AAOMS’s Position paper on medication related osteonecrosis of the jaw (2014)

在本次修订中将双膦酸盐相关性颌骨坏死（Biphosphonate-related osteonecrosis of the jaw, BRONJ）的名称更改为药物相关性颌骨坏死（Medication-related osteonecrosis of the jaw, MRONJ），因为新近发现的能够引起颌骨坏死的药物除了双膦酸盐类，还有比如antiresorptive drugs (denosumab/迪诺赛麦/诺单抗)以及 antiangiogenic therapy drugs。

Purpose

本次更新的目的：

1. 发生MRONJ的风险评估；
2. 对可能引起MRONJ的药物进行风险获益评估，以为医师及患者在药物选择方面提供参考；
3. 为临床医师提供相关指南：
   • 存在antiresorptive and/or antiangiogenic agents相关用药史的患者发生MRONJ后的诊断和鉴别诊断；
   • MRONJ预防措施及MRONJ患者的分阶段治疗方案

Background

Antiresorptive medications

Intravenous (IV) phosphonates (BPs)

采用静脉给药的双膦酸盐类药物主要是用于癌症相关骨病变的治疗，如恶性肿瘤导致的高钙血症、实体肿瘤——如乳腺癌、前列腺癌、肺癌等——发生骨转移导致的skeletal-related events以及多发性骨髓瘤导致的骨溶解病变等。尽管双膦酸盐类药物在提高癌症患者生存率方面的潜能尚存争议，但是对于波及骨骼的进展期癌症患者而言，双膦酸盐类药物能够显著地提高该类人群的生活质量。

目前获得FDA批准用于治疗骨质疏松的IVBPs包括：zolendronate (Reclast®)（采用一年一次的给药方式），以及ibandronate (Boniva®)（采用三月一次，肠外给药）等等。

Oral bisphosphonates

采用口服给药的双膦酸盐类药物主要用于骨质疏松（osteoporosis）的治疗，目前也常常用来治疗osteopenia。在一些少见病如Paget’s disease of bone, and osteogenesis imperfecta中，也有其用武之地。

RANK ligand inhibitor (denosumab)

迪诺赛麦是一种人IgG2单克隆抗体，通过与RANK-L结合抑制破骨细胞功能及其相关的骨吸收病变。给药方式不用其治疗作用亦有差异：

• 采用每六个月皮下给药的方式时——denosumab (Prolia®)，可有效降低骨质疏松患者(osteoporotic patient)的vertebral, non-vertebral, and hip fractures机率
• 采用每月给药的方式时——Denosumab (Xgeva®)，可有效治疗实体肿瘤骨转移相关的骨病变（skeletal-related events）。

迪诺赛麦无法用于多发性骨髓瘤患者的治疗。

与双膦酸盐类药物不同，RANK-L抑制剂发挥作用时不和骨结合（do not bind to bone），其对于骨改建的影响大多数在停药6个月后消失。

Antiangiogenic medications

抗血管生成药物通过阻断促血管生成信号通路发挥作用，对胃肠肿瘤（gastrointestinal tumors）, 肾细胞癌（renal cell carcinomas），神经内分泌肿瘤（neuroendocrine tumors）等具有治疗作用。

（因全文较长，翻译用时过多，所以后文为原文引用）

Risk of jaw necrosis related to antiresorptive therapy

Oral and maxillofacial surgeons first recognized and reported cases of non-healing exposed bone in the maxillofacial region in patients treated with IV bisphosphonates. In September 2004, Novartis, the manufacturer of the IV bisphosphonates pamidronate (Aredia®) and zoledronic acid (Zometa®), notified healthcare professionals of additions to the labeling of these products, which provided cautionary language related to the development of osteonecrosis of the jaws. This was followed in 2005 by a broader drug class warning of this complication for all bisphosphonates including the oral preparations. More recently, other antiresorptive agents and novel anti-cancer drugs have been linked to the development of jaw necrosis.

MRONJ case definition

目前对于诊断MRONJ需复合下了全部条件：

• 目前或既往曾有抗骨吸收及抗血管生成药物用药史；
• 颌面部——包括口内和口外——有骨暴露或虽无骨暴露但经瘘管可探及骨面者，时间长达八周以上；
• 相应区域无放疗史，无明显转移性肿瘤。

需要注意的是，MRONJ高风险人群及MRONJ患者可能同时有其他常见的临床疾病——如alveolar osteitis, sinusitis, gingivitis/periodontitis, caries, periapical pathology, fibro-osseous lesion, sarcoma, chronic sclerosing osteomyelitis, and TMJ disorders。不得将这些表现和MRONJ相混淆。同时也要注意颌骨坏死也可发生于无antiresorptive or antiangiogenic agents用药史的人群中。

Pathophysiology

尽管距离最初发现已有十余年的历史，但是关于MRONJ发病机制仍不清楚。研究者们提出了一些假说来解释MRONJ特异性发生于颌骨的机制，这些假说包括：altered bone remodeling or oversuppression of bone resorption, angiogenesis inhibition, constant microtrauma, suppression of innate or acquired immunity, vitamin D deficiency, soft tissue BP toxicity, and inflammation or infection。

Inhibition of osteoclastic bone resorption and remodeling

双膦酸盐类药物以及其他抗吸收药物如迪诺赛麦通过抑制破骨细胞分化及功能、促进其凋亡来发挥减轻骨吸收及骨改建的目的。破骨细胞分化及其正常功能对于所有部位骨骼的愈合及改建都具有重要的作用，但是为何骨坏死最初只发生在颌骨的牙槽骨？研究者认为这与颌骨活跃的骨改建有关。在一项大型动物模型的长期研究中已证实骨皮质内更新速率（intracortical bone turnover）降低的情况存在。在其他抗吸收药物如迪诺赛麦作用中发现的抑制骨改建这一关键机制的存在也进一步证实了之前提出的假说。实验已初步证实甲状旁腺激素促进给予唑来膦酸（zoledronic acid）处理动物的拔牙窝愈合的现象，可能源于其作用于破骨细胞促进骨改建的作用。

