Prevalence and Risk Factors of Osteonecrosis of the Jaw in Patients with Bisphosphonate Exposure in Casablanca, Morocco: An Observational Study

Objective: To study the prevalence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and to determine the risk factors associated with the occurrence of this pathology. Method: An observational retrospective study was conducted in the Department of Oncology, Rheumatology, and Maxillofacial Surgery of Ibn Rochd University Hospital, Casablanca. The study utilized complete medical records from 2014 to 2022 and included consultations of patients receiving bisphosphonates (BPs) in July and September 2022. Statistical analysis was performed using SPSS version 16.0. Results: Our study population comprised 104 patients, of whom 91% were women and 49% were over 65 years old. Seventy-two percent of patients had a general pathology. Among them, 64 patients were treated with zoledronate, 43 with alendronate, and the remainder with risedronate, ibandronate, and pamidronate. The most common indications for treatment were bone metastasis following breast cancer (29.8%) and osteoporotic fractures (19.2%). Sixty-seven patients received intravenous (IV) treatment;only 10.5% exhibited good oral health. Fifty percent of patients underwent dental treatment, primarily tooth extractions. Osteonecrosis of the jaw (ONJ) was diagnosed in 1.9% of patients, predominantly in stages 1 and 2. Conclusion: Second and third-generation bisphosphonates are more strongly associated with the development of ONJ. Risk factors include monthly IV administration, poor oral health, comorbidities such as diabetes, medications like corticosteroids, invasive dental procedures, and not only oncological conditions but also rare indications such as bone algodystrophy. Nevertheless, our observed prevalence of 1.9% aligns with international rates ranging from 0.8% to 12%. However, most of the studies that have been carried out have been retrospective studies with insufficient numbers of patients. Further prospective epidemiological studies based on standardized protocols with rigorous and appropriate follow-up over several years are essential to determine the exact prevalence of ONJ.

Surgical Treatment of Osteonecrosis of the Femoral Head Using Minimally Invasive Surgical Drilling and Cancellous Grafting at Brazzaville University Hospital

Introduction: Osteonecrosis of the femoral head (ONTF) is a debilitating condition. Several treatments have been proposed with controversial results. The aim of our study was to evaluate treatment by surgical drilling coupled with in situ cancellous grafting. Materials and methods: Our study was a case-control study conducted at Brazzaville University Hospital from 1st January 2018 to 31 December 2023. It compared two groups of patients with ONTF: non-operated (13 patients, 20 hips) and operated (22 patients, 35 hips). We used the visual digital scale (VDS) for pain assessment, the Merle D’Aubigne-Postel (MDP) scoring system for clinical and functional assessment, and the evolution of necrosis. Results: The group of non-operated patients had a mean age of 35.69 ± 3.4 years, no improvement in pain with an EVN above seven at the last recoil and a mean global MDP score falling from 12.7 before offloading to 10.13 at one year. The group of patients operated on had a mean age of 37.86 ± 7.02 years, a significant reduction in pain (p = 0.00004) and a significantly increased MDP score (p = 0.0034). A comparison of the two groups of patients showed significant stabilization of the necrotic lesions in the operated patients (p = 0.00067), with better satisfaction in the same group. Conclusion: Surgical drilling combined with grafting in the treatment of early-stage ONTF has improved progress in our series. The technique is reproducible and less invasive. It has made it possible to delay unfavorable progression and, consequently, hip replacement surgery.

