Photodynamic Therapy for Medication-Related Osteonecrosis of the Jaws: A Case Report

Medication-related osteonecrosis of the jaws (MRONJ) is a relatively new disease. MARX reported first cases in 2003. MRONJ relates to oral and parenteral bisphosphonates as well as to the so-called target cancer therapies but the list of medications only grows. Although MRONJ is a relatively rare condition, it can be associated to significant morbidity with feeding limitations and intense pain. More severe cases can lead to potentially life-threatening infections. Every patient initiating bisphosphonate and/or target cancer therapy must visit a dentist before starting medication because preventive measures for MRONJ are much more effective compared to surgical management of the lesions. Surgical resolution can be especially difficult to obtain in the coexistence of certain complication factors like wider bone exposures, history of nitrogen containing bisphosphonates use (mainly zolendronate) and immunodeficiency. Recently, researchers have given attention to laser therapy associated to photosensitive agents as a possible option to management of some MRONJ lesions. Our case report demonstrates the use of photodynamic therapy in a denosumab related lesion in the mandible. It seems that denosumab related lesions are more amenable to treatment and total resolution because of the marked differences between its chemical and metabolic characteristics when compared to bisphosphonates.

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.

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.

Bisphosphonate-related osteonecrosis of the jaws: A report on 30 cases

Aim: To report a series of thirty cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Material and Methods: For 30 patients with BRONJ, gender, age, underlying diagnosis, type of bisphosphonate (BP), administration route and duration, location and stage of osteonecrosis, symptoms and oral health status, radiological findings of the jaws, treatment and outcome, were recorded. Results: Underlying diagnoses in the series (12 male;18 female;mean age 70.50 ± 9.62) were: 12 multiple myeloma, 7 breast cancer, 3 prostate carcinoma, 1 kidney/lung/ bladder/mediastinal cancer, 1 chronic lymphocytic leukemia, 1 osteoporosis, 1 palatal osteosarcoma + osteoporosis, 1 non-Hodgkin’s lymphoma. Forty-seven osteonecrotic lesions were detected;30 localized in the mandible,17 inthe maxilla;trigger events were tooth extraction in 31 cases (66%), periodontal disease in 4 (8.50%), incongruous dentures in 3 (6.40%), perimplantitis in 1 (2.10%), unknown in 8 (17%). Twenty-nine patients had received treatment using amino bisphosphonates (25 zoledronate, 2 pamidronate, 2 alendronate) and 1 clodronate;the administration route was intravenous in 27 patients, oral in 2 and intramuscular in 1. Mean number of doses to bone exposure for patients was 34.11 for zoledronate, 50.50 for pamidronate, 146 for alendronate, and 500 for clodronate. Among statistical data the only significant finding was that panoramic dental radiography gave no concrete support for diagnosis of ONJ lesions (p ≤ 0.04). Conclusions: Our case series reflects literature data. We emphasize the insufficient role of panoramic radiography to study osteonecrotic lesions and the role of poor oral hygiene.

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.

Jaw Osteonecrosis in Patients Receiving Oral Bisphosphonates Therapy

We describe the cases of three patients, under the care of the rheumatology service, who presented with osteonecrosis of the jaw whist on oral bisphosphonate therapy. The first case is of a 74-year-old woman with a 12 year history of sero-negative inflammatory arthritis, having been on oral steroids for 11 years, Methotrexate for the preceding 6 years, and oral bisphosphonates for 9 years. Clinical and radiographic examination revealed extensive jaw necrosis. The second patient was a 72-year-old woman with temporal arteritis, on long term oral steroids, and oral bisphosphonates presenting with jaw osteonecrosis. The third case is of an 81-year-old lady with a diagnosis of Polymyalgia Rheumatica on reducing dose of prednisolone along with calcium and vitamin D3 and oral bisphosphonate therapy as part of steroid induced prophylaxis guidelines. On reviewing the literature regarding bisphosphonate-associated osteonecrosis of the jaw, there is indeed recognition of this occurring with oral bisphosphonates. However, this is far less common than with intravenous preparations. Reports to the UK MHRA regarding adverse reactions have shown 53 cases of osteonecrosis of the jaw associated with oral bisphosphonates, but this is thought to represent under-reporting. We suggest consideration of patient counselling and consent, and preventive dental work prior to initiation of oral bisphosphonate therapy.