Inflammation/Infection

局部和全身风险因素在MRONJ发生中的作用已得到证实，牙科疾病以及口腔细菌感染也认为是其中之一。尽管在最初报道的大多数颌骨坏死病例中都曾有拔牙史，但是在拔牙之前这些患牙即有牙周或者根尖周病变存在。基于这些临床现象，在进一步的动物实验中发现，全身性给予抗吸收药物后，炎症或者感染二者中任意一者的存在即足以引发颌骨坏死。

炎症和感染长久以来即被视作引起颌骨坏死的病因。早期研究曾在颌骨坏死患者颌骨样本中发现了细菌——特别是放线菌属——的存在。细菌的在这些病例中发现，促使研究者开始考虑暴露颌骨上面形成的细菌生物膜在疾病中的作用。随后研究发现，在这一复杂生态系统中除了细菌外，还有真菌以及病毒等存在，预示着有效的抗感染措施需要针对这一复杂的multiorganism ONJ-associated biofilm进行。

Inhibition of angiogenesis

颌骨坏死is classically被认为是由于颌骨血供受损发生的缺血性坏死，所以抑制血管生成很自然地成了其病因假说之一。体外试验证实了zoledronic acid可抑制血管生成，在使用zoledronic acid的肿瘤患者中也检测出了循环VEGF水平降低。同时也有越来越多的文献报道使用新型抗血管生成药物（tyrosine kinase inhibitors and monoclonal antibody targeting VEGF）患者发生颌骨以及其他部位骨坏死的案例。然而，是目前尚未发现denosumab的抗血管生成作用。

Other hypotheses

1. 软组织毒性
   虽然双膦酸盐类药物主要是和破骨细胞以及骨中的羟基磷灰石结合发生作用，也有文献报道其具有软组织毒性。多种类型的细胞如宫颈细胞、前列腺细胞以及口腔上皮细胞等，暴露于双膦酸盐类药物后均表现出了凋亡增加以及增殖抑制的现象。但是由于BPs给药数小时后即可通过尿液排除体外，所以其在骨外组织中的浓度是很低的。与BPs不同的是目前尚无迪诺赛麦具有软组织毒性的报道。
2. 先天性或获得性免疫功能不足（dysfunction）
   最初建立MRONJ的动物试验模型时发现，除非将BPs与类固醇类药物联合用于拔牙窝，否则难以建立稳定的模型。此后又相继有报道将BPs和化疗药物同时应用于拔牙后的啮齿类动物时出现粘膜溃疡、创口愈合延迟、骨暴露并出现组织学坏死以及炎症等现象。

Risk factors for MRONJ

Medication-related risk factors

To interpret MRONJ disease frequency estimates, two parameters need to be considered: therapeutic indications and type of medications. The therapeutic indications are grouped into two categories: osteoporosis/osteopenia or malignancy. Medications will be grouped into two categories, BP and non-BP (other antiresorptive or antiangiogenic medications). Disease frequency will be reported as incidence (number of new cases per sample [or population] per unit time) or prevalence (number of cases in the sample [or population] reported as a percentage).

Given the proliferation of data since MRONJ was originally reported in 2003, the committee has tried to limit the inclusion of studies to:

1. those published since the last report (2009),

Older studies, case reports and case series, and studies that rely on medical record review or insurance-claim data were excluded from analyses.

Due to the low frequency of disease, studies with small samples (<500 subjects) need to be interpreted cautiously. It is particularly challenging to obtain good estimates of disease frequency when studying low frequency events, ie cases of MRONJ. Consistently, as the sample size increases, MRONJ disease frequency estimates get smaller. Therefore when reviewing the literature cited below, the reader should weight more heavily studies with large sample sizes than a comparable study with a smaller sample size (ie disease estimates of a study with a sample size of 10,000 should be weighted more heavily than a study with 500 subjects).

1. MRONJ risk among cancer patients

To measure the risk for ONJ among patients exposed to a medication, we must know the risk for ONJ in patients not exposed to antiresorptive or antiangiogenic medications. The risk for ONJ among cancer patients enrolled in clinical trials and assigned to placebo groups ranges from 0% to 0.019% (0-1.9 cases per 10,000 cancer patients).

Among cancer patients exposed to zolendronate, the cumulative incidence of MRONJ is in the low single digits (range = 0.7% – 6.7%). When limited to studies with Level 1 evidence, ie systematic reviews or RCTs, the risk of MRONJ in subjects exposed to zolendronate approximates 1% (100 cases per 10,000 patients). The risk of ONJ among cancer patients exposed to zolendronate ranges between 50-100 times higher than cancer patients treated with placebo.

Among cancer patients exposed to denosumab, a RANK L inhibitor, the risk of MRONJ ranges from 0.7% – 1.9% (70-90 cases per 10,000 patients). The risk for ONJ among cancer patient exposed to denosumab is comparable to the risk of ONJ in patients exposed to zolendronate.

The risk for ONJ among cancer patients exposed to bevacizumab, an antiangiogenic agent, is 0.2%. (20 cases per 10,000). The risk may be higher among patients exposed to both bevacizumab and zolendronate, 0.9% (90 cases per 10,000).

