Periodontal Disease as a Risk Factor for Bisphosphonate‐Related Osteonecrosis of the Jaw

Background: Previous case reports and animal studies suggest that periodontitis is associated with bisphosphonate‐related osteonecrosis of the jaw (BRONJ). This case‐control study is conducted to evaluate the association between clinical and radiographic measures of periodontal disease and BRONJ. Methods: Twenty‐five patients with BRONJ were matched with 48 controls. Trained examiners measured probing depth, clinical attachment level (CAL), and bleeding on probing on all teeth except third molars and gingival and plaque indices on six index teeth. Alveolar bone height was measured from orthopantomograms. Most patients with BRONJ were using antibiotics (48%) or a chlorhexidine mouthrinse (84%) at enrollment. Adjusted comparisons of patients with BRONJ versus controls used multiple linear regression. Results: The average number of bisphosphonate (BP) infusions was significantly higher in patients with BRONJ compared with controls (38.4 versus 18.8, P = 0.0001). In unadjusted analyses, patients with BRONJ had more missing teeth (7.8 versus 3.1, P = 0.002) and higher average CAL (2.18 versus 1.56 mm, P = 0.047) and percentage of sites with CAL ≥3 mm (39.0 versus 23.3, P = 0.039) than controls. Also, patients with BRONJ had lower average bone height (as a fraction of tooth length, 0.59 versus 0.62, P = 0.004) and more teeth with bone height less than half of tooth length (20% versus 6%, P = 0.001). These differences remained significant after adjusting for age, sex, smoking, and number of BP infusions. Conclusions: BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared with controls after adjusting for number of BP infusions. Group differences in antibiotics and chlorhexidine rinse usage may have masked differences in the other clinical measures.     

Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw

Oral Diseases (2012) 18, 602–612 Objective: Infection has been hypothesized as a contributing factor to bisphosphonate (BP)‐related osteonecrosis of the jaw (BRONJ). The objective of this study was to determine the bacterial colonization of jawbone and identify the bacterial phylotypes associated with BRONJ. Materials and methods: Culture‐independent 16S rRNA gene‐based molecular techniques were used to determine and compare the total bacterial diversity in bone samples collected from 12 patients with cancer (six, BRONJ with history of BP; six, controls without BRONJ, no history of BP but have infection). Results: Denaturing gradient gel electrophoresis profile and Dice coefficient displayed a statistically significant clustering of profiles, indicating different bacterial population in BRONJ subjects and control. The top three genera ranked among the BRONJ group were Streptococcus (29%), Eubacterium (9%), and Pseudoramibacter (8%), while in the control group were Parvimonas (17%), Streptococcus (15%), and Fusobacterium (15%). H&E sections of BRONJ bone revealed layers of bacteria along the surfaces and often are packed into the scalloped edges of the bone. Conclusion: This study using limited sample size indicated that the jawbone associated with BRONJ was heavily colonized by specific oral bacteria and there were apparent differences between the microbiota of BRONJ and controls.     

Non-exposed bisphosphonate-related osteonecrosis of the jaw: a critical assessment of current definition, staging, and treatment guidelines

Oral Diseases (2012) 18 , 625–632 Non‐exposed bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a newly reported complication arising from bisphosphonate therapy that presents with atypical symptoms and no apparent mucosal fenestration or exposure of necrotic bone. The clinical observation of the presence of necrotic bone underneath normal epithelial coverage was not conclusive for the diagnosis of BRONJ based on current guidelines established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the American Society for Bone and Mineral Research (ASBMR), which specify the presence of clinically exposed necrotic bone for more than 8 weeks. Hence, the purpose of this review is to critically assess the current guidelines for diagnosis and management of BRONJ and propose a modified staging system and treatment guidelines to properly address the non‐exposed variant of BRONJ lesions.     