Prevention and treatment of osteonecrosis of the jaw

Purpose: to update recommendations for the prevention and treatment of osteonecrosis of the jaw in patients on bisphophonate therapy. Osteonecrosis of the jaw is a rare and serious complication of bisphosphonate therapy. Also, it is one of the important and growing clinical public health issues, because biphosphonates are now more commonly used than before. Bisphophonates are primarly used in the treat-ment of cancer-related conditions such as bone metastases, hypercalcemia, lytic skeletal lesions. More recently, bisphophonate has been approved for the management of osteoporosis. The etiology and pathogenesis remain unknown, however, two important risk factors have been identified, i.e. the potency and length of bisphos- phonate use, and recent dental intervention. Recommendations: prior to the introduction of bisphosphonate therapy, all patients should undergo complete dental examination, any active oral cavity infec-tion should be treated and the potential sites of new infection removed. During bisphosphonate therapy, patients should strictly comply with oral hygiene and avoid any invasive procedure of the oral cavity.

使用双膦酸盐药物患者种植体早期失败率及术后药物相关性颌骨坏死的单组率Meta分析

目的系统评价使用双膦酸盐药物(bisphosphonates,BPs)患者种植体早期失败率及种植术后药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)发生率,为临床评估相关风险提供依据。方法计算机检索Cochrane Library、Wiley Online Library、PubMed、中国知网、万方数据知识服务平台,收集纳入各数据库建库至2022年5月发表的关于使用BPs患者种植体早期失败或种植术后发生MRONJ的临床研究。采用Stata 15.0软件对种植体早期失败率进行单组率Meta分析。结果共纳入13篇文献,其中口服BPs患者植入1182颗种植体,静脉注射BPs患者植入79颗,共计1261颗种植体。口服BPs患者合并种植体早期失败率为1.7%(95%CI:0.3%~3.9%),MRONJ发生率为0。静脉注射BPs患者种植体早期失败率为0,MRONJ发生率为5.6%。结论口服BPs患者种植体早期失败率及术后MRONJ发生率低,与健康人群基本相当。静脉使用BPs患者种植术后发生MRONJ风险较高,临床适应证选择应慎重。

舌下腺瓣修复临床Ⅱ期慢性黄磷性颌骨骨髓炎和药物相关性颌骨坏死术后缺损

目的:探讨利用舌下腺瓣修复临床Ⅱ期慢性黄磷性颌骨骨髓炎(PNJ)和药物相关性颌骨坏死(MRONJ)术后颌骨缺损的临床效果。方法:利用舌下腺瓣修复慢性下颌骨坏死术后颌骨缺损的5例患者。其中慢性黄磷性颌骨骨髓炎3例,药物相关性颌骨坏死患者2例。结果:5例患者临床检查评价治疗效果,术后2周内创口愈合良好,无感染,舌下腺功能正常。结论:利用舌下腺瓣修复慢性黄磷性颌骨骨髓炎和药物相关性颌骨坏死术后下颌骨缺损有效可行。