Bone palsy eliminates granules to regulate Wnt/PI3K-AKT signaling pathway and intervene in hormonal osteonecrosis of the femoral head in rabbits

Objective:To investigate the therapeutic effect of osteopathic osteopathy on hormonal osteonecrosis in rabbits by regulating the Wnt/PI3K-AKT signaling pathway.Methods:Thirty clean-grade New Zealand rabbits were randomly divided into control group,model group and experimental group,and all except for the control group,allogeneic serum combined with glucocorticoids were used to establish animal models of simulated hormonal osteonecrosis of the femoral head.After successful modeling,the experimental group was given the model group and the control group the same amount of normal saline,and the experimental group was given bone palsy granule concentrate according to the equivalent dose of humans and rabbits,once a day for 8 weeks,and after intraperitoneal anesthesia,blood was collected from the extracorporeal heart and the serum ALP and TGF-β1 levels were detected by immunoenzyme-linked adsorption.The experimental animals were sacrificed,,and the bilateral femoral heads of rabbits were removed for hematoxylin-eosin staining,and the apoptosis of cells in the femoral head area was observed by TUNEL staining.RT-qPCR analyzed the expression of Bax and Bcl-2 genes,and Western blot detected the expression levels of pathway proteins Wnt,β-catenin,GSK-3β,AKT and p-AKT.Results:Compared with the control group,the expression levels of ALP and TGF-β1 in rabbit bone tissue in the model group decreased significantly(P<0.05),the bone trabeculae were sparse and thinned,the number of hollow bone fosses and the number of apoptosis-positive cells increased significantly(P<0.05),the expression of pro-apoptotic gene Bax was increased,and the expression of anti-apoptotic gene Bcl-2 was inhibited(P<0.05).After the intervention and treatment of bone palsy granules,the hollow bone depression and apoptosis of rabbit bone tissue in the experimental group were effectively improved(P<0.05).In addition,compared with the model group,the osteopathic elimination particles could upregulate the expression of ALP and TGF-β1(P<0.05),promote the expression of pathway proteins Wnt andβ-catenin,increase the phosphorylation level of AKT,and downregulate the expression of GSK-3β(P<0.05).Conclusion:Under glucocorticoids,osteoblast development dysfunction and apoptosis increase.Bone palsy granules can regulate the two signaling pathways of Wnt/PI3K-AKT,promote osteoblast development and inhibit apoptosis,effectively maintain bone metabolic balance,prolong the collapse time of the femoral head,and further treat osteonecrosis of the femoral head.

The role and research progress of PI3K/AKT signaling pathway in non-traumatic osteonecrosis of the femoral head

Non-traumatic osteonecrosis of the femoral head(NONFH)is one of the most common orthopedic diseases,influenced by multiple signaling pathways and inflammatory factors.The PI3K/AKT signaling pathway is closely related to various biological processes such as apoptosis,autophagy,and metabolism in cells.Increasing evidence suggests that it plays an important role in the development of femoral head necrosis.This paper aims to explore the mechanism of the PI3K/AKT signaling pathway in the pathogenesis of NONFH by analyzing its regulation of lipid metabolism,cell apoptosis and autophagy,and intravascular coagulation.This study provides new insights for the research of NONFH.

Design and Implementation of a Control System to Mitigate Osteonecrosis in Orthopedic Bone Drilling Procedures

The drilling process in orthopedic surgery can sometimes lead to an undesired increase in temperature,which can cause serious damage to bones and soft tissues.This overheating is typically identified as a temperature above 47℃,known as the critical limit,and can result in the condition known as osteonecrosis.This study aims to develop a new control system,using a proportional-integral-derivative(PID)controller,to prevent overheating and the resulting osteonecrosis.The bone temperature is constantly measured using a thermocouple and,when it reaches the critical temperature of 47℃,the cooling device is activated by the PID-controlled system.This new control system makes the drill machine with cooling device more user-friendly and allows surgeons to set a desired temperature level manually.