There are several case reports describing jaw necrosis in cancer patients receiving targeted therapies, specifically tyrosine kinase inhibitors (TKIs) and monoclonal antibody targeting VEGF. In 2009 Brunello and colleagues reported consecutive episodes of ONJ, characterized by cutaneous fistula and bone sequestration, in a patient with renal cell carcinoma treated with bisphosphonates and the tyrosine kinase inhibitor (TKI) sunitinib. Disease improved after discontinuation of sunitinib and then rapidly worsened with resumption of sunitinib. The investigators hypothesized “that the antiangiogenic activity of sunitinib may amplify the inhibition of bone remodeling exerted by amino bisphosphonates entrapped within the osteonecrotic matrix, antagonize mucosal healing and expose to infections during treatment.” Subsequent reports have highlighted the potential additive toxic effect of antiangiogenic drugs (TKIs and monoclonal antibody targeting VEGF) in patients receiving or having a history of bisphosphonate medication use. Beuselink, et al, reported an overall incidence of ONJ to be 10% in renal cell carcinoma patients with bone metastasis treated with oral TKIs and concomitant bisphosphonates. They concluded that the combined use of bisphosphonates and TKIs in renal cell carcinoma patients with bone involvement probably improves treatment efficacy but is associated with a high incidence of ONJ. Smidt-Hansen, et al, in a retrospective study of renal cell carcinoma patients who received zoledronic acid and sirolimus found that patients who developed ONJ had a significantly improved median survival of 31.6 months compared to 14.5 months in patients without ONJ.

Moreover, there have been multiple case reports detailing the development of ONJ in patients receiving these targeted antiangiogenic therapies who are bisphosphonate naïve. These case reports underscore the potential for novel medications such as TKIs and VEGF inhibitors being implicated in the development of ONJ in the absence of concomitant antiresorptive medication use.

This preliminary level of evidence supporting the association of antiangiogenic medications with the development of jaw necrosis is primarily based on case reports (Level V evidence). While the FDA has issued an ONJ advisory only for bevacizumab and sunitinib, the committee remains concerned about a similar potential risk associated with several other medications within the same drug class which have a similar mechanism of action. Further controlled, prospective studies will be required to characterize the risk of jaw necrosis associated with these agents.

2. MRONJ risk among osteoporosis patients

Most dentists and oral and maxillofacial surgeons see patients in their practices who have been exposed to antiresorptive therapy, eg oral BPs, for management of osteoporosis. When evaluated by age, 5.1 million patients over the age of 55 years received a prescription for a bisphosphonate in year 2008. A recent federal study estimated that the prevalence of BP exposure was 7 for every 100 US population receiving a prescription for a bisphosphonate in the outpatient setting for the treatment of osteoporosis. Ironically, the studies estimating MRONJ risk in this patient population have the weakest levels of evidence of the various study groups, eg survey or retrospective cohort studies with ascertainment of disease based on a combination of examination or review of medical records.

• 2a. Risk for ONJ among osteoporotic patients exposed to oral BPs

In a survey study of over 13,000 Kaiser Permanente members, the prevalence of BRONJ in patients receiving long-term oral bisphosphonate therapy was reported at 0.1% (10 cases per 10,000) which increased to 0.21 (21 cases per 10,000) among patients with greater than 4 years of oral BP exposure. Felsenberg and Hoffmeister reported a prevalence of MRONJ among patients treated with bisphosphonates for osteoporosis of 0.00038% (<1 case per 100,000 exposed), based on reports of 3 cases to the German Central Registry of Necrosis of the Jaw. In a more recent report, Malden, et al, derived an incidence of 0.004% (0.4 cases per 10,000 patient-years of exposure to alendronate) from 11 cases of MRONJ reported in a population of 90,000 people living in southeast Scotland.

• 2b. MRONJ risk among osteoporotic patients exposed to IV BP or RANK-L inhibitors

Studies analyzing patients with osteoporosis exposed to yearly zolendronate therapy for 3 years reported a risk for MRONJ of 0.017% (1.7 cases per 10,000 subjects). An extension of this study through 6 years did not demonstrate a change in frequency of MRONJ. In recent reports studying patients exposed to denosumab, the risk for MRONJ is 0.04% (4 cases per 10,000 subjects). Interestingly, among patients with osteoporosis exposed to placebo medications, the risk for ONJ ranges from 0% to 0.02% (0-2 cases per 10,000 subjects). The risk for ONJ among patients treated with either zolendronate or denosumab (0.017 – 0.04%) approximates the risk for ONJ of patients enrolled in placebo groups (0%-0.02%).

Based on this current review of data, the risk of developing ONJ among osteoporotic patients exposed to oral, IV BPs, or denosumab is real but remains very low. The frequency of cases reported in the population (albeit very small) is best explained by the large number of patients, 5.1 million over the age of 55, exposed to these drugs.

3. Duration of medication therapy as a risk factor for MRONJ

Regardless of indications for therapy, the duration of BP or antiresorptive therapy continues to be a risk factor for developing ONJ. Among cancer patients exposed to zolendronate or denosumab, the incidence of developing ONJ was, respectively, 0.6 and 0.5% at 1 year, 0.9 and 1.1% at 2 years, and 1.3 and 1.1% at 3 years with the risk for ONJ among denosumab-exposed subjects plateauing between years 2 and 3.86 In a study by Saad, et al, the investigators combined three-blinded phase three trials and found similar results, including a plateau after 2-years for patients exposed to denosumab. Among cancer patients exposed to zolendronate or denosumab (n=5723), the incidence of developing ONJ was, respectively, 0.5 and 0.8% at 1 year, 1.0 and 1.8% at 2 years, and 1.3 and 1.8% at 3 years.

For patients receiving oral bisphosphonate therapy to manage osteoporosis, the prevalence of ONJ increases over time from near 0 at baseline to 0.21% after four or more years of BP exposure (see Figure 1). The median duration of BP exposure for patients with ONJ and ONJ-like features was 4.4 years. For patients without ONJ, the median exposure to oral BPs was 3.5 years. When compared to cancer patients receiving antiresorptive treatment, the risk of ONJ for patients with osteoporosis exposed to antiresorptive medications is about 100 times smaller.