双层软组织缝合封闭技术在下颌骨中早期药物相关性颌骨骨坏死患者手术治疗中的应用

目的:探究双层软组织缝合封闭技术在单纯应用抗骨吸收药物引起的发生在下颌骨的中早期药物相关性颌骨骨坏死(medication-related osteonecrosis of the jaw,MRONJ)患者手术治疗中的临床应用效果。方法:选择2021年10月至2022年9月于北京大学口腔医院四病区经手术治疗的中早期下颌骨MRONJ患者的病历资料进行回顾性分析,收集患者术前基线临床资料,包括原发疾病、伴发疾病、用药方案(药物种类、用药时长)、MRONJ分期、临床症状、影像学表现等,所有患者在手术中行下颌骨边缘切除术去除坏死骨,运用双层软组织缝合封闭技术关闭伤口,术后定期复查随访,评价双层软组织缝合封闭技术的治疗效果及并发症,并对患者进行疼痛评分和功能状态评价。结果:研究共纳入13例患者(女12例,男1例),年龄(66.69±13.14)岁。原发疾病包括骨质疏松7例,肺癌2例,乳腺癌3例,前列腺癌1例;2例伴发糖尿病,2例伴发心血管疾病,1例伴发干燥综合征。9例患者静脉注射唑来膦酸,平均用药时间(37.7±20.0)个月,7例患者同时服用了来曲唑片等其他药物;3例患者应用地舒单抗注射液,平均用药时间(10.3±11.9)个月;5例患者服用阿仑膦酸钠片,平均用药时间(55.20±27.20)个月,2例患者不同程度地服用醋酸泼尼松片或阿卡波糖片。MRONJ 1期4例,2期9例。13例患者均采用双层软组织缝合封闭技术关闭伤口,术后平均随访11.9个月(9~17个月),13例患者皆治愈,无溢脓等并发症发生。患者术前Karnofsky功能状态评分量表(Karnofsky performance status,KPS)评分为(68.46±14.05)分,术后评分为(82.31±15.36)分,差异有统计学意义(P<0.05)。患者术前疼痛评估视觉模拟评分量表(visual analogue scale,VAS)评分为(5.77±0.73)分,术后评分为(0.38±0.51)分,差异有统计学意义(P<0.001)。结论:双层软组织缝合封闭技术在中早期单纯使用抗骨吸收类药物的下颌骨MRONJ患者中可以取得良好的临床治疗效果,可为用药情况更加复杂的MRONJ患者提供临床治疗思路。

骨管技术在Ⅱ期下颌骨药物相关性颌骨坏死手术中的应用初探

目的 探讨手术联合骨管技术在Ⅱ期下颌骨药物相关性颌骨坏死(MRONJ)治疗中的效果。方法 纳入2020年6月—2023年6月期间21例行手术治疗的Ⅱ期下颌骨MRONJ患者,回顾分析患者的临床资料(性别、年龄、原发疾病、药物名称及给药方式、术前是否停药和预后)。其中男性14例,女性7例,发病时平均年龄为(68.33±10.74)岁。根据美国口腔颌面外科医师协会的指南对患者进行分期,纳入患者为Ⅱ期下颌骨MRONJ,治疗方式为颌骨部分切除术联合骨管技术,术中软组织无张力严密缝合。术后定期随访,并根据患者的临床表现及影像学检查等评价手术疗效。采用简版SF-12量表对所有患者进行术前和术后生活质量评价。结果 本组患者共21例,术后随访8~38个月,17例患者黏膜愈合良好(80.95%),临床伴随症状消失,无新的死骨形成。患者术后生活质量评分[(83.62±5.90)分]显著高于术前[(63.67±4.70)分](P<0.05)。结论 手术联合骨管技术在较为难治的Ⅱ期MRONJ患者中是一种有效的治疗方法,成功率高。

干细胞复合物防治医源性颌骨坏死的研究进展

药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)及放射性颌骨坏死(osteoradionecrosis of the jaw,ORNJ)是两种常见的难治性医源性颌骨坏死。随着骨组织工程的迅猛发展,将生物材料负载干细胞所制成的干细胞复合物,用于对MRONJ及ORNJ的预防和治疗成为本领域研究的重点和热点。本文通过对干细胞复合物防治MRONJ和ORNJ的相关研究进行回顾,阐述干细胞复合物对MRONJ及ORNJ的防治效果和影响因素,分析该技术有待探究的问题,以期为进一步研究指明方向,为临床应用提供依据。