Current concepts on osteonecrosis of the femoral head

It is estimated that 20000 to 30000 new patients are diagnosed with osteonecrosis annually accounting for approximately 10% of the 250000 total hip arthroplasties done annually in the United States. Thelack of level 1 evidence in the literature makes it difficult to identify optimal treatment protocols to manage patients with pre-collapse avascular necrosis of the femoral head, and early intervention prior to collapse is critical to successful outcomes in joint preserving procedures. There have been a variety of traumatic and atraumatic factors that have been identified as risk factors for osteonecrosis, but the etiology and pathogenesis still remains unclear. Current osteonecrosis diagnosis is dependent upon plain anteroposterior and frog-leg lateral radiographs of the hip, followed by magnetic resonance imaging(MRI). Generally, the first radiographic changes seen by radiograph will be cystic and sclerotic changes in the femoral head. Although the diagnosis may be made by radiograph, plain radiographs are generally insufficient for early diagnosis, therefore MRI is considered the most accurate benchmark. Treatment options include pharmacologic agents such as bisphosphonates and statins, biophysical treatments, as well as joint-preserving and joint-replacing surgeries. the surgical treatment of osteonecrosis of the femoral head can be divided into two major branches: femoral head sparing procedures(FHSP) and femoral head replacement procedures(FHRP). In general, FHSP are indicated at pre-collapse stages with minimal symptoms whereas FHRP are preferred at post-collapse symptomatic stages. It is difficult to know whether any treatment modality changes the natural history of core decompression since the true natural history of core decompression has not been delineated.

Osteonecrosis of the femoral head: An update in year 2012

Osteonecrosis is a phenomenon involving disruption to the vascular supply to the femoral head, resulting in articular surface collapse and eventual osteoarthritis. Although alcoholism, steroid use, and hip trauma remain the most common causes, several other etiologies for osteonecrosis have been identified. Basic science research utilizing animal models and stem cell applications continue to further elucidate the pathophysiology of osteonecrosis and promise novel treatment options in the future. Clinical studies evaluating modern joint-sparing procedures have demonstrated significant improvements in outcomes, but hip arthroplasty is still the most common procedure performed in these affected younger adults. Further advances in joint-preserving procedures are required and will be widely studied in the coming decade.

Vascular endothelial growth factor for the treatment of femoral head osteonecrosis: An experimental study in canines

AIM To evaluate the treatment of osteonecrosis of the femoral head(ONFH) with the use of vascular endothelial growth factor(VEGF).METHODS In 30 mature beagles(6 groups of 5 beagles) ONFH was induced cryosurgically and one of the following solutions was administered locally in the femoral head(FH) in each group: Single injection of 500 μg VEGF(t-VEGFμ group); single injection of 500 ng VEGF(t-VEGFn group); continuous delivery of 500 μg VEGF through osmotic micropump(t-VEGFpump-μ group); continuous delivery of 500 ng VEGF through osmotic micropump(t-VEGFpump-n group); single injection of 0.9% sodium chloride(t-NS group), while one group that served as control group did not receive any local solution(No-t group). FHs were retrieved 12 wk postoperatively, underwent decalcification and hematoxylin/eosin and toluidine blue staining. In two canines per group, one half of FH was processed without decalcification and stained with modified Masson Trichrome. Histological sections were observed by light microscopy and measured with a semi-automatized bone histomorphometry system and Bone Volume/Total Volume(BV/TV), Marrow Volume/Total Volume(MaV/TV), and Trabecular Thickness(TbT h) were assessed. Standard and robust tests(Welch, Brown Forsythe) of analysis of variance along with multiple comparisons, were carried out among the categories.RESULTS The untreated(No-t) group had signs of osteonecrosis, whereas the VEGF groups revealed reversal of the osteonecrosis. Statistical analysis of the decalcified specimens revealed a significantly better BV/TV ratio and a higher Tb Th between the VEGF treatment groups(except the t-VEGFn group) and the No-t group or the control t-NS group. Single dose 500 μg VEGF group had significantly better BV/TV ratio and higher Tb Th when compared to the No-t group(50.45 ± 6.18 vs 29.50 ± 12.27, P = 0.002 and 151.44 ± 19.07 vs 107.77 ± 35.15, P = 0.161 respectively) and the control t-NS group(50.45 ± 6.18 vs 30.9 ± 6.67, P = 0.004 and 151.44 ± 19.07 vs 107.14 ± 35.71, P = 0.151 respectively). Similar differences were found for the prolonged VEGF delivery/pump groups of 500 μg and 500 ng. Analysis of the totality of specimens(decalcified/non-decalcified) enhanced the aforementioned differences and additionally revealed significant differences in the comparison of the TbT h.CONCLUSION In an experimental model of ONFH in canines it was found that local treatment with VEGF leads to bone tissue remodeling and new bone formation.

