mouse with DRONJ decreased the number of empty osteocyte lacunae and the prevalence of ONJ. In tissues surrounding the extraction sockets in the DPSC-CM-treated group, the expression of inflammatory cytokines was attenuated and that of osteogenesis-related molecules was enhanced compared to that in the control group. Further, the expression of Wnt signaling molecules, which had been suppressed, was improved. These findings collectively suggest that DPSC-CM prevents ONJ development in a murine DRONJ model.

Microarchitecture Alternations of Osteochondral Junction in Patients with Osteonecrosis of the Femoral Head.

The study was aimed to investigate microarchitecture of osteochondral junction in patients with osteonecrosis of the femoral head (ONFH). We hypothesis that there were microarchitecture alternations in osteochondral junction and regional differences between the necrotic region (NR) and adjacent non-necrotic region(ANR) in patients with ONFH. Femoral heads with ONFH or femoral neck fracture were included in ONFH group (n = 11) and control group (n = 11). Cylindrical specimens were drilled on the NR/ANR of femoral heads in ONFH group and matched positions in control group (CO.NR/ CO.ANR). Histology, micro-CT, and scanning electron microscope were used to investigate microarchitecture of osteochondral junction. Layered analysis of subchondral bone plate was underwent. Mankin scores on NR were higher than that on ANR or CO.NR, respectively (P < 0.001, P < 0.001). Calcified cartilage zone on the NR and ANR was thinner than that on the CO.NR and CO.ANR, respectively (P = 0.002, P = 0.002). Tidemark roughness on the NR was larger than that on the ANR (P = 0.002). Subchondral bone plate of NR and ANR was thicker than that on the CON.NR and CON.ANR, respectively (P = 0.002, P = 0.009). Bone volume fraction of subchondral bone plate on the NR was significantly decreasing compared to ANR and CON.NR, respectively (P = 0.015, P = 0.002). Subchondral bone plate on the NR had larger area percentages and more numbers of micropores than ANR and CON.NR (P = 0.002/0.002, P = 0.002/0.002). Layered analysis showed that bone mass loss and hypomineralization were mainly on the cartilage side of subchondral bone plate in ONFH. There were microarchitecture alternations of osteochondral junction in ONFH, including thinned calcified cartilage zone, thickened subchondral bone plate, decreased bone mass, altered micropores, and hypomineralization of subchondral bone plate. Regional differences in microarchitecture of osteochondral junction were found between necrotic regions and adjacent non-necrotic regions. Subchondral bone plate in ONFH had uneven distribution of bone volume fraction and bone mineral density, which might aggravate cartilage degeneration by affecting the transmission of mechanical stresses.

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

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

Instructions for the use of L-PRF in different clinical indications.

Autologous platelet concentrates (APCs) have demonstrated clear benefits across various clinical applications, including alveolar ridge preservation, guided tissue regeneration, guided bone regeneration, sinus floor elevation (both lateral window approach and transcrestal technique), endodontic surgery, the treatment of medication-related osteonecrosis of the jaw bones, and periodontal plastic surgery. To ensure an optimal clinical outcome, clinicians must adhere strictly to the protocol to prepare the APCs and, especially follow evidence-based surgical guidelines, often simple but crucial, to minimize the likelihood of errors. The majority of clinical trials reported on second-generation APCs [the leukocyte- and platelet-rich fibrin (L-PRF) family, including its modifications (A-PRF, A-PRF+, CGF, T-PRF, H-PRF, etc.)]. These second-generation APCs offer additional benefits compared to the first-generation APCs, making them the preferred choice for the development of clinical recommendations. These recommendations have been formulated through a meticulous examination of the available clinical data and the clinical experience of the authors of this paper.

Medication-related osteonecrosis of the jaw: evolving research for multimodality medical management.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating side effect of antiresorptive and antiangiogenic agents that can lead to progressive bone destruction in the maxillofacial region. Dental surgery, including tooth extractions, commonly trigger the onset of MRONJ. While guidelines suggest avoiding extraction when possible, complete avoidance is not always feasible, as necrosis can develop from dental and periodontal disease without dental procedures. The goal of this article is to provide an update review of current preventive and therapeutic approaches for MRONJ. METHODS: A comprehensive electronic search was conducted on PubMed/MEDLINE, Embase, and Scopus databases. All English articles encompassing randomized controlled trials, systematic reviews, observational studies, and case studies were reviewed. The current medical treatments and adjuvant therapies for managing MRONJ patients were critically assessed and summarized. RESULTS: Pentoxifylline and alpha tocopherol (PENT-E), teriparatide, photobiomodulation (PBM), photodynamic therapy (PDT), and the use of growth factors have shown to enhance healing in MRONJ patients. Implementing these methods alone or in conjunction with surgical treatment has been linked to reduced discomfort and improved wound healing and increased new bone formation. DISCUSSION: While several adjuvant treatment modalities exhibit promising results in facilitating the healing process, current clinical practice guidelines predominantly recommend antibiotic therapy as a non-surgical approach, primarily addressing secondary infections in necrotic areas. However, this mainly addresses the potential infectious complication of MRONJ. Medical approaches including PENT-E, teriparatide, PBM, and PDT can result in successful management and should be considered prior to taking a surgical approach. Combined medical management for both preventing and managing MRONJ holds potential for achieving optimal clinical outcomes and avoiding surgical intervention, requiring further validation through larger studies and controlled trials.

