Fibroblast growth factor 23 inhibition attenuates steroid-induced osteonecrosis of the femoral head through pyroptosis.

Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12 h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.

Deep learning approach to femoral AVN detection in digital radiography: differentiating patients and pre-collapse stages.

OBJECTIVE: This study aimed to evaluate a new deep-learning model for diagnosing avascular necrosis of the femoral head (AVNFH) by analyzing pelvic anteroposterior digital radiography. METHODS: The study sample included 1167 hips. The radiographs were independently classified into 6 stages by a radiologist using their simultaneous MRIs. After that, the radiographs were given to train and test the deep learning models of the project including SVM and ANFIS layer using the Python programming language and TensorFlow library. In the last step, the test set of hip radiographs was provided to two independent radiologists with different work experiences to compare their diagnosis performance to the deep learning models' performance using the F1 score and Mcnemar test analysis. RESULTS: The performance of SVM for AVNFH detection (AUC = 82.88%) was slightly higher than less experienced radiologists (79.68%) and slightly lower than experienced radiologists (88.4%) without reaching significance (p-value > 0.05). Evaluation of the performance of SVM for pre-collapse AVNFH detection with an AUC of 73.58% showed significantly higher performance than less experienced radiologists (AUC = 60.70%, p-value < 0.001). On the other hand, no significant difference is noted between experienced radiologists and SVM for pre-collapse detection. ANFIS algorithm for AVNFH detection with an AUC of 86.60% showed significantly higher performance than less experienced radiologists (AUC = 79.68%, p-value = 0.04). Although reaching less performance compared to experienced radiologists statistically not significant (AUC = 88.40%, p-value = 0.20). CONCLUSIONS: Our study has shed light on the remarkable capabilities of SVM and ANFIS as diagnostic tools for AVNFH detection in radiography. Their ability to achieve high accuracy with remarkable efficiency makes them promising candidates for early detection and intervention, ultimately contributing to improved patient outcomes.

Mandibular fracture in medication-associated osteonecrosis following infliximab therapy: A case report.

INTRODUCTION: Medication-associated osteonecrosis of the jaws (MRONJ) is characterized by the presence of exposed bone or an intraoral or extraoral fistula in the maxillofacial region in patients with a history of treatment with anti-resorptive and anti-angiogenic drugs, such as monoclonal antibodies, and without a history of radiotherapy or metastatic diseases in the area. OBJECTIVE: The aim of this study is to report a case of a pathological mandibular fracture in an area of MRONJ in a patient diagnosed with Crohn's disease treated with infliximab. CASE REPORT: A 53-year-old male patient, an active smoker for 35 years, diagnosed with Crohn's disease, undergoing intravenous administration of infliximab 300 mg for 1 year and 3 months, with no previous history of anti-angiogenic or anti-resorptive medication, presenting with an extraoral fistula in the submandibular region for 4 months, with painful symptoms, diagnosed as MRONJ. He was initially treated conservatively, using antimicrobial photodynamic therapy (aPDT), antibiotic therapy, and the PENTO protocol. However, the patient evolved with a pathological fracture in the mandibular parasymphysis, requiring surgical reconstruction. FINAL CONSIDERATIONS: Pathological fracture of the mandible is a complication of MRONJ that compromises the patient's quality of life. The management of patients with MRONJ is complex and challenging.

Epstein-Barr Virus-Positive Mucocutaneous Ulcer With Medication-Related Osteonecrosis of the Jaw Arising in the Mandible of a Rheumatoid Arthritis Patient: A Case Report.

This study presents a rare case of an Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) co-existing with medication-related osteonecrosis of the jaw (MRONJ) in the mandible of a 54-year-old Japanese man who complained of painful swelling of the left mandibular gingiva over the past three months. The patient had a history of methotrexate (MTX) and bisphosphonates (BPs) use. Intraoral examination revealed a 35 mm large ulcerative lesion with marginal gingival swelling and bone exposure on the left side of the mandible. A biopsy was performed, confirming the diagnosis of EBVMCU with MRONJ. Due to the enlargement of the bone exposure, marginal resection of the mandible was performed under general anesthesia as a treatment for residual MRONJ. At the two-year follow-up, no evidence of recurrence was observed.