Local factors

1. Operative treatment

Dentoalveolar surgery is considered a major risk factor for developing MRONJ. Several studies report that among patients with MRONJ, tooth extraction is a common predisposing event ranging from 52 to 61% of patients reporting tooth extraction as the precipitating event. In a case-control study among cancer patients exposed to zolendronate, tooth extraction was associated with a 16-fold increased risk for ONJ when compared to cancer patients without ONJ (odds ratio [OR] = 16.4; 95% confidence interval [CI], 3.4 – 79.6). In a longitudinal cohort study in a sample of cancer patients exposed to intravenous BPs (predominately zolendronate), tooth extraction was associated with a 33-fold increased risk for ONJ.

The above information, while important, is not what most patients or clinicians want to know. Most clinicians and patients want to know: “Among patients exposed to antiresorptive medications, what is the risk for developing ONJ following tooth extraction (or other dentoalveolar procedures such as implant placement or periodontal procedures)?” The best current estimate for the risk of ONJ among patients exposed to oral bisphosphonates following tooth extraction is 0.5%. The estimate was derived from a prospective evaluation of 194 patients exposed to oral BPs that underwent extraction of > 1 tooth. In this sample, one patient developed ONJ after tooth extraction.

Estimates for developing ONJ after tooth extraction among cancer patients exposed to intravenous BPs ranges from 1.6 to 14.8%. In a retrospective cohort study composed of a sample of cancer patients exposed to zolendronate (n=27), 4 (14.8%) subjects develop ONJ after tooth extraction. In a prospective cohort study composed of 176 subjects with cancer who were exposed to zolendronate, 5 (2.8%) developed ONJ. In a prospective cohort study of 63 subjects with a history of cancer and intravenous BP exposure who underwent extraction of > 1 tooth, one subject (1.6%) developed ONJ. Among the studies reported above, the prospective studies should be weighted more heavily due to the larger sample sizes and the prospective, not retrospective, study designs.

The risk of developing ONJ among patients who have been exposed to antiresorptive medications for other dentoalveolar operations such as dental implant placement and endodontic or periodontal procedures is unknown. Absent data, the committee considers the risk for ONJ after dental implant placement and endodontic or periodontal procedures that require exposure and manipulation of bone to comparable to the risk associated with tooth extraction.

2. Anatomic factors

Limited new information regarding anatomic risk factors for MRONJ is available. MRONJ is more likely to appear in the mandible (73%) than the maxilla (22.5%) but can appear in both jaws (4.5%). Denture use was associated with an increased risk for ONJ among cancer patients exposed to zolendronate (OR = 4.9; 95% CI =1.2 – 20.1). In a study by Vahtsevanos, et al, a sample of 1,621 cancer patients treated with intravenous zolendronate, ibandronate, or pamidronate, there was a 2-fold increased risk for ONJ among denture wearers.

3. Concomitant oral disease

Pre-existing inflammatory dental disease such as periodontal disease or periapical pathology is a well-recognized risk factor. Among cancer patients with MRONJ, pre-existing inflammatory dental disease was a risk factor among 50% of the cases. Given that a common treatment of inflammatory dental disease is tooth extraction, pre-existing dental disease may confound the relationship between tooth extraction and risk for MRONJ noted above. It would be valuable to see an estimate of the association between tooth extraction and MRONJ adjusted for pre-existing inflammatory dental disease.

Demographic and systemic factors and other medication factors

Age and sex are variably reported as risk factors for MRONJ. The higher prevalence of this complication in the female population is likely a reflection of the underlying disease for which the agents are being prescribed (ie osteoporosis, breast cancer). There are very limited data describing the occurrence of MRONJ in the pediatric population. In an observational study, Brown, et al, reviewed a total of 42 pediatric patients who had received IV bisphosphonate therapy (mean duration of therapy 6.5 years) for a variety of metabolic bone diseases. No cases of ONJ were reported despite invasive dental treatment in 11 patients. The risk of developing MRONJ in the pediatric population certainly requires more complete investigation.

Corticosteroids are associated with an increased risk for MRONJ. Antiangiogenic agents, when given in addition to antiresorptive medications, are associated with an increased risk of ONJ.

Co-morbid conditions among cancer patients that are inconsistently reported to be associated with an increased risk for MRONJ include anemia (hemoglobin < 10g/dL) and diabetes. Cancer type is also variably reported as a risk factor.

Tobacco use has been inconsistently reported as a risk factor for MRONJ. In a case-control study, tobacco use approached statistical significance as a risk factor for ONJ in cancer patients (OR=3.0; 95% CI= 0.8 – 10.4). In a more recent case-controlled study, tobacco use was not associated with ONJ in a sample of cancer patients exposed to zolendronate. Vahtsevanos did not report an association between tobacco use and MRONJ.

Genetic factors

Since the previous position paper there have been several reports describing single nucleotide polymorphisms (SNPs) that were associated with the development MRONJ. Most of these SNPs were located within regions of the gene associated with either bone turnover, collagen formation, or certain metabolic bone diseases. Katz reported an ONJ event rate of 57% when SNPs were present in 5 candidate genes that were responsible for bone turnover. In a genome wide study, Nicoletti reported that patients with an SNP in the RBMS3 gene (associated with bone density and collagen formation) were 5.8 times more likely to develop ONJ. In a study that analyzed polymorphisms related to farnesyl diphosphate synthase activity (the enzyme specifically inhibited by bisphosphonates) a positive correlation was established with the carrier status and ONJ. Collectively, these studies suggest that a germ line sensitivity to bisphosphonates may exist.

In summary, the current literature reaffirms that the risk of MRONJ is significantly greater in cancer patients receiving antiresorptive therapy as compared to treatment regimens for osteoporosis. Moreover, the risk of MRONJ in osteoporosis patients receiving antiresorptive therapy continues to be very low regardless of drug type (bisphosphonates, denosumab) or dosing schedule. Targeted cancer therapies (VEGF and tyrosine kinase inhibitors) are also associated jaw necrosis but further studies with these medications are warranted.