Treatment of bone metastases from solid tumors with bone-modifying agents: a web survey of Italian oncologists investigating patterns of practice drug prescription and prevention of side effects.

PURPOSE: Optimal use of bone-modifying agents (BMAs) in patients with bone metastases from solid tumors is uncertain in some aspects: the drug choice; the planned treatment duration and long-term therapy; the prevention and management of possible side effects, including renal toxicity, hypocalcaemia, and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Italian oncologists were invited to fulfil a 24-question web survey about prescription of BMAs for bone metastases of breast cancer, prostate cancer, and other solid tumors. Prevention and management of side effects were also investigated. RESULTS: Answers of 191 oncologists were collected. BMAs are usually prescribed at the time of diagnosis of bone metastases by 87.0% (breast cancer) and 76.1% (solid tumors except breast and prostate cancers) of oncologists; the decision is more articulated for prostate cancer (endocrine-sensitive versus castration-resistant). The creatinine level (32.3%), the availability of patient venous access (15.8%), and the type of primary neoplasm (13.6%) are the most reported factors involved in choice between bisphosphonates and denosumab. Zoledronic acid every 3 months was considered as a valid alternative to monthly administration by 94% of Italian oncologists. Oncologists reported a good confidence with measures aimed to prevent MRONJ, whereas uncertainness about prevention and management of hypocalcemia was registered. CONCLUSION: Italian oncologists showed a high attitude in prescribing bisphosphonates or denosumab at the time of diagnosis of bone metastases, with a large application of preventive measures of side effects. Further studies are needed to investigate some controversial aspects, such as optimal drug treatment duration and long-term drug schedules.

MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1.

BACKGROUND: The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is not only the primary pathological feature but also a major contributor to the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH). Cellular senescence is one of the main causes of imbalanced BMSCs differentiation. The purpose of this study was to reveal whether cellular senescence could participate in the progression of SONFH and the related mechanisms. METHODS: The rat SONFH model was constructed, and rat BMSCs were extracted. Aging-related indicators were detected by SA-ß-Gal staining, qRT-PCR and Western Blot experiments. Using H2O2 to construct a senescent cell model, and overexpressing and knocking down miR-601 and SIRT1 in hBMSCs, the effect on BMSCs differentiation was explored by qRT-PCR, Western Blot experiment, oil red O staining (ORO), alizarin red staining (ARS), and luciferase reporter gene experiment. A rat SONFH model was established to test the effects of miR-601 and metformin in vivo. RESULTS: The current study showed that glucocorticoids (GCs)-induced BMSCs senescence, which caused imbalanced osteogenesis and adipogenesis of BMSCs, was responsible for the SONFH progression. Further, elevated miR-601 caused by GCs was demonstrated to contribute to BMSCs senescence through targeting SIRT1. In addition, the anti-aging drug metformin was shown to be able to alleviate GCs-induced BMSCs senescence and SONFH progression. CONCLUSIONS: Considering the role of BMSCs aging in the progression of SONFH, this provides a new idea for the prevention and treatment of SONFH.

Recognizing bisphosphonate-induced ear osteonecrosis in primary care: a case report.

INTRODUCTION: Medication-related ear canal osteonecrosis (MRECO) is a growing concern linked to prolonged anti-resorptive medication use. Despite primary care providers being key prescribers of these medications, there is limited information about MRECO in primary care literature. This article presents a case of bisphosphonate-induced osteonecrosis of the external auditory canal (EAC), emphasizing the vital role of primary care providers in identifying this rare yet significant side effect of anti-resorptive medication. MAIN SYMPTOMS AND CLINICAL FINDINGS: A 65-year-old female, on long-term alendronic acid for osteoporosis, presented to primary care with a 2-year history of left-sided ear blockage and itchiness. Despite prolonged topical treatment for ear wax, symptoms persisted, leading to an Otolaryngology referral. Microsuction revealed exposed bone in the left EAC. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: A computed tomography scan confirmed bony erosion of the left EAC, and in the absence of other osteonecrosis risk factors, bisphosphonate-induced osteonecrosis was diagnosed. Management involved bisphosphonate discontinuation, regular aural toilet, and topical treatment, achieving complete ear canal epithelialisation within 6 months. CONCLUSION: MRECO, a rare complication of anti-resorptive therapy, is anticipated to rise with increasing antiresorptive medication use in the ageing population. Unexplained ear symptoms in those with a history of current or prior anti-resorptive therapy should raise clinical concern, prompting evaluation for exposed bone in the EAC. Raising awareness of MRECO among primary care providers is crucial for early diagnosis and timely management.

Efficacy of adjunctive modalities during tooth extraction for the prevention of osteoradionecrosis: A systematic review and meta-analysis.