Treatment of Medication-Related Osteonecrosis of the Jaws (MRONJ) with Topical Therapy Using Active Oxygen Gel.

Medication-related osteonecrosis of the jaw (MRONJ) can be a debilitating complication that can arise in patients who took or are taking antiresorptive (including bisphosphonates) or antiangiogenic agents, leading to visible bone or a fistula that continues for more than eight weeks, without any history of radiotherapy. This clinical case aimed to describe the treatment of MRONJ with topical active oxygen therapy using blue®m oral gel. A 63-year-old female patient that had been taking weekly sodium alendronate (70 mg) for four years by oral via, presented discomfort and implant movement in the #46 region, by that underwent surgical extraction of the implant. After three months the patient returned and was diagnosed with MRONJ. Initially, conventional therapies were performed, including surgical debridement and antibiotic therapy, but without success. The patient still had clinical signs of osteonecrosis six months after the implant extraction. The entire socket was then filled with blue®m oral gel by topical application. The patient was instructed to continue applying the gel to the region every 8 hours for 15 days. After this period, the patient returned, and it was observed that the wound was in the healing process, with the presence of epithelialized tissue and without bone exposure. The 2-year clinical follow-up showed the lesion had healed entirely, and a new implant was installed. After the osseointegration period, the final prosthesis was placed. The patient remains under clinical follow-up. Therefore, it can be concluded that the application of blue®m oral gel in this clinical case assisted in the recovery of the osteonecrosis lesion.

Recent advances in nanomaterials for the treatment of femoral head necrosis.

Osteonecrosis of the femoral head (ONFH) is a condition that causes considerable pain and discomfort for patients, and its pathogenic mechanisms are not yet fully understood. While there have been many studies that suggest multiple factors may contribute to its development, current treatments involve both surgical and nonsurgical options. However, there is still much room for improvement in these treatment methods, particularly when it comes to preventing postoperative complications and optimizing surgical procedures. Nanomaterials, as a type of small molecule material, have shown great promise in treating bone tissue diseases, including ONFH. In fact, several nanocomposite materials have demonstrated specific effects in preventing ONFH, promoting bone tissue repair and growth, and optimizing surgical treatment. This article provides a comprehensive overview of current treatments for ONFH, including their advantages and limitations, and reviews the latest advances in nanomaterials for treating this condition. Additionally, this article explores the therapeutic mechanisms involved in using nanomaterials to treat ONFH and to identify new methods and ideas for improving outcomes for patients.

Impact of dose distribution by a 3D planning system for brachytherapy with 198Au grains for head and neck cancer.

BACKGROUND: There has been no study in which the correlation between clinical results and dosimetry based on a 3D treatment planning system in patients with 198Au grains for head and neck cancer was evaluated. METHODS: Thirty-two patients who were treated with 198Au grains for head and neck cancer were reviewed. Twenty-five patients were treated with brachytherapy alone and seven patients were treated with a combination of brachytherapy and neoadjuvant external beam radiation therapy. RESULTS: With a median observation period of 60 months, the 5-year local control rate was 82.9%. V85Gy of CTV in patients with local recurrence tended to be lower than that in patients without local recurrence (p = 0.07). The maximum dose of the keratinized gingiva in patients in whom bone exposure occurred was significantly higher than that in patients in whom bone exposure did not occur (p = 0.001). CONCLUSIONS: Dose distribution with 198Au grains can predict local control and late adverse events.

Maxillary Mucormycotic Osteonecrosis as a Manifestation of Post-COVID-19 Infection in Non-diabetic Patients: Report of Two Cases.

Mucormycosis is a rare, opportunistic fungal infection prevalent in the elderly, especially in patients with uncontrolled diabetes or a compromised immune system. However, the outbreak of the pandemic declared by the World Health Organization in late 2019 increased the incidence of mucormycosis cases in COVID-19 patients due to increased steroid usage that resulted in an immunocompromised state. The current report presents two cases of oral mucormycotic osteomyelitis in patients who developed diabetes post-COVID infection, along with a review and relevant literature.

Lincoln Sign: A Rare Presentation of Medication-related Osteonecrosis of the Jaw.