Association of Toll-like receptor 4 Signaling Pathway with Steroid-induced Femoral Head Osteonecrosis in Rats

Osteonecrosis of the femoral head is frequently observed in patients treated with excessive corticosteroids. However, the pathogenesis of corticosteroid-induced osteonecrosis remains unclear. The purpose of this study was to investigate the role of Toil-like receptor 4 （TLR4） signaling pathway in steroid-induced femoral head osteonecrosis in rats. Male Sprague-Dawley rats were injected intramus- cularly with 20 mg/kg methylprednisolone （MP） for 8 weeks, twice per week. The animals were sacri- ficed at 2, 4 and 8 weeks after the last MP injection, respectively, and then allocated to the 2-, 4- and 8-week model groups （n=24 each）. Rats in the control group （n=12） were not given any treatment. Histopathological analysis was performed and the concentration of tartrate-resistant acid phosphatase （TRAP） in plasma was determined. The activation of osteoclasts in the femoral head was assessed by TRAP staining. The expression of TLR4, MyD88, TRAF6 and NF-Id3 p65 that are involved in TLR4 signaling, and MCP-1 production were detected by using real-time PCR （RT-PCR） and Western blotting. The results showed that the osteonecrosis in the femoral head was clearly observed and the concentra- tion of TRAP in the plasma was increased in the model rats. The femoral head tissues in MP-treated rats were positive for TRAP and the intensity of TRAP staining was greater in MP-treated rats than in con- trol rats. As compared with the control group, the mRNA expression of TLR4 signaling-related factors was enhanced significantly at 4 and 8 weeks, and the protein levels of these factors increased signifi- cantly with time. It was concluded that MP could induce the femoral head osteonecrosis in rats, which was associated with osteoclast activation via the TLR4 signaling pathway. These findings suggest that TLR4 signaling pathway plays a pivotal role in the pathogenesis of steroid-induced osteonecrosis.

Surface-based map plasticity of brain regions related to sensory motor and pain information processing after osteonecrosis of the femoral head

Pain is one of the manifestations of hip disorder and has been proven to lead to the remodeling of somatotopic map plasticity in the cortex.However,most studies are volume-based which may lead to inaccurate anatomical positioning of functional data.The methods that work on the cortical surface may be more sensitive than those using the full brain volume and thus be more suitable for map plasticity study.In this prospective cross-sectional study performed in Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine,China,20 patients with osteonecrosis of the femoral head(12 males and 8 females,aged 56.80±13.60 years)and 20 healthy controls(9 males and 11 females,aged 54.56±10.23 years)were included in this study.Data of resting-state functional magnetic resonance imaging were collected.The results revealed that compared with healthy controls,compared with the healthy controls,patients with osteonecrosis of the femoral head(ONFH)showed significantly increased surface-based regional homogeneity(Re Ho)in areas distributed mainly in the left dorsolateral prefrontal cortex,frontal eye field,right frontal eye field,and the premotor cortex and decreased surface-based Re Ho in the right primary motor cortex and primary sensory cortex.Regions showing significant differences in surfacebased Re Ho values between the healthy controls and patients with ONFH were defined as the regions of interests.Seed-based functional connectivity was performed to investigate interregional functional synchronization.When the areas with decreased surface-based Re Ho in the frontal eye field and right premotor cortex were used as the regions of interest,compared with the healthy controls,the patients with ONFH displayed increased functional connectivity in the right middle frontal cortex and right inferior parietal cortex and decreased functional connectivity in the right precentral cortex and right middle occipital cortex.Compared with healthy controls,patients with ONFH showed significantly decreased cortical thickness in the para-insular area,posterior insular area,anterior superior temporal area,frontal eye field and supplementary motor cortex and reduced volume of subcortical gray matter nuclei in the right nucleus accumbens.These findings suggest that hip disorder patients showed cortical plasticity changes,mainly in sensorimotor-and pain-related regions.This study was approved by the Medical Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine(approval No.2018-041)on August 1,2018.