BACKGROUND: Jaw osteoradionecrosis (ORN) is a complication in patients with previous head and neck radiotherapy. Its incidence increases with dental extractions. Hence, this review aimed to evaluate the efficacy of adjunctive treatment modalities undertaken at the time of extraction in previous head and neck radiotherapy patients in preventing ORN. METHODS: A systematic review was conducted, where studies with data on ORN incidence after extraction with or without adjunctive interventions were included. Meta-analyses were conducted to estimate the pooled prevalence of ORN per intervention and the pooled odds ratio for incidence of ORN between interventions. RESULTS: In total, 1520 patients in 29 studies were included. Interventions identified were hyperbaric oxygen (HBO), pentoxifylline-tocopherol (PENTO), antibiotics (ABX), platelet-rich fibrin and photobiomodulation. The pooled prevalence of ORN for HBO (4.6%), PENTO (3.4%) and ABX (3.8%) was significantly lower than the Control (17.6%). For studies with direct comparisons between groups, HBO had lower but not significant odds of developing ORN than the Control (OR 0.27) and ABX (OR 0.57). CONCLUSIONS: HBO, PENTO and ABX may reduce the incidence of ORN compared to no intervention. Given that all three have similar incidences of ORN, ABX may be the most cost-effective and accessible adjunctive modality.

Anti-resorptive therapy and MRONJ. A survey of the Italian Society of Periodontology and Implantology.

OBJECTIVES: Anti-resorptive agents have been linked to the development of MRONJ in patients undergoing dental surgical procedures. This survey aims to explore the level of knowledge and experience of Italian Society of Periodontology and Implantology members in the management of patients treated with anti-resorptive agents and with the risk of developing MRONJ. MATERIALS AND METHODS: An 18-item questionnaire was submitted by e-mail to the SIdP members. Statistical analyses were carried out. Continuous variables were described as mean ± standard deviation (SD) or median, and first and third quartile according to distribution's normality. Normality of data was checked with Shapiro-Wilk test. RESULTS: Four hundred and fifty-one questionnaires were returned by e-mail (32%). Most of the respondents were private practitioners (81.8%). Only 47.7% declared to be highly confident in managing patients on anti-resorptive therapy while 92.5% reported to have performed tooth extractions and 52.3% implant surgery in patients under anti-resorptive therapy for osteometabolic disorders. One or more MRONJ-affected patients were encountered by 63.2% of the respondents. CONCLUSIONS: This survey highlights the need to develop a "dedicated" program both for dentists and prescribers to improve the level of cooperation and to increase the level of awareness of patients treated with anti-resorptive agents.

Reduction of MRONJ risk after exodontia by virtue of ozone infiltration: A randomized clinical trial.

INTRODUCTION: Exodontia is commonly considered as a risk factor for the development of medication-related osteonecrosis of the jaw (MRONJ) in individuals exposed to bone modifying agents. This study was aimed at assessing the efficiency and safety of a gaseous oxygen-ozone mixture as an adjuvant to a standard exodontia to reduce the risk of MRONJ development. METHODS: A randomized, open-label, phase II, single-center clinical trial involving 117 patients at risk of MRONJ was conducted. The study protocol tested injections of an oxygen-ozone mixture in the post-extraction site. Participants were randomly assigned to two groups: oxygen-ozone therapy, and standard tooth extraction protocol. Post-extraction wound healing was assessed using the Inflammatory Proliferative Remodeling (IPR) Wound Healing Scale. RESULTS: The oxygen-ozone therapy group exhibited a significant improvement in wound healing post-extraction during the inflammatory and proliferative phases, as indicated by the IPR scale scores at 3-5 days (p = 0.006) and 14 days (p < 0.001) respectively. CONCLUSION: Oxygen-ozone therapy shows promise in improving post-extraction healing in patients at risk of MRONJ. Future studies with larger sample sizes and multicenter collaborations are recommended to confirm the validity of these findings and explore the long-term efficacy of ozone therapy.

Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ).

OBJECTIVE: This paper aims to describe the 2023 update position paper on MRONJ developed by the Italian Societies of Oral Pathology and Medicine (SIPMO) and of Maxillofacial Surgery (SICMF). METHODS: This is the second update following the 2013 and 2020 Italian position papers by the Expert panel, which is a representation of the two scientific societies (SIPMO and SICMF). The paper is based on an extensive analysis of the available literature from January 2003 to February 2020, and the subsequent review of literature conducted between March 2020 and December 2022 to include all new relevant published papers to confirm or modify the previous set of recommendations. RESULTS: This position paper highlights the main issues of MRONJ on risk estimates, disease definition, diagnostic pathway, individual risk assessment, and the fundamental role of imaging in the diagnosis, classification, and management of MRONJ. CONCLUSION: The Expert Panel confirmed the MRONJ definition, the diagnostic work-up, the clinical-radiological staging system and the prophylactic drug holiday, as recognized by SIPMO-SICMF; while, it presented novel indications regarding the categories at risk of MRONJ, the prevention strategies, and the treatment strategies associated with the therapeutic drug holiday.