Management Strategies for Patients Treated with Antiresorptives or Antiangiogenics

1. Prevention of MRONJ

The AAOMS Special Committee on MRONJ supports a multi-disciplinary approach to the treatment of patients who benefit from antiresorptive or antiangiogenic medications. This approach would include consultation with an appropriate dental professional when it is determined a patient would benefit from an antiresorptive or antiangiogenic drug. There is considerable support for early screening and initiation of appropriate dental care, which not only decreases the incidence of ONJ but would also accrue the benefits that all patients enjoy with optimum oral health.

The implementation of dental screening and appropriate dental measures before initiating antiresorptive therapy reduced the risk of ONJ in several prospective studies when compared in a retrospective fashion to patients who did not undergo dental preventive measures.

Dimopoulos found a statistically significant, almost threefold reduction in the incidence of osteonecrosis in patients when preventive measures were applied. Bonacina did not report any new cases of ONJ in patients who received dental screening and necessary dental treatment before initiating IV bisphosphonate treatment. Vandone found the incidence rate of developing ONJ was reduced by 50% in patients who were screened and received preventive dental care before initiating drug therapy.

Treatment planning for patients who may be prescribed antiresorptive or antiangiogenic therapy should include thorough examination of the oral cavity and a radiographic assessment when indicated. It is important to identify both acute infection and sites of potential infection to prevent future sequelae that could be exacerbated once drug therapies begin. Considerations during the clinical and radiographic assessment include: patient motivation, patient education regarding dental care, fluoride application, chlorhexidine rinses, tooth mobility, periodontal disease, presence of root fragments, caries, periapical pathology, edentulism, and denture stability.

An additional benefit of early dental consultation when the use of antiresorptive or antiangiogenic therapy is being considered is that the patient is being informed of the low risk associated with these drug therapies and the risk incurred by not undergoing recommended dental preventive measures before consenting to treatment.

2. Cessation of at-risk medication therapy prior to tooth extraction or other procedures, which involve osseous injury (eg dental implant placement, periodontal or apical endodontic treatment)

Antiresorptive Therapy for Osteoporosis/Osteopenia

The concept of a drug holiday in individuals receiving oral bisphosphonates or denosumab who require tooth extractions has been an ongoing area of controversy with little data to support current recommendations. The AAOMS Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw, revised in 2009, recommended discontinuing oral bisphosphonates for 3 months prior to and 3 months following invasive dental surgery – systemic conditions permitting. However there is currently no evidence that interrupting bisphosphonate therapy alters the risk of ONJ in patients following tooth extraction. In 2011 the ADA Council on Scientific Affairs revised their prior recommendation of a drug holiday and suggested that patients receiving lower cumulative doses of bisphosphonate (<2 years) or denosumab may continue antiresorptive therapy during invasive dental treatment. An International ONJ Task Force recommended a drug holiday in patients at higher risk for developing ONJ, including those with greater cumulative bisphosphonate exposure (>4 years), and those with comorbid risk factors such as rheumatoid arthritis, prior or current glucocorticoid exposure, diabetes and smoking until the site has healed. In a 2011 summary document on the long term safety of bisphosphonate therapy for osteoporosis, the FDA determined that there was “no substantial data available to guide decisions regarding the initiation or duration of a drug holiday.”

Damm and Jones proposed several alternatives to a drug holiday in BP-exposed patients who require invasive dental treatment. While there are no studies to support these recommendations their approach is based on bone physiology and pharmacokinetics of the antiresorptive medications and merit consideration (Level 5 evidence). They note that since 50% of serum BP undergoes renal excretion the major reservoir of BP is the osteoclast whose life span is 2 weeks. Thus the majority of free BP within the serum would be extremely low 2 months following the last dose of an oral bisphosphonate and a 2-month drug free period should be adequate prior to an invasive dental procedure.

This committee recognized that there are limited data to support or refute the benefits of a drug holiday for osteoporosis patients receiving antiresorptive therapy. However, a theoretical benefit may still apply for those patients with extended exposure histories (>4 yrs). Therefore the committee considers the modified drug holiday strategy as described by Damm and Jones to be a prudent approach for those patients at risk.

Oncology Patients Receiving Monthly Antiresorptive Therapy

Individuals receiving monthly intravenous bisphosphonates or denosumab for treatment of oncologic disease have an increased risk of developing ONJ following tooth extraction and thus these procedures should be avoided if possible. Increased awareness, preventive dental care and early recognition of the signs and symptoms of ONJ have resulted in earlier detection. Data are scant regarding the effect of discontinuing intravenous bisphosphonates prior to invasive dental treatments should these be necessary. However, if ONJ develops the oncologist may consider discontinuing antiresorptive therapy until soft tissue closure has occurred, depending on disease status.

As a fully humanized antibody, denosumab blocks the receptor-mediated activation of osteoclasts and has no binding affinity for bone matrix. Therefore, unlike bisphosphonates, the antiresorptive effects of denosumab should be mostly dissipated within 6 months of stopping the drug. However, there are no studies to support or refute the strategy of stopping denosumab therapy in the prevention or treatment of MRONJ.

There are no data to support or refute the cessation of antiangiogenic therapy in the prevention or management of MRONJ and therefore continued research in the area is indicated.

Treatment Goals

The major goals of treatment for patients at risk of developing or who have MRONJ are:

• Prioritization and support of continued oncologic treatment in patients receiving IV antiresorptive and antiangiogenic therapy.
  • Oncology patients can benefit greatly from the therapeutic effect of antiresorptive therapy by controlling bone pain and reducing the incidence of other skeletal complications
  • The antiangiogenic class of chemotherapy agents have demonstrated efficacy in the treatment of a variety of malignancies with proven survival benefits
• Preservation of quality of life through:
  • Patient education and reassurance
  • Control of pain
  • Control of secondary infection
  • Prevention of extension of lesion and development of new areas of necrosis

Management Strategies

Patients about to initiate intravenous antiresorptive or antiangiogenic treatment for cancer therapy

The treatment objective for this group of patients is to minimize the risk of developing MRONJ. Although a small percentage of patients receiving antiresorptives develop osteonecrosis of the jaw spontaneously, the majority of affected patients experience this complication following dentoalveolar surgery. Therefore if systemic conditions permit, initiation of antiresorptive therapy should be delayed until dental health is optimized. This decision must be made in conjunction with the treating physician and dentist and other specialists involved in the care of the patient.