A 52-year-old female patient with metastatic breast cancer receiving denosumab for 7 years presented with marked diffuse tracer uptake in the mandible on Tc-99m-methylene diphosphonate bone scintigraphy, resembling the Lincoln sign. A diagnosis of medication-related osteonecrosis of the jaw (MRONJ) was confirmed, leading to immediate discontinuation of denosumab. Conservative therapy, including limited debridement and oral rinses, was initiated. MRONJ, a potential complication of bone-modifying agents, is more prevalent in advanced malignancy cases. The Lincoln sign has not been previously reported in MRONJ, emphasizing its consideration in cancer patients undergoing bone-modifying agent treatment.

Is the use of Pentoxifylline and Tocopherol effective in the treatment of Osteoradionecrosis of the jaws or for the treatment of medicationosteonecrosis of the jaw? An overview.

PURPOSE: The aim of the present study was to determine the methodological quality of systematic reviews that evaluated the effectiveness of pentoxifylline and tocopherol (PENTO) in the treatment of osteoradionecrosis of the jaw (ORNJ) and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Searches were performed in Databases including PubMed, Scopus, LILACS, DARE, Cochrane Library, and SIGLE through OpenGrey until March 2024, were evaluated by two independent reviewers to answer the following question: Is the use of PENTO protocol effective in the treatment of ORNJ or for the treatment of MRONJ? RESULTS: A total of 256 articles were initially identified; however, following the use of appropriate inclusion and exclusion criteria, five systematic reviews were identified for detailed analysis. The final study sample comprised 588 patients: 397 patients with ORN and 197 patients with MRONJ who were treated with PENTO. The total recovery of individuals who used the PENTO protocol was 62,2 % for ORN and 100 % for MRONJ, with a follow-up period of 1 month to 10 years. The methodological quality of the studies was assessed using the AMSTAR 2 tool, in which four were of low quality and 1 moderate quality. CONCLUSION: The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone exposure. However, the low quality of the relevant reports highlights the need for primary and secondary studies with better methodological rigor to reduce bias and provide reassurance for this treatment option.

Advantages of cone beam computed tomography for evaluation of subchondral insufficiency fractures of the knee compared to MRI.

To determine the diagnostic yield of cone beam computed tomography (CBCT) compared with 3 T magnetic resonance imaging (MRI) for the evaluation of subchondral insufficiency fractures of the knee. Consecutive patients with subchondral insufficiency fractures of the knee examined by 3 T MRI and CBCT of the femoral condyles were reviewed. Two experienced raters graded the lesion severity on 3 T MRI and CBCT images: grade 1: no signs of a subchondral bone lesion; grade 2: subchondral trabecular fracture or cystic changes, but without infraction of the subchondral bone plate; grade 3: collapse of the subchondral bone plate. Ratings were repeated after six weeks to determine reliability. In addition, the bone lesion size was measured as elliptical area (mm2) and compared between CBCT and T1-weighted MRI sequences. Among 30 patients included (43.3% women; mean age: 60.9 ± 12.8 years; body mass index (BMI) 29.0 ± 12.8 kg/m2), the medial femoral condyle was affected in 21/30 patients (70%). The grading of subchondral lesions between MRI and CBCT did not match in 12 cases (40%). Based on MRI images, an underestimation (i.e., undergrading) compared with CBCT was observed in nine cases (30%), whereas overgrading occurred in three cases (10%). Compared to CBCT, routine T1-weighted 3 T sequences significantly overestimated osseus defect zones in sagittal (84.7 ± 68.9 mm2 vs. 35.9 ± 38.2 mm2, p < 0.01, Cohen's d = 1.14) and coronal orientation (53.1 ± 24.0 mm2 vs. 22.0 ± 15.2 mm2, p < 0.01, Cohen's d = 1.23). The reproducibility of the grading determined by intra- and inter-rater agreement was very high in MRI (intra-class correlation coefficient (ICC) 0.78 and 0.90, respectively) and CBCT (ICC 0.96 and 0.96, respectively). In patients with subchondral insufficiency fractures of the knee, the use of CBCT revealed discrepancies in lesion grading compared with MRI. These findings are clinically relevant, as precise determination of subchondral bone plate integrity may influence the decision about conservative or surgical treatment. CBCT represents our imaging modality of choice for grading the lesion and assessing subchondral bone plate integrity. MRI remains the gold standard modality to detect especially early stages.