特立帕肽对大鼠药物相关性颌骨坏死模型作用的实验研究

目的:建立稳定的药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)模型,探究特立帕肽对MRONJ的治疗作用。方法:选择10月龄SD大鼠,经尾静脉注射唑来膦酸(80μg/kg),每周1次,持续7周,第8周拔除右上颌第一、第二磨牙。拔牙术后8周,观察大鼠颌骨坏死情况。将颌骨坏死建模成功的动物随机分为对照组和实验组,分别接受生理盐水和特立帕肽(60μg/kg,每周3次)皮下注射治疗,4周后处死大鼠,进行大体观察、组织学检测、micro-CT检测,评价特立帕肽对MRONJ的治疗效果。结果:对照组大鼠颌骨坏死未见愈合,且坏死程度加重;micro-CT影像见颌骨纹理紊乱,边缘粗糙,死骨形成,骨破坏区与鼻旁窦相通。实验组见大鼠拔牙创逐渐缩小,67%的大鼠拔牙创完全愈合;micro-CT影像见拔牙创内新骨形成,牙槽骨愈合征象。结论:特立帕肽对大鼠MRONJ具有显著的治疗作用。

Three cases of uncommon medication-associated osteonecrosis of temporal bone

Introduction:Medication-related osteonecrosis of the temporal bone is rare and has been reported to be associated with the use of anti-resorptive and biologic agents.Here,we present the first case of tyrosine-kinase inhibitor-related external auditory canal(EAC)osteonecrosis as well as two cases related to anti-resorptive therapies.Methods:A retrospective case series.Results:Case one:an 84-year-old female presented with chronic otitis externa and osteonecrosis of EACs bilaterally.She had a history of osteoporosis treated with denosumab and risedronic acid.She successfully underwent left EAC reconstruction using an inferiorly-based pedicle periosteal flap while the right ear canal was managed conservatively.Case two:a 69-year-old male presented with osteonecrosis of the right EAC.He had a history of osteoporosis treated with alendronic acid and zoledronic acid.His osteonecrosis is conservatively managed with local debridement and antibiotic application.Case three:a 60-year-old male presented with osteonecrosis of the right inferior EAC.He had a history of chronic myelogenous leukemia treated with a tyrosine-kinase inhibitor,imatinib.After failing conservative therapy,he underwent right ear canal reconstruction using a periosteal vascular pedicle flap without complication and experienced complete resolution to his symptoms.Conclusion:Anti-resorptive agents and/or tyrosine kinase inhibitors may lead to dysregulation of bone remodeling and result in rare cases of temporal bone osteonecrosis.When a local debridement and antibiotic therapy fail,definitive surgical excision of necrotic bone with subsequent reconstruction of the EAC may offer patients a possible resolution in symptoms.

双膦酸盐类药物相关性颌骨坏死的研究及进展

双膦酸盐类(bisphosphonates,BPs)在临床上广泛应用于预防和治疗骨质疏松症等疾病,取得了良好的治疗效果,但大量报道指出其可通过抗血管生成及抑制骨吸收等作用引发药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)。MRONJ是一种严重的不良反应,根据剂量和使用时间的不同,这种药物不良反应可能很少发生(如口服双膦酸盐治疗骨质疏松症),也可能经常发生(如静脉注射双膦酸盐治疗癌症)。当前导致颌骨坏死的病理机制尚未完全明确,针对MRONJ的诊治也未形成统一共识,本文通过整理归纳近年来有关MRONJ的发病机制及临床治疗等相关问题研究结果,叙述现国内外研究进展,为临床应用研究工作提供指导和帮助。

甲状旁腺激素预防双膦酸盐性颌骨坏死的动物实验研究

目的:通过建立小鼠模型探究甲状旁腺激素(PTH)对双膦酸盐性颌骨坏死(BRONJ)发生、发展的影响。方法:采用长期腹腔注射唑来膦酸(ZOL)与地塞米松(DXMS)建立高危SD大鼠模型,采用有创拔牙的方式刺激颌骨,以有效地引发BRONJ样疾病的发展。拔牙后治疗组预防性皮下注射PTH,实验组及空白组不作处理。结果:在拔牙创面的刺激下,成功采用ZOL和DEX联合用药建立BRONJ模型。实验组骨小梁厚度、密度以及数量均较空白组降低(P<0.05),而骨小梁分离度上升(P<0.05);治疗组骨小梁厚度、密度以及数量均较实验组上升(P<0.05),而骨小梁分离度下降(P<0.05)。结论:本研究成功建立了大鼠BRONJ模型,证实PTH可在一定程度上抑制BRONJ的发生,对BRONJ的治疗有一定的效果。