Non-restorable teeth and those with a poor prognosis should be extracted. Other necessary elective dentoalveolar surgery should also be completed at this time. Based on experience with osteoradionecrosis, it appears advisable that antiresorptive or antiangiogenic therapy should be delayed, if systemic conditions permit, until the extraction site has mucosalized (14-21 days) or until there is adequate osseous healing. Dental prophylaxis, caries control and conservative restorative dentistry are critical to maintaining functionally sound teeth. This level of care must be continued indefinitely.

Patients with full or partial dentures should be examined for areas of mucosal trauma, especially along the lingual flange region. It is critical that patients be educated as to the importance of dental hygiene and regular dental evaluations, and specifically instructed to report any pain, swelling or exposed bone.

Medical oncologists should evaluate and manage patients scheduled to receive IV antiresorptive or antiangiogenic therapy similar to those patients scheduled to initiate radiation therapy to the head and neck. The osteoradionecrosis prevention protocols are guidelines that are familiar to most oncologists and general dentists.

Patients about to initiate antiresorptive treatment for osteoporosis

At the initiation of treatment, patients should be educated as to the potential risks of MRONJ as the antiresorptive therapy is likely to exceed beyond 4 years treatment. The importance of optimizing dental health throughout this treatment period and beyond should be stressed.

Asymptomatic patients receiving intravenous bisphosphonates or antiangiogenic drugs for cancer

Maintaining good oral hygiene and dental care is of paramount importance in preventing dental disease that may require dentoalveolar surgery. Procedures that involve direct osseous injury should be avoided. Non-restorable teeth may be treated by removal of the crown and endodontic treatment of the remaining roots. Placement of dental implants should be avoided in the oncology patient receiving intravenous antiresorptive therapy or antiangiogenic medications. There is no data regarding the risk of ONJ associated with implant placement in patients receiving antiangiogenic medications.

Asymptomatic patients receiving antiresorptive therapy for osteoporosis

Sound recommendations based on strong clinical research designs are still lacking for patients taking oral bisphosphonates. The committee strategies outlined below have been updated from those in the original Position Paper and are based on clinical studies that demonstrate a low prevalence of disease. The risk of developing MRONJ associated with oral bisphosphonates increased when duration of therapy exceeded four years. Although the current level of evidence is not strong, the committee continues to consider these strategies for patients receiving oral bisphosphonates as a prudent set of guidelines that will not compromise the long-term management of their osteoporosis. As more data become available and a better level of evidence is obtained, these strategies will be updated and modified as necessary.

Patients receiving antiresorptive therapy for osteoporosis are also at risk for developing MRONJ, but to a much lesser degree than those treated with intravenous antiresorptive therapy. MRONJ can develop spontaneously or after minor trauma. In general, these patients seem to have less severe manifestations of necrosis and respond more readily to stage specific treatment regimens. Elective dentoalveolar surgery does not appear to be contraindicated in this group. It is recommended that patients be adequately informed of the very small risk (<1%) of compromised bone healing. The risk of developing MRONJ associated with oral bisphosphonates, while exceedingly small, appears to increase when the duration of therapy exceeds 4 years. This time frame may be shortened in the presence of certain comorbidities, such as chronic corticosteroid or antiangiogenic use. If systemic conditions permit, the clinician may consider discontinuation of oral bisphosphonates for a period of two months prior to and three months following elective invasive dental surgery in order to lower the risk of MRONJ. The rationale for this approach is based on extrapolated data that demonstrate fluctuations of osteoclast function, which is related to bisphosphonate therapy, and recent outcomes studies that show improved outcome of MRONJ treatment with drug cessation.

The efficacy of utilizing a systemic marker of bone turnover to assess the risk of developing jaw necrosis in patients at risk has not been validated. Therefore the use of systemic markers of bone turnover as a measure of MRONJ risk is not recommended although the Committee supports continued research in this area.

1. For individuals who have taken an oral bisphosphonate for less than four years and have no clinical risk factors, no alteration or delay in the planned surgery is necessary. This includes any and all procedures common to oral and maxillofacial surgeons, periodontists and other dental providers.

It is suggested that if dental implants are placed, informed consent should be provided related to possible long-term implant failure and the low risk of developing osteonecrosis of the jaws if the patient continues to take an antiresorptive agent. These concerns are based on recent animal studies that have demonstrated impaired long-term implant healing. Such patients should be placed on a regular recall schedule. It is also advisable to contact the provider who originally prescribed the oral bisphosphonate and suggest monitoring such patients and considering either alternate dosing of the bisphosphonate, drug holidays, or an alternative to the bisphosphonate therapy.

2. For those patients who have taken an oral bisphosphonate for less than four years and have also taken corticosteroids or antiangiogenic medications concomitantly, the prescribing provider should be contacted to consider discontinuation of the oral bisphosphonate (drug holiday) for at least two months prior to oral surgery, if systemic conditions permit. The antiresorptive should not be restarted until osseous healing has occurred. These strategies are based on reports that corticosteroid and antiangiogenic agents, in combination with antiresorptive therapy, may increase the risk of developing MRONJ and that a drug holiday may mitigate this risk. Long-term, prospective studies however are still required to establish the efficacy of drug holidays in reducing the risk of MRONJ for these patients.