Bisphosphonate-related osteonecrosis of the jaws: a report of three cases demonstrating variability in outcomes and morbidity

BACKGROUND: Bisphosphonates are used widely to manage skeletal disorders resulting from malignancies that destroy bone and from some metabolic bone diseases. A strong association between bisphosphonate treatment and the appearance of painful exposed nonvital bone in the mandible and maxilla after oral surgery has been reported in the last decade. Extensive reviews have appeared in the dental literature regarding bisphosphonate-related osteonecrosis of the jaws (BRONJ), including protocols for diagnosis, management and diagnostic imaging for early detection; feature definition; and determination of extent of the disease. CASE DESCRIPTION: The authors provide three case reports to show the contrast in treatment outcomes and morbidity in patients with BRONJ. The cases involved diagnostic imaging modalities commonly used in the practice of dentistry: panoramic radiography and cone-beam volumetric computed tomography. CLINICAL IMPLICATIONS: These case reports demonstrate the usefulness of dental diagnostic imaging in the detection and management of BRONJ, corroborate the increasing number of reports regarding high levels of morbidity associated with various BRONJ treatments, and underscore the danger of performing invasive dental procedures for patients receiving bisphosphonate therapy.     

Bisphosphonate associated osteomyelitis of the jaw in patients with bony exposure: prevention,a new way of thinking

Objective

There is strong evidence of a link between the use of systemic bisphosphonates (BPs) and osteonecrosis of the jaw, especially in cancer patients. Among risk factors for BRONJ, tooth extraction and immune suppressive drugs seem to have significant role on bone healing. Therefore, the importance of these parameters in development of BRONJ was reviewed in this retrospective study in two maxillofacial surgery units.

Material and Methods

From 2007 to 2012, 46 patients on bisphosphonate who had developed oral bony lesions participated in this study. The pharmacological exposure, comorbidities, maxillofacial findings, types of treatment and outcome data were collected from clinical and radiological records.

Results

The most frequently used BP was alendronate (67%). Tooth extraction was reported in 61% of patients with BRONJ. Systemic corticosteroids were prescribed in 35 cases (76%) as an adjuvant for BP. Patients on corticosteroids had a lower probability of bony lesion healing (p<0.05) than patients without corticosteroids. Of the 46 patients who underwent conservative treatments, only ten were completely healed (21%).

Conclusions

Beside tooth extraction, corticosteroids were shown to be an implant risk factor for low rate of bone healing and hence the development of BRONJ. The outcome of conservative treatment was uncertain and this emphasizes the importance of prevention.     

The feasibility of locating the affected bone of BRONJ with indocyanine green

The morbidity of bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is also increasing with the use of bisphosphonates (BPs). Removing affected bone accurately is the most effective treatment. This study aimed to explore the feasibility of Indocyanine green (ICG)‐based Near‐Infrared fluorescence (NIF) imaging to remove BRONJ affected bone. Firstly, the rat model of BRONJ was constructed. And 5 mg/kg ICG were injected via tail vein, after 12 hr, the affected and healthy bone were dissected for ICG‐based NIF imaging and quantification detection of fluorescence intensity. Finally, all the bone samples were sent for further pathological examination. All the affected bone tissues in rat BRONJ model were fluorescence developed with ICG. And the fluorescence developed regions were further confirmed as affected bone tissues with pathological examination. The fluorescence intensity in affected bone tissues, adjacent, and opposite bone tissues was 1.93*107 ± 2.08*106, 1.19*106 ± 2.33*105, and 1.24*106 ± 1.57*105, respectively (p < .05). Conclusions It was feasible that the extent of affected bone in rat model with BRONJ could be estimated intraoperative via ICG‐based NIF imaging. This novel approach would become an auxiliary method in the treatment of patients with BRONJ in the future.     

Bisphosphonate‐related osteonecrosis of the jaws: Report of a case using conservative protocol

Bisphosphonates have been the first‐line treatment option for osteometabolic diseases, such as osteoporosis, hypercalcaemia in malignant bone diseases, and in bone metastasis. It is possible to observe a growing number of cases of osteonecrosis of the jaws in patients using this medication, called bisphosphonate‐related osteonecrosis of the jaws. The purpose of this study was to report a conservative treatment for bisphosphonate‐related osteonecrosis of the jaws—Stage 2, using antibacterial solution and low‐level laser therapy. At the end of the treatment, the patient presented improvement of the lesion with the healing of the mucosa. The literature still lacks successful definite protocols, thus the present case may contribute with another option for conservative management for bisphosphonate‐related osteonecrosis of the jaws. More research is necessary in order to develop a good protocol management for bisphosphonate‐related osteonecrosis of the jaws.     

A simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed tomography

ObjectivesThe aim of this study was to establish a simple method for the early detection of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using computed tomography (CT).Materials and methodsCT images of the mandible were obtained from a total of 20 patients with BRONJ and 20 control subjects. BRONJ was classified into 2 groups, with bone exposure (Stage 1–3 BRONJ) or without (Stage 0 BRONJ). In each patient, 15 transaxial CT images were selected and 30 configured regions of interest (ROI) were identified. The ANOVA test was applied to test the relationship between the severity of systemic risk factors.ResultsRegarding the local status of the mandible, significant differences were observed among the Stage 0 BRONJ, Stage 1–3 BRONJ, non-BRONJ and control groups in the cancellous bone CT radiodensity values, but there were no significant differences between the Stage 0 and Stage 1–3 BRONJ groups. In the cortical bone widths, significant differences were observed only between BRONJ and the controls.ConclusionsMeasuring cancellous bone CT radiodensity value has the potential to be a simple and quantitative method to detect the early stages of BRONJ.     

Atraumatic tooth extraction in patients taking bisphosphonates: a review of literature and experience with three cases

Purpose

Regev et al. first re-introduced the method of atraumatic tooth extraction with orthodontic elastics in 2008. Since then, the method has been mentioned regularly in literature. Nevertheless, the need for additional more detailed information remains.

Methods

We present a review of literature and a retrospective analysis of our three patients receiving bisphosphonate medication. Two of our patients suffered from bisphosphonate-related osteonecrosis of the jaw (BRONJ). All three patients underwent atraumatic tooth extraction, which we describe in detail.

Results

Regev et al. reported satisfactory results using the novel method. We removed six teeth in two patients with continued chemotherapy or bisphosphonate therapy in a time span of 26.2?±?16.4 weeks successfully. None of the patients developed exposed bone in the follow-up (7.4?±?0.2 months). In one case, the technique had to be discontinued due to increasing tooth soreness.

Conclusions

Atraumatic tooth extraction seems to be a safe method to prevent bone exposure, even in cases with BRONJ. The time required of our patients for exfoliation exceeded the time mentioned in literature considerably. This proved to be a major limitation. Our cases showed that patients with good compliance, no sore teeth, or painful BRONJ lesions, benefited from atraumatic tooth extraction. One of the method’s major advantages might be the possibility to continue chemotherapy and bisphosphonate therapy throughout the treatment.     

Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate‐related osteonecrosis of the jaws: can they be utilized as risk markers?

Purpose: The purpose of this retrospective study was to examine the possibility of utilizing serum C‐terminal telopeptide cross‐link of type I collagen (s‐CTX) and serum osteocalcin (s‐OC) as risk markers for oral bisphosphonate‐related osteonecrosis of the jaws (BRONJ). Patients and methods: The s‐CTX values and the s‐OC values were measured from 23 patients (one male, 22 females) diagnosed with BRONJ using clinical and radiographic examinations. The two biochemical markers were evaluated during a regular checkup for osteoporosis management. For the control group of s‐CTX study, s‐CTX values were obtained from 61 independently recruited postmenopausal women who have been on bisphosphonate therapy for >6 months. The s‐CTX values of the ONJ group and the control group were compared. Because of retrospective nature of this study, the control group for s‐OC study could not be established. A single sample t‐test was performed for the s‐OC value from the ONJ group. Result: Twenty‐three ONJ patients had taken alendronate for osteoporosis treatment, and the s‐CTX testing results were low levels of 10–192 pg/ml (mean: 93.2±49.4 pg/ml). Mean of s‐CTX of the control (n=61) was 125±85.7 pg/ml. The duration of BP therapy ranged between 1 and 10 years (4.82±2.6). The s‐OC level was estimated between 0.2 and 5.4 ng/ml (1.91±1.51 ng/ml). The mean s‐CTX value of the control group was higher but without significance (P=0.12). The s‐OC values of the ONJ group were significantly lower than the lowest value of the reference range (P<0.001). Conclusion: As a result of the s‐CTX and s‐OC testings at the diagnosis of BRONJ, the values of the two markers were decreased. The decrease of the s‐OC values implies a problem during the bone‐formation process. Therefore, we can assume that in this patient group, invasive dental surgery contributes to an increase in the risk of BRONJ incidence. This result may imply that, during bisphosphonate therapy, simultaneous consideration of s‐CTX showing inhibition of bone resorption and s‐OC indicating the degree of bone formation might be a set of risk markers assessing risk prediction for BRONJ before invasive dental surgery. To cite this article:
Kwon Y‐D, Ohe J‐Y, Kim D‐Y, Chung D‐J, Park Y‐D. Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate‐related osteonecrosis of the jaws: can they be utilized as risk markers?
Clin. Oral Impl. Res. 22 , 2011; 100–105.
doi: 10.1111/j.1600‐0501.2010.01965.x     