Clinical Performance of Implant-Supported Prostheses in the Rehabilitation of Patients Previously Treated for Medication-Related Osteonecrosis of the Jaws (MRONJ): A Systematic Review.

There is a lack of consensus on managing resultant bone and soft tissue defects or on restoring oral function and aesthetics following medication-related osteonecrosis of the jaws (MRONJ) lesion healing. This clinical challenge presents a dilemma for practitioners. Removable prostheses pose a recurrence risk if poorly fitted and may inadequately restore function or aesthetics in cases of significant bone defect. Dental implant-supported prostheses could enhance function and quality of life, though their risks and indications are not well-defined. This systematic review examines the clinical outcomes and complications associated with implant-supported rehabilitations post-MRONJ surgery. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations and it was pre-registered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42023492539).

Does the osteonecrotic volume/other factors predict progression to total knee arthroplasty in spontaneous osteonecrosis of the knee? An MRI study.

Background: The aim of this study is to determine whether the volume of the osteonecrotic lesion in spontaneous osteonecrosis of the knee (SONK) or other prognostic factors predict progression to total knee arthroplasty (TKA). The secondary aim is to analyse co-relation of volume of osteonecrotic lesion versus other prognostic factors The authors hypothesize that a greater osteonecrotic volume predicts progression to TKA. Materials and methods: A retrospective study was conducted at a single tertiary hospital. All patients under the care of a single surgeon with magnetic resonance imaging (MRI)-proven SONK were included from the period of January 2011 to January 2018. Survival analysis was conducted to evaluate for progression to TKA based on volume and location of osteonecrotic lesion. Univariate and multivariate analyses were performed to identify potential risk factors for TKA. Results: 42 patients with MRI-proven SONK were evaluated. 9 patients (21.4 %) required TKA. There was no significant association between progression to TKA with volume of the osteonecrotic lesion. Other factors such as age, gender, body mass index, degree of bony edema and cartilage damage, presence of meniscal tear and subchondral fractures and location of osteonecrotic lesion were also not significant. Conclusion: The volume of the osteonecrotic lesion and other evaluated prognostic factors were not predictive of the progression to TKA for patients with SONK.

Can necrotic depth be a substitute of necrotic volume to predict collapse progression in osteonecrosis of the femoral head?

OBJECTIVE: Although some patients may experience collapse progression while others may not in post-collapse osteonecrosis of the femoral head (ONFH) with a necrotic lesion located within the weight-bearing part of the acetabulum (Type B/C1), few studies have focused on the natural course after collapse. This study aimed to clarify the correlation between necrotic volume (NV) and necrotic depth (ND) in predicting collapse progression in patients with post-collapse ONFH Type B/C1. MATERIALS AND METHODS: We retrospectively reviewed 54 hips with post-collapse ONFH Type B/C1 from 52 consecutive patients who were conservatively followed up for more than 1 year. We measured the amount of femoral head collapse using biplane radiographs at each follow-up period, and produced Kaplan-Meier survival curves with collapse progression (≥ 1 mm) as the endpoint. We compared NV and ND, which were calculated as the ratio of the distance from the articular surface of the femoral head to the deepest point of a necrotic lesion to the femoral head diameter in the mid-coronal slice of T1-weighted magnetic resonance imaging (MRI). RESULTS: We observed collapse progression in 31 hips (57.4%). The NV and ND were significantly greater in hips with collapse progression than in those without collapse progression (p = 0.0127 and 0.0047, respectively). Necrotic volume was significantly correlated with ND　(rs = 0.56, p < 0.0001). CONCLUSION: This study suggests that necrotic depth on the mid-coronal slice of T1-weighted MRI can be a substitute for necrotic volume to predict collapse progression in ONFH Type B/C1.

Chemotactic Recruitment of Genetically Engineered Cell Membrane-Camouflaged Metal-Organic Framework Nanoparticles for Ischemic Osteonecrosis Treatment.