3. For those patients who have taken an oral bisphosphonate for more than four years with or without any concomitant medical therapy, the prescribing provider should be contacted to consider discontinuation of the antiresorptive for two months prior to oral surgery, if systemic conditions permit. The bisphosphonate should not be restarted until osseous healing has occurred. The risk of long-term oral bisphosphonate therapy requires continued analysis and research.

Patients with established MRONJ

Treatment objectives for patients with an established diagnosis of MRONJ are to eliminate pain, control infection of the soft and hard tissue, and minimize the progression or occurrence of bone necrosis. Patients with established MRONJ should avoid elective dentoalveolar surgical procedures, since these surgical sites may result in additional areas of exposed necrotic bone.

Since the publication of the 2009 guidelines there have been several reports of successful treatment outcomes for all stages of MRONJ following operative therapy (sequestrectomy, resection) and non-operative therapy. Except for the more advanced cases of Stage 3 disease or in those cases with a well-defined sequestrum, it appears that a more prudent approach would be to consider operative therapies when non-operative strategies have failed. Regardless of the stage of disease, areas of necrotic bone that are a constant source of soft tissue irritation and loose bony sequestra should be removed or recontoured so that soft tissue healing can be optimized. The extraction of symptomatic teeth within exposed, necrotic bone should be considered, since it appears unlikely that the extraction will exacerbate the established necrotic process.

A randomized controlled trial of hyperbaric oxygen therapy (HBO) as an adjunct to non-surgical and surgical treatment of MRONJ demonstrated some improvement in wound healing, long-term pain scores and quality of life scores. However given the small sample size, there was no statistically significant difference between the control and HBO group with regard to complete gingival coverage which was a major study endpoint. Therefore the use of HBO as the sole treatment modality for MRONJ cannot be supported at this time.

Case reports with small sample sizes have documented the use of other non-surgical treatment strategies, such as platelet rich plasma, low-level laser irradiation, parathyroid hormone, and bone morphogenic protein. The efficacy of these treatment modalities needs to be established through additional research and controlled studies.

Staging and Treatment Strategies

(See Table 1)

1. Staging

Modifications in the staging system are necessary to ensure that it remains an accurate reflection of disease presentation and to assist in the appropriate stratification of patients. A Stage 0 category was added in 2009 to include patients with non-specific symptoms, or clinical and radiographic abnormalities that may be due to exposure to an antiresorptive agent. At that time the risk of a patient with Stage 0 disease advancing to a higher disease stage was unknown. Since then several case studies have reported that up to 50% of patients with Stage 0 have progressed to Stage 1, 2 or 3. Therefore, it appears that Stage 0 may be a valid disease category that captures patients with prodromal disease (non-exposed variant). Also, the definition of exposed bone was broadened (see above) to include the presence of cutaneous or mucosal fistulae that probe to bone for Stage 1, 2 and 3 categories. Other research groups have proposed including radiographic signs alone, eg sclerosis, persistent extraction sockets, etc, to define a case of MRONJ. The Special Committee members recognize the potential benefits and risks of diagnosing MRONJ based on radiographic signs alone. The Special Committee elected to not use radiographic signs alone in the case definition. The committee members accepted the consequence that the current case definition may underestimate the true frequency of the disease. Revising the definition to include cases with radiographic signs alone may overestimate the true disease frequency by including false positives in the numerator, eg cases with radiographic findings suggestive of MRONJ, but are not MRONJ.

In order to direct rational treatment guidelines and collect data to assess the prognosis in patients who have used either IV or oral antiresorptive and antiangiogenic agents, the Committee proposes use of the following revised staging system:

• Patients at risk

No apparent necrotic bone in asymptomatic patients who have been treated with IV or oral antiresorptive or antiangiogenic therapy

• Stage 0 (Non-exposed bone variant)

Patients with no clinical evidence of necrotic bone, but present with non-specific symptoms or clinical and radiographic findings, such as,
Symptoms
– odontalgia not explained by an odontogenic cause
– dull, aching bone pain in the body of the mandible, which may radiate to the temporomandibular joint region
– sinus pain, which may be associated with inflammation and thickening of the maxillary sinus wall
– altered neurosensory function

Clinical Findings
– loosening of teeth not explained by chronic periodontal disease
– periapical/periodontal fistula that is not associated with pulpal necrosis due to caries

Radiographic Findings
– alveolar bone loss or resorption not attributable to chronic periodontal disease
– changes to trabecular pattern—dense woven bone and persistence of unremodeled bone in extraction sockets
– regions of osteosclerosis involving the alveolar bone and/or the surrounding basilar bone
– thickening/obscuring of periodontal ligament (thickening of the lamina dura and decreased size of the periodontal ligament space)

These non-specific findings, which characterize this non-exposed variant of ONJ, may occur in patients with a prior history of Stage 1, 2, or 3 disease who have healed and have no clinical evidence of exposed bone.

• Stage 1

Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection. These patients may also present with radiographic findings mentioned for Stage 0 which are localized to the alveolar bone region.

• Stage 2

Exposed and necrotic bone, or fistulae that probe to bone, with evidence of infection. These patients are typically symptomatic. These patients may also present with radiographic findings mentioned for Stage 0 which are localized to the alveolar bone region.

• Stage 3

Exposed and necrotic bone, or fistulae that probe to bone, with evidence of infection, and one or more of the following:
– exposed necrotic bone extending beyond the region of alveolar bone, ie, inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla
– pathologic fracture
– extra-oral fistula
– oral antral/oral nasal communication
– osteolysis extending to the inferior border of the mandible or sinus floor

2. Stage-Specific Treatment Strategies

At risk – Patients who are at risk of developing MRONJ due to an exposure history with an antiresorptive or an antiangiogenic drug. They do not have exposed bone nor do they require any treatment. However, these patients should be informed of the risks of developing MRONJ, as well as the signs and symptoms of this disease process.