Role of Electromagnetic Stimulation in the Treatment of Osteonecrosis of the Femoral Head in Early Stages

Osteonecrosis of the femoral head is a disorder that leads to collapse and osteoarthritis in young patients. This study examines the effectiveness of pulsed electromagnetic fields [PEMF] in the treatment of osteonecrosis of the head in precollapse bone stages. A retrospective evaluation was done of 51 patients including 70 hips with symptomatic osteonecrosis of the hip treated with pulsed electromagnetic fields. Criteria for inclusion in the study group were evidence of osteonecrosis and absence of collapse of the femoral head. The average follow-up was 26 months (range, 18 - 90). Etiologies included idiopathic (40 cases), steroid use (26) and alcohol (4). To demonstrate the existence of osteonecrosis and its evolution, magnetic resonance imaging [MRI] and plain radiography techniques were used. Results: Procedures were radiological success in 80% of cases, and no progression to collapse in 88.57% of hips. Eight of the 70 hips had radiographic progression to collapse. This study suggests that selected PEMF reduce the incidence of progression of osteonecrosis of femoral head in early stage.

A tree shrew model for steroid-associated osteonecrosis

DEAR EDITOR,Osteonecrosis is a common human disease in orthopedics.It is difficult to treat,and half of patients may need artificial joint replacement,resulting in a considerable economic burden and a reduction in quality of life.Hormones are one of the major causes of osteonecrosis and high doses of corticosteroids are considered the most dangerous factor.

Protective Effect of Human Umbilical Cord Mesenchymal Stem Cells in Glucocorticoid-induced Osteonecrosis of Femoral Head

Objective:To evaluate the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on preventing rats from glucocorticoid-induced osteonecrosis of femoral head(GC-ONFH)in the early stage in vivo and to investigate the possible mechanism of hUC-MSCs in regulating the balance of osteogenesis and adipogenesis.Methods:All rats were randomly divided into 3 groups:control group(C group),model group(M group),and intervention group(Ⅰ group).The model of GC-ONFH was developed by a sequential administration of lipopolysaccharide and methylprednisolone.The rats in the Ⅰ group were treated with caudal vein injection of hUC-MSCs.Six weeks later,the blood samples were obtained to measure the activity of alkaline phosphatase(ALP)and the content of triglyceride(TG)in serum,and the femoral heads were harvested and observed by hematoxylin-eosin staining,Micro-CT,Western blot and real-time quantitative polymerase chain reaction.Results:After intervention of hUC-MSCs,the necrosis rate of femoral head decreased from 83%(10/12)to 33%(4/12),the rate of empty bone lacuna was significantly decreased,the activity of ALP increased significantly,the content of TG decreased significantly,the bone density increased obviously,the expression of RUNX2 and Col Ⅰ increased significantly and the expression of PPARγ decreased significantly.Conclusion:These results revealed that caudal vein injection of hUC-MSCs can effectively reduce the incidence of GC-ONFH in rats by increasing ALP activity and reducing TG content in serum,increasing bone mineral density,promoting the expression of RUNX2 and Col I,and inhibiting the expression of PPARγ.