Ischemic osteonecrosis, particularly glucocorticoid-induced osteonecrosis of the femoral head (GIONFH), is primarily due to the dysfunction of osteogenesis and angiogenesis. miRNA, as a therapeutic system with immense potential, plays a vital role in the treatment of various diseases. However, due to the unique microenvironmental structure of bone tissue, especially in the case of GIONFH, where there is a deficiency in the vascular system, it is challenging to effectively target and deliver to the ischemic osteonecrosis area. A drug delivery system assisted by genetically engineered cell membranes holds promise in addressing the challenge of targeted miRNA delivery. Herein, we leverage the potential of miR-21 in modulating osteogenesis and angiogenesis to design an innovative biomimetic nanoplatform system. First, we employed metal-organic frameworks (MOFs) as the core structure to load miR-21-m (miR-21-m@MOF). The nanoparticles were further coated with the membrane of bone marrow mesenchymal stem cells overexpressing CXCR4 (CM-miR-21-m@MOF), enhancing their ability to target ischemic bone areas via the CXCR4-SDF1 axis. These biomimetic nanocomposites possess both bone-targeting and ischemia-guiding capabilities, actively targeting GIONFH lesions to release miR-21-m into target cells, thereby silencing PTEN gene and activating the PI3K-AKT signaling pathway to regulate osteogenesis and angiogenesis. This innovative miRNA delivery system provides a promising therapeutic avenue for GIONFH and potentially other related ischemic bone diseases. STATEMENT OF SIGNIFICANCE: 1. CXCR4-Engineered Membranes Enhance Targeting for Ischemic Osteonecrosis. 2. miR-21-Based Gene Therapy for Regulating Osteogenesis and Angiogenesis. 3. Expanding the Use of Membrane-Cloaked MOF Nanoparticles.

Unusual Pattern of Osteochondral Marginal Impaction in Acetabular Fractures: A Report of Two Cases.

Acetabular fractures could be accompanied by articular impaction injuries, affecting the outcomes if missed or treated less than optimally. Marginal impaction detected either in preoperative or intraoperatively imaging studies should be anatomically reduced using the femoral head as a template and augmenting the defect with bone graft if needed. The impacted segment articular surface looks enface during surgery, which is the classic description of such injuries. In the present report, we describe an unusual pattern of marginal impaction injuries appearance in two patients, in which the impacted fragment articular surface is facing toward the joint cavity, which is the reverse of the classic description, alluding to the probable mechanism of its occurrence, the technique for reduction, and the consequences of missing such injuries. Marginal impaction injuries should be diagnosed and treated correctly to preserve joint congruency; however, the surgeon should be aware of the possibility of an unusual pattern of marginal impaction in which the fragment could be reversed, and keeping this possibility in mind would make its diagnosis and management easier.

The Multiplicative Effects of Individual Risk Factors in the Development of Osteonecrosis of the Femoral Head.

BACKGROUND: While individual risk factors, including chronic corticosteroid use, alcohol abuse, and smoking, are implicated in osteonecrosis of the femoral head (ONFH), the degree to which multiple risk factors increase risk is unknown. This study aimed to: (1) identify the demographic characteristics of patients who have ONFH; (2) quantify the effects of individual risk factors on ONFH development; (3) quantify the effects of combined risk factors on ONFH development; and (4) determine the prognostic implications of combined risk factors on ONFH development. METHODS: This was a retrospective cohort study. A national insurance database was used to study a population of 2,612,383 adult patients who had a 10-year follow-up period. There were 10,233 patients identified who had a diagnosis of ONFH. We identified patients who had chronic corticosteroid use, tobacco use, and/or alcohol abuse and assessed the risk of developing ONFH over a 10-year period. Patients who had individual and multiple risk factors were grouped for comparison, and Chi-square analyses were performed. RESULTS: Higher proportions of patients who had each individual risk factor developed ONFH compared to proportions of patients who did not have risk factors. Patients who had combined risk factors were at greater risk of developing ONFH compared to patients who had no risk factors and those who had single risk factors. Combined risk factors demonstrated multiplicative effects on the development of ONFH: tobacco-alcohol risk ratio (RR) 5.25, corticosteroid-alcohol RR 10.20, tobacco-corticosteroid RR 8.69, and corticosteroid-tobacco-alcohol RR 12.54. Patients who had combined risk factors developed ONFH at younger ages than those who had single risk factors. Kaplan-Meier curve analyses demonstrated worse 10-year hip survival in the setting of combined risk factors. CONCLUSIONS: Combined risk factors have a multiplicative effect on the risk of developing of atraumatic ONFH. Orthopaedic surgeons may care for at-risk individuals through modulation of risk factors. LEVEL OF EVIDENCE: Retrospective Cohort Study, Level III.