Stage 0 – Provide symptomatic treatment, and conservatively manage other local factors, such as caries and periodontal disease. Systemicmanagement may include the use of medication for chronic pain and control of infection with antibiotics, when indicated. These patients will require close monitoring given the potential for progression to a higher stage of disease. Among patients with radiographic signs alone suggesting Stage 0, (see above), the committee recommends close monitoring for progression to a higher stage of disease. Other diagnoses, eg fibro-osseous disease, chronic sclerosing osteomyelitis should also be considered.

Stage 1 – These patients benefit from medical management including the use of oral antimicrobial rinses, such as chlorhexidine 0.12%. No immediate operative treatment is required.

Stage 2 – These patients benefit from the use of oral antimicrobial rinses in combination with antibiotic therapy. Although local bone and soft tissue infection is not considered the primary etiology for this process, the colonization of the exposed bone is a very common occurrence. Most of the isolated microbes have been sensitive to the penicillin group of antibiotics. Quinolones, metronidazole, clindamycin, doxycycline and erythromycin have been used with success in those patients who are allergic to penicillin. Microbial cultures should also be analyzed and the antibiotic regimen should be adjusted accordingly. Biofilm formation on the surface of the exposed bone has been reported in several reports and may be responsible for the failure of systemic antibiotic therapies that are described in some refractory cases. In such cases, operative therapy directed at reducing the volume of colonized, necrotic bone may serve as a beneficial adjunct to antibiotic therapy.

Stage 3 – These patients benefit from debridement, including resection, in combination with antibiotic therapy, which may offer long-term palliation with resolution of acute infection and pain. Symptomatic patients with stage 3 disease may require resection and immediate reconstruction with a reconstruction plate or an obturator. The potential for failure of the reconstruction plate because of the generalized effects of the bisphosphonate exposure needs to be recognized by the clinician and patient. Case reports with small sample sizes describe successful immediate reconstruction with vascularized bone.

Regardless of the disease stage, mobile bony sequestra should be removed to facilitate soft tissue healing. The extraction of symptomatic teeth within exposed, necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process. A thorough histologic analysis is indicated for all resected bone specimens (especially for patients with a history a malignant disease) since metastatic cancer has been reported in such specimens.

Table 1 Staging and Treatment Strategies

MRONJ Staging(*)	Treatment Strategies(**)
At risk category No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates	1.No treatment indicated 2.Patient education
Stage 0 No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms	Systemic management, including the use of pain medication and antibiotics
Stage 1 Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection	1.Antibacterial mouth rinse 2.Clinical follow-up on a quarterly basis 3.Patient education and review of indications for continued bisphosphonate therapy
Stage 2 Exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage	1.Symptomatic treatment with oral antibiotics 2.Oral antibacterial mouth rinse 3.Pain control 4.Debridement to relieve soft tissue irritation and infection control
Stage 3 Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone,(i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor	1.Antibacterial mouth rinse 2.Antibiotic therapy and pain control 3.Surgical debridement/resection for longer term palliation of infection and pain

*Exposed or probable bone in the maxillofacial region without resolution for greater than 8 weeks in patients treated with an antiresorptive and/or an antiangiogenic agent who have not received radiation therapy to the jaws

**Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed, necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process.

Future Research

The National Institutes of Health have provided funding opportunities for research on the pathophysiology of bisphosphonate-associated osteonecrosis of the jaw. This has resulted in multiple research efforts focusing on several facets of this disease entity that have occurred since the last position paper. These studies are responsible for many of the new data and information that was presented in this paper. Areas of continued investigation include, but are not limited to: 1) analysis of alveolar bone hemostasis and the response to antiresorptive therapies; 2) the role of novel antiangiogenic medications and their effects on jaw bone healing; 3) pharmacogenetic research; 4) development of valid MRONJ risk assessment tools; 5) animal studies to validate existing and proposed treatment and prevention strategies.

Continued governmental and institutional support is required in order to further elucidate the underlying pathophysiological mechanisms of MRONJ at the cellular and molecular level. Moreover, improved strategies for the prevention, risk reduction, and treatment of MRONJ need to be developed further so that more accurate judgments about risk, prognosis, treatment selection, and outcome can be established for patients with MRONJ.

Appendix I: Antiresorptive Preparations Commonly Used in the U.S.

Appendix II: Medications Used in the Treatment of Various Cancers that are Antiangiogenic or Targets of the Vascular Endothelial Growth Factor (VEGF) Pathway that have been Associated with Jaw Necrosis*

Drug	Mechanism of action	Primary indication
Sunitinib (Sutent®)	Tyrosine kinase inhibitor	GIST, RCC, pNET
Sorafenib (Nexavar®)	Tyrosine kinase inhibitor	HCC, RCC
Bevacizumab (Avastin®)	Humanized monoclonal antibody	mCRC, NSCLC, Glio, mRCC
Sirolimus (Rapamune®)	Mammalian target of rapamycin pathway	Organ rejection in renal transplant

Abbreviations: GIST gastrointestinal stromal tumor; RCC renal cell carcinoma; pNET pancreatic neuroendocrine tumor, HCC hepatocellular carcinoma; mCRC metastatic colorectal carcinoma; NSCLC non-squamous non-small cell lung carcinoma; Glio Glioblastoma; mRCC metastatic renal cell carcinoma

*While the FDA has issued an ONJ advisory only for
bevacizumab and sunitinib,99,100 the committee remains concerned about a similar potential risk associated with several other medications within the same drug class which have a similar mechanism of action. Therefore further controlled, prospective studies will be required to more fully characterize the risk of jaw necrosis associated with these agents.

¹Sample size in parentheses
²Zolendronate
³Prevalence estimate. All other frequencies reported in the figure are incidences.

原文/Original paper：https://www.aaoms.org/practice-resources/aaoms-advocacy-and-position-statements/white-papers