The effect of bisphosphonate therapy on neutrophil function: a potential biomarker

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) occurs subsequent to intravenous and oral bisphosphonate exposure in a small subset of patients. The identification of the pathophysiologic mechanisms has not been fully elucidated. Evidence of concurrent bacterial colonization at sites of bone necrosis, previous reports of neutrophil-related complications in some patients taking some bisphosphonates, along with perturbed neutrophil function in bisphosphonate-treated mice, suggest an innate immune role in the development of BRONJ. This study investigated neutrophil function in BRONJ patients to determine if neutrophil functional defects may serve as a potential biomarker for BRONJ susceptibility. Two populations were studied: patients with BRONJ and those beginning intravenous pamidronate. Healthy control patients were used for comparison. Twenty-three patients with BRONJ and five patients who were beginning pamidronate therapy provided neutrophil samples from the mouth (oral rinses) and from blood. Neutrophils from the population of patients with BRONJ and from those post-pamidronate treatment showed lower reactive-oxygen species production and impaired chemotaxis relative to controls. These data suggest that a compromise in neutrophil function may be a potential biomarker for BRONJ susceptibility.     

双膦酸盐类药物相关性颌骨坏死临床研究

目的：了解双膦酸盐类药物相关性颌骨坏死（bisphosphonate?related osteonecrosis of the jaw ,BRONJ）的发病机制,探讨其诊断、临床表现、治疗和预防方法。方法对近两年收治的4例BRONJ患者资料进行回顾分析,结合国内外相关文献报道进行临床总结。结果报告的4例患者均有使用双膦酸盐类药物史,临床主要表现为患区反复疼痛、流脓,骨暴露及死骨形成。3例患者接受手术,同时抗生素对症治疗,其中1例术前病情最重的患者出院后半年内曾有小范围感染灶,口服抗生素控制,其余患者均无明显感染及复发。结论恰当的手术治疗对BRONJ可控制感染,缓解症状,使病情趋于静止。     

Characteristics of bisphosphonate-related osteonecrosis of the jaw after kidney transplantation

ABSTRACT: Renal transplantation is the definitive treatment of chronic renal failure, and osteoporosis in patients after renal transplantation is caused by the use of high-dose corticosteroids, reduced renal function, and the use of immunosuppressant. While bisphosphonates inhibit osteoclastic activities, they are the drug of choice for the treatment and prevention of osteoporosis. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) becomes a problematic issue. There are few reports on BRONJ in patients after renal transplantation, so many oral bisphosphonates commonly prescribed in patients after renal transplantation to prevent osteoporosis have no warning of BRONJ. We analyzed the records of patients with BRONJ from January 2009 to December 2010. Among the patients with BRONJ, we selected patients who underwent transplantation of the kidney. Demographic data, drug-related factors, and clinical characteristics were evaluated using chart review. A total of 128 patients were categorized as having BRONJ, and there were 3 patients with a history of kidney transplantation. The average age was 54.6 years, and 2 victims were men. All patients received oral bisphosphonates for more than 2 years (range, 2-7 y; average, 58.6 mo). All patients had hypertension, diabetes mellitus, history of high-dose corticosteroids, and taking immunosuppressant drugs. Bisphosphonate-related osteonecrosis of the jaw occurred in the maxilla in all patients, which is classified as stage 3 because of the involved sinus. Extraction was the main provoking factor in all patients. In conclusion, even at a relatively young age, BRONJ in the maxilla can be developed by intake of oral bisphosphonate after kidney transplantation. Dental care for patients before and after undergoing renal transplantation should be emphasized to reduce the risk of BRONJ.     