Comparing the effects of low-level laser therapy and gaseous ozone as a preventive measure on medication-related osteonecrosis of the jaws following tooth extraction: a rat model.

OBJECTIVES: Use of numerous medications such as tyrosine kinase inhibitors (sunitinib), monoclonal antibodies (bevacizumab), fusion proteins (aflibercept), mTOR inhibitors (everolimus), radiopharmaceuticals (radium 223), selective estrogen receptor modulators (raloxifene), and immunosuppressants (methotrexate and corticosteroids) has been reported to be a risk factor for development of medication-related osteonecrosis of the jaws till date. This study aimed to evaluate the preventive effect of low-level laser therapy (LLLT) and gaseous ozone on the onset of MRONJ following tooth extraction. MATERIALS AND METHODS: A total of 40 male Wistar rats were randomly allocated into 4 groups of 10 rats each. The groups laser (L), ozone (O), and control (C) received weekly intraperitoneal injections of zoledronic acid (0.06 mg/kg), while group sham (S) received saline solution for 4 weeks. After the 4th injection, all subjects underwent mandibular first molar extraction and adjunctive laser or ozone was applied according to the groups. All the rats were sacrificed at 4 postoperative weeks for comparative histomorphometric evaluation of bone healing in extraction sites. RESULTS: Laser and ozone groups demonstrated significantly higher bone formation compared to control group (p < 0.05), while no significant difference was found between laser and ozone groups (p = 1.00). Furthermore, the greatest bone formation was observed with the sham group (p < 0.05). CONCLUSIONS: Findings of the current study support that adjunctive LLLT and ozone therapy following tooth extraction may help prevent MRONJ and improve bone healing in subjects under zoledronic acid therapy. CLINICAL RELEVANCE: Since the introduction in 2003, great effort has been devoted to developing a certain management protocol for MRONJ. Several publications have appeared in recent years documenting promising results of adjunctive LLLT and ozone application in treatment of MRONJ. However, experimental data are limited on this regard and the present study, for the first time, aimed to evaluate and compare the effects of LLLT and ozone in prevention of MRONJ.

Role of sclerostin deletion in bisphosphonate-induced osteonecrosis of the jaw.

PURPOSE: Bone resorption inhibitors, such as bisphosphonates (BP) and denosumab, are frequently used for the management of osteoporosis. Although both drugs reduce the risk of osteoporotic fractures, they are associated with a serious side effect known as medication-related osteonecrosis of the jaw (MRONJ). Sclerostin antibodies (romosozumab) increase bone formation and decrease the risk of osteoporotic fractures: however, their anti-resorptive effect increases ONJ. Thus, this study aimed to elucidate the role of sclerostin deletion in the development of MRONJ. METHODS: Sclerostin knockout (SostΔ26/Δ26) mice were used to confirm the development of ONJ by performing tooth extractions. To confirm the role of sclerostin deficiency in a more ONJ-prone situation, we used the BP-induced ONJ model in combination with severe periodontitis to evaluate the development of ONJ and bone formation in wild-type (WT) and SostΔ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and SostΔ26/Δ26 mice. RESULTS: ONJ was not detected in the extraction socket of SostΔ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the SostΔ26/Δ26 mice treated with BP compared to that of the WT mice. Osteogenic proteins, osteocalcin, and runt-related transcription factor 2, were expressed in the bone surface in SostΔ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in SostΔ26/Δ26 mice than in WT mice. CONCLUSION: Sclerostin deficiency did not cause ONJ and reduced the risk of developing BP-induced ONJ. Enhanced bone formation and wound healing were observed in the tooth extraction socket. The use of romosozumab (anti-sclerostin antibody) has proven to be safe for surgical procedures of the jaw.

Local E-rhBMP-2/ß-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model.

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/ß-Tricalcium phosphate (E-rhBMP-2/ß-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/ß-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/ß-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/ß-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.