Modified technique of advanced core decompression for treatment of femoral head osteonecrosis

BACKGROUND Osteonecrosis of the femoral head(ONFH)is a destructive condition most commonly affecting young and middle-aged patients.The leading consequence of ONFH is often a significant articular disability.Effective joint-preserving surgical treatments are urgently needed for patients with early stage ONFH when outcomes of treatment are in general better than the advanced stage disease.AIM To introduce a new surgery procedure called percutaneous expanded core decompression and mixed bone graft technique,which is a new way of jointpreserving surgical treatments.METHODS The clinical data of 6 patients with ONFH diagnosed and treated with the procedure called percutaneous expanded core decompression and mixed bone graft technique at The First Hospital of Qiqihar from March 2013 to August 2019 were retrospectively analyzed;the follow-up ended in December 2019.RESULTS There were 6 male patients with an average age of 43 years in our study.Gratifying results have been obtained from the comparison of Harris hip score,visual analogue scale,and imaging examination before and after operation.CONCLUSION This new modified technique is simple,safe,and reliable.No serious perioperative complications were observed in our cases.Advantages of the single blade expandable reamer are obvious.The adjuvant substance is inexpensive and easy to obtain.Thus,this technique is an effective joint-preserving surgical treatment for patients with early stage of ONFH.

Potential role of the compound Eucommia bone tonic granules in patients with osteoarthritis and osteonecrosis: A retrospective study

BACKGROUND Osteoarthritis is a major source of pain,disability,and socioeconomic cost worldwide.Osteonecrosis is a disabling disorder that frequently occurs in the younger population aged from 20-50 years.The compound Eucommia bone tonic granules,a traditional Chinese medicine,can alleviate the damage of osteoarthritis and osteonecrosis.AIM To investigate the potential role of the compound Eucommia bone tonic granules(Eucommia)in the treatment of patients with osteoarthritis and osteonecrosis.METHODS One-hundred forty osteoarthritis and osteonecrosis cases admitted to our hospital from January 2013 to December 2017 were selected.Patients were divided into two groups:Eucommia-meloxicam group and meloxicam group.Clinical efficacy and the Western Ontario and McMaster Universities Arthritis Index(WOMAC)score were evaluated according to the evaluation criteria of orthopedic diseases.The levels of bone-GLA protein,interleukin-17,recombinant human S100 calcium binding protein A12,sphingosine 1-phosphate,cystatin C,creatinine,and hemoglobin in peripheral blood were determined.RESULTS The total effective rate in the two osteoarthritis groups was not different,but the total effective rate in the two osteonecrosis groups was significantly different.The overall efficacy of Eucommia-meloxicam group was superior to that of the meloxicam group.WOMAC showed that pain,stiffness,and dysfunction in the two groups of osteoarthritis and osteonecrosis before and after treatment were significantly different.The concentration of recombinant human S100 calcium binding protein A12,sphingosine 1-phosphate,cystatin C,creatinine,and hemoglobin before and after treatment in the Eucommia-meloxicam group and meloxicam group of osteoarthritis and osteonecrosis were significantly different,and the two treatment groups were significantly different from each other for osteoarthritis.CONCLUSION Our findings indicate that Eucommia can effectively enhance the curative effect of meloxicam,and the combination of Eucommia and meloxicam is superior to meloxicam alone.

Surgical management of osteonecrosis of the femoral head in patients with sickle cell disease

Sickle cell disease is a known risk factor for osteonecrosis of the hip.Necrosis within the femoral head may cause severe pain,functional limitations,and compromise quality of life in this patient population.Early stages of avascular necrosis of the hip may be managed surgically with core decompression with or without autologous bone grafting.Total hip arthroplasty is the mainstay of treatment of advanced stages of the disease in patients who have intractable pain and are medically fit to undergo the procedure.The management of hip pathology in sickle cell disease presents numerous medical and surgical challenges,and the careful perioperative management of patients is mandatory.Although there is an increased risk of medical and surgical complications in patients with sickle cell disease,total hip arthroplasty can provide substantial relief of pain and improvement of function in the appropriately selected patient.