Auto-fluorescence of the bone and its use for delineation of bone necrosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication of long-term bisphosphonate treatment. Currently, the drawback in the surgical management of BRONJ is the difficulty distinguishing between viable and necrotic bone. Intraoperative bone fluorescence induced by tetracyclines has been shown to be a valuable aid to overcome this problem. In this technical note we report the finding that viable bone is auto-fluorescent using the VELscope Vx fluorescence lamp. Necrotic bone shows an altered fluorescence pattern (pale or no fluorescence). Thus it is suggested that auto-fluorescence of bone might be of similar use during the surgical therapy of BRONJ.     

Bisphosphonates and their clinical implications in endodontic therapy

This review gives an overview of the factors that may play a role in the development of osteonecrosis of the jaw in patients treated with bisphosphonates (BPs) and undergoing nonsurgical endodontic treatment as well as some recommendations for its prevention. BPs are a widely prescribed group of drugs for diverse bone diseases. The occasional but devastating adverse effect of these drugs has been described as bisphosphonate‐related osteonecrosis of the jaw (BRONJ). As this condition is debilitating and difficult to treat, all efforts should be made to prevent its occurence in patients at risk. The main triggering event is considered to be dental extraction. Even though nonsurgical endodontic treatment appears to be a relatively safe procedure, care remains essential. After an overview of this class of drugs, the clinical presentation, epidemiology and pathogenesis of BRONJ, as well as the possible risk factors associated with its development after nonsurgical endodontic treatment will be described. Finally, several strategies will be proposed for the prevention of BRONJ during nonsurgical endodontic treatment.     

Alternative treatments for oral bisphosphonate-related osteonecrosis of the jaws: A pilot study comparing fibrin rich in growth factors and teriparatide

Objectives: The aim of this study is to describe and compare the evolution of recurrent bisphosphonate-related osteonecrosis of the jaws (BRONJ) in patients treated with plasma rich in growth factors or teriparatide. Material and Methods: Two different types of treatments were applied in patients diagnosed of recurrent BRONJ in a referral hospital for 1.100.000 inhabitants. In the group A, plasma rich in growth factors was applied during the surgery. In the group B, the treatment consisted in the subcutaneous administration of teriparatide. All the cases of BRONJ should meet the following conditions: recurrent BRONJ, impossibility of surgery in stage 3 Ruggiero classification and absence of diagnosed neoplastic disease. Clinical and radiographic evolution of the patients from both groups was observed. Results: Nine patients were included, 5 in group A and 4 in group B. All the patients were women on oral bis-phosphonate therapy for primary osteoporosis (5 patients) or osteoporosis-related to the use of corticosteroids (4 patients). Alendronate was the most common oral bisphosphonate associated with BRONJ in our study (four patients in group A and two in group B). The mean age was 72,8 years in the group A and 73,5 years in the group B. All the patients from group A showed a complete resolution of their BRONJ. Only one patient in the group B showed the same evolution. Conclusions: In our series, the plasma rich in growth factors showed better results than the teriparatide in the treatment of recurrent BRONJ. Key words:Osteonecrosis, oral bisphosphonate, treatment, teriparatide, plasma rich in growth factors.     

Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: Systematic review and a new case series

IntroductionThere is currently no gold standard for the treatment of Stage III bisphosphonate-related osteonecrosis of the jaw (BRONJ). The question remains whether osseous reconstruction can offer an additional gain in outcome given the theoretical risk of non-union at the resection margins and recurrence in the osseous free flap. The objective was to conduct a systematic review of articles describing outcomes of osseous microsurgical reconstruction in cases of BRONJ with a minimum follow-up of 12 months, and to present the long-term outcomes of a new case series of three patients.Material and methodsA multi-database QUORUM-based single-reviewer systematic review identified eight papers that fulfilled the selection criteria. There are only case series and case reports available (Level 4 of the Oxford Evidence-based medicine scale). A total of 31 patients were analysed including the cases described in this article.ConclusionThe limited overall rate of non-union at the resection margins and the 6.5% recurrence rate of BRONJ in the transplant counters the theoretical objections and advocates for considering osseous free flap reconstruction in the treatment of refractory BRONJ Stage III lesions. However, additional data derived from larger case series or case-control studies are imperative to support this hypothesis.     

不同临床分期二膦酸盐颌骨骨髓炎的临床特点及其治疗：附16例报告

目的: 分析二膦酸盐颌骨骨髓炎（bisphosphonate related osteonecrosis of the jaw, BRONJ）的临床特点及相关检查结果,为临床预防提供依据。方法: 回顾分析2013—2019年就诊于新疆医科大学第一附属医院和新疆维吾尔自治区人民医院被确诊为BRONJ的16例患者的病例资料,包括一般资料、实验室检查、影像学检查等。采用SPSS 24.0软件包对数据进行统计学分析。结果: 16例患者中,男6例 （37.5%）,女10例（62.5%）;15例有原发肿瘤,1例为骨质疏松。其中使用二磷酸盐（BPs）类药物时间<12个月4例（25%）、12~36个月8例（50%）、≥36个月4例（25%）。16例BRONJ患者的临床分期为Ⅱ期或Ⅲ期。使用BPs药物时间与BRONJ分期之间比较,差异有统计学意义（P<0.05）。使用BPs药物后出现临床症状到就诊时间与BROBJ分期之间比较、使用BPs药物时间与实验室检查结果比较,差异均无统计学意义（P>0.05）。骨密度测量发现,BPs组在2个区域的骨密度均显著高于化脓性颌骨骨髓炎组和健康组（P<0.05）,而化脓性颌骨骨髓炎组和健康组之间骨密度无显著差异（P>0.05）。结论: 使用BPs类药物的时间越长,BRONJ的感染程度越重。骨密度差异表明,使用BPs药物后骨松质的骨密度明显升高,更容易发生颌骨骨坏死。     

Survival of dental implants in post-menopausal bisphosphonate users

PurposeTo determine whether post-menopausal women with a history of bisphosphonate use are at greater risk for implant failure or osteonecrosis of the jaw (ONJ) than an age- and gender-matched population with no history of bisphosphonate use.MethodsA retrospective chart review and phone interview was conducted of patients seen at the Mayo Clinic who had implants placed after November 2006. Bisphosphonate users were identified by medical chart review. Dental implant survival and ONJ incidence were determined in a total of 82 post-menopausal non-bisphosphonate users and 55 post-menopausal bisphosphonate users using a phone interview. Implant failures were recorded and survival percentages were calculated for comparison.ResultsONJ was not observed consequent to implant placement in any of the bisphosphonate users or non-users. In non-users, 163 out of 166 implants were surviving for a cumulative survival rate of 98.19%. In bisphosphonate users, 120 out of 121 implants were surviving for a cumulative survival rate of 99.17%.ConclusionDental implants placed in post-menopausal women have the same survival potential regardless of whether patients have a history of bisphosphonate use. Bisphosphonate users who undergo dental implant surgery are at low risk for osteonecrosis of the jaw and a bisphosphonate “drug holiday” is not indicated in these patients.     

�����������ǹǻ����ٴ������о���չ

??Bisphosphonates are the most commonly used drugs to treat bone metastases. In recent years?? many authors found that long-term use of bisphosphonate drugs can lead to bisphosphonate-related osteonecrosis of the jaws ??BRONJ??. The life quality of patients with the BRONJ symptoms ??oral fistula?? swelling?? limited opening and fractures??will be seriously affected. These patients often seek help in dentistry??therefore the treatment knowledge of this disease is very important. This article reviews the recent literature about treatment for this disease??hoping to help oral clinical work.