药物相关性颌骨坏死研究进展

在应用抗骨吸收药物,如双膦酸盐和地舒单抗,以及血管生成抑制剂的患者群体中,进行相关口腔疾病的治疗可能会诱发药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)。然而,MRONJ的确切机制尚不清楚,尽管大量研究已经创建了临床治疗数据库,但明确的治疗策略尚未制定。本研究通过文献回顾,对MRONJ的定义、病因、分期、危险因素、治疗和预防进行了相关讨论,为口腔临床工作提供参考。

Osteonecrosis of the jaw in a patient with acute myeloid leukemia,who received azacitidine

The first case of osteonecrosis of the jaw(ONJ)related to azacitidine therapy was reported.A 64-year-old male with acute myeloid leukemia,who received 5-azacitidine,presented with pain and purulence of the right second premolar.An unsuccessful endodontic therapy resulted in dental extraction 6 months later.The post-extraction non-healing socket was managed with antibiotics and multiple surgical debridements without response.ONJ stage 2 was diagnosed 12 months after the initial symptoms of pain and purulence and was managed conservatively.Currently the patient is still receiving 5-azacitidine therapy,while ONJ remains asymptomatic.This case highlights the presence of alveolar bone disease prior to the appearance of ONJ.Osteonecrosis in chemotherapy,although rare,may increase as long-term survival of cancer patients,who receive those medications increases.Health care professionals need to be alert,while collaboration with an experienced oral/dental oncologist would be beneficial to the patient.

二膦酸盐药物治疗乳腺癌骨转移发生颌骨坏死的临床特点

目的:乳腺癌是女性最常见的恶性肿瘤之一,骨转移在该类患者中较为常见。二膦酸盐药物是预防和控制恶性肿瘤骨转移的一线化学治疗药物,长期应用可以发生颌骨坏死。本研究旨在深入了解应用二膦酸盐药物治疗乳腺癌骨转移后患者发生颌骨坏死的临床特点。方法:回顾分析自2011年1月至2015年8月于北京大学口腔医院就诊并明确诊断为二膦酸盐颌骨坏死的患者,筛选出其中的乳腺癌患者,分析其临床症状、影像学特征及治疗情况。结果:共纳入14例乳腺癌患者,平均年龄60.21岁,平均罹患肿瘤时间9.77年,平均出现骨转移时间为5.67年,平均应用二膦酸盐药物的时间为3.29年。患者均无系统应用激素治疗史,无糖尿病史。9例患者曾经拔牙,口腔内颌骨坏死症状的平均时间为8.58个月,发生在下颌骨者10例,上颌骨3例,上、下颌骨1例。10例经手术治疗的患者中,3例治愈,6例好转,而4例经保守治疗的患者中2例临床症状明显加重。结论:乳腺癌患者自开始应用二膦酸盐药物至发生颌骨坏死的用药时间较长,多数患者没有糖尿病及应用激素治疗史。拔牙本身与颌骨坏死的严重程度没有直接关系,下颌骨是最常受累的部位,手术治疗可以在一定程度上缓解乳腺癌患者发生二膦酸盐相关性颌骨坏死的临床症状。

双膦酸盐相关性颌骨坏死

双膦酸盐类(BPs)药物是一种强有力的骨吸收抑制剂,已广泛应用于临床治疗中。近年来,有关双膦酸盐相关性骨坏死(BRONJ)的报道日渐增多,该病临床上以骨面裸露、死骨形成、疼痛、口臭等为特征。由于目前发病机理不明确,临床上尚无完全有效的治疗方法,因此BRONJ的预防十分重要。本文就BRONJ的发病机制、危险因素、临床特征、治疗预后等方面的研究现状进行阐述,以期为临床提供帮助。