Effect of <i>Qing’e Pill</i>plus <i>Salvia</i>on Non-Traumatic Osteonecrosis of the Femoral Head of Idiopathic Type in Earlier Stage: A Case Report of a Twelve-Month of Period

Background: Compromised circulatory and bone/lipid metabolic dysfunction are two major contributors to non-traumatic osteonecrosis of the femoral head (ONFH). Qing’e pill plus Salvia has significant anti-inflammatory and anti-atherosclerotic action, and it could also regulate bone formation and remodeling by suppressing osteoclasts. Case Report: We describe a case of a 62-year- old man with ONFH of idiopathic type in earlier stage that could not be adequately controlled with oral non-steroidal analgesics and restoring bone loss agents for past 3 years. After six months treatment with Qing’e pill plus Salvia, the plasma low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (apo A1), apolipoprotein B (apo B), total cholesterol (TC), triglycerides (TG), and blood viscosity were measured on an empty stomach. The Harris scores were maintained during a six months follow-up after discontinuation of Qing’e pill plus Salvia. Discussion: Our case has shown that plasma levels of inflammatory and atherosclerotic relaxed factors and the Harris scores may be controlled with herbal medication in ONFH of idiopathic type in earlier stage that could not be adequately controlled with oral non-steroidal analgesics and restoring bone loss agents.

Establishment and assessment of rodent models of medication-related osteonecrosis of the jaw(MRONJ)

Medication-related osteonecrosis of the jaw(MRONJ)is primarily associated with administering antiresorptive or antiangiogenic drugs.Despite significant research on MRONJ,its pathogenesis and effective treatments are still not fully understood.Animal models can be used to simulate the pathophysiological features of MRONJ,serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ.Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ,but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ.Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic.This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency.Currently,there is a lack of a unified assessment system for MRONJ models,which hinders a standard definition of MRONJ-like lesions in rodents.Therefore,this review comprehensively summarizes assessment systems based on published peer-review articles,including new approaches in gross observation,histological assessments,radiographic assessments,and serological assessments.This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ.

Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw

Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate（BP）-related osteonecrosis of the jaw（ONJ） or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts（n530）; patients with periodontal disease without a history of BP therapy（Control, n510）, patients with periodontal disease having history of BP therapy but without ONJ（BP, n55） and patients with BRONJ（BRONJ, n515）. Denaturing gradient gel electrophoresis of polymerase chain reaction（PCR）-amplified 16 S r RNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ（71.6%）, BP（70.3%） and Control（59.1%）. Significant differences（P,0.05） in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay（ELISA）results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix–loop–helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.

The initial phase of oxidative stress in a steroid-induced osteonecrosis rabbit model

Using a rabbit model, we examined N epsilon-(hexanoyl) lysine (HEL) levels in bone and urine to detect when peroxidative reaction first occurs after steroid administration. Japanese white rabbits weighing about 3.5 kg each were injected with a single intramuscular dose of methylprednisolone 40 mg/kg and divided into groups consisting of 10 rabbits each, which were killed after 1, 3, 5 and 14 days (groups A, B, C and D respectively). As a control, 10 untreated rabbits (group N) were also studied. The proximal femurs were examined histopathologically and immunohistochemically using monoclonal antibody HEL, which is a highly specific antibody against N epsilon-(hexanoyl) lysine, an early peroxidation marker. In addition, urinary levels of HEL were measured by enzyme-linked immunosorbent assay in group N, A, B and C. Osteonecrosis was detected only in group D (90%). Increase of positive reaction of HEL in the bone was observed in group A and D. HEL expression in group D was judged to be a secondary reaction resulting from the development of osteonecrosis. Urinary level of HEL showed a significant increase in only group A (P < 0.001). The present findings suggest that peroxidation in bone occurred within 24 hours after steroid administration in a rabbit model and that it is possible to noninvasively grasp the timing of this peroxidative reaction by measuring the urinary level of HEL.