Rollason Victoria, Laverrière Alexandra, MacDonald Laura C I, Walsh Tanya, Tramèr Martin R, Vogt-Ferrier Nicole B
Division of Clinical Pharmacology and Toxicology, Department APSI, Geneva University Hospitals, Hopital Cantonal de Geneve, Geneva, Switzerland, 1211.
Cochrane Database Syst Rev. 2016 Feb 26;2(2):CD008455. doi: 10.1002/14651858.CD008455.pub2.
Bisphosphonate drugs can be used to prevent and treat osteoporosis and to reduce symptoms and complications of metastatic bone disease; however, they are associated with a rare but serious adverse event: osteonecrosis of the maxillary and mandibular bones. This condition is called bisphosphonate-related osteonecrosis of the jaw or BRONJ. BRONJ is diagnosed when people who are taking, or have previously taken, bisphosphonates have exposed bone in the jaw area for more than eight weeks in the absence of radiation treatment. There is currently no "gold standard" of treatment for BRONJ. The three broad categories of intervention are conservative approaches (e.g. mouth rinse, antibiotics), surgical interventions and adjuvant non-surgical strategies (e.g. hyperbaric oxygen therapy, platelet-rich plasma), which can be used in combination.
To determine the efficacy and safety of any intervention aimed at treating BRONJ.
We searched the following databases to 15 December 2015: the Cochrane Oral Health Group Trials Register, the Cochrane Breast Cancer Group Trials Register (20 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, EMBASE via Ovid, CancerLit via PubMed, CINAHL via EBSCO and AMED via Ovid. We scanned the references cited in retrieved articles and contacted experts in the field, the first authors of included papers, study sponsors, other bisphosphonates investigators and pharmaceutical companies. We searched for ongoing trials through contact with trialists and by searching the US National Institutes of Health Trials Register (clinicaltrials.gov) and the World Health Organization Clinical Trials Registry Platform. We also conducted a grey literature search to September 2015.
Randomised controlled trials (RCTs) comparing the effects of any treatment for BRONJ with another treatment or placebo.
Two review authors independently screened the search results, assessed the risk of bias in the included trials and extracted data. When in dispute, we consulted a third review author.
One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral-maxillofacial surgeon) to standard care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores.At three months, the study found that the participants in intervention group were more likely to have an improvement in their osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was no clear difference between the groups for the outcome 'healed' at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact.The study did not give any information on adverse events.Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only study was underpowered and was at high risk of bias due to lack of blinding, cross-over of participants between groups and very high attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow-up of 24 months).
AUTHORS' CONCLUSIONS: There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to "standard" care and could not confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations for their focus and design.
双膦酸盐药物可用于预防和治疗骨质疏松症，并减轻转移性骨病的症状和并发症；然而，它们与一种罕见但严重的不良事件相关：上颌骨和下颌骨骨坏死。这种情况被称为双膦酸盐相关颌骨骨坏死（BRONJ）。当正在服用或曾服用双膦酸盐的人在没有接受放射治疗的情况下，颌骨区域的骨暴露超过八周时，即可诊断为BRONJ。目前尚无BRONJ的“金标准”治疗方法。三大类干预措施为保守方法（如漱口、抗生素）、手术干预和辅助非手术策略（如高压氧治疗、富血小板血浆），这些方法可联合使用。
确定任何旨在治疗BRONJ的干预措施的疗效和安全性。
我们检索了以下数据库至2015年12月15日：Cochrane口腔健康组试验注册库、Cochrane乳腺癌组试验注册库（2011年9月20日）、Cochrane对照试验中央注册库（CENTRAL）、通过Ovid检索的MEDLINE、通过Ovid检索的EMBASE、通过PubMed检索的CancerLit、通过EBSCO检索的CINAHL以及通过Ovid检索的AMED。我们浏览了检索到的文章中引用的参考文献，并联系了该领域的专家、纳入论文的第一作者、研究资助者、其他双膦酸盐研究者和制药公司。我们通过与试验者联系以及检索美国国立卫生研究院试验注册库（clinicaltrials.gov）和世界卫生组织临床试验注册平台来查找正在进行的试验。我们还进行了至2015年9月的灰色文献检索。
比较任何BRONJ治疗方法与另一种治疗方法或安慰剂效果的随机对照试验（RCT）。
两位综述作者独立筛选检索结果，评估纳入试验的偏倚风险并提取数据。出现争议时，我们会咨询第三位综述作者。
一项存在高偏倚风险的小型试验符合纳入标准。该试验将49名参与者随机分组，其中大多数患有癌症。它将标准治疗（定义为口腔颌面外科医生酌情进行的手术、抗生素和口腔冲洗）与标准治疗加高压氧治疗（每天两次，2个大气压，共40次治疗）进行了比较。该试验测量了在3个月、6个月、12个月、18个月以及最后一次随访时病情改善或愈合的参与者百分比。它还测量了每周平均疼痛评分。在3个月时，研究发现干预组的参与者骨坏死改善的可能性高于标准治疗组参与者（风险比（RR）1.94，95%置信区间（CI）1.01至3.74）。在3个月时，两组在“愈合”这一结果上没有明显差异（RR 3.60，95%CI 0.87至14.82）。在对6个月、12个月、18个月以及最后一次随访时的改善或愈合情况进行评估时，两组之间没有明显差异。该研究未提供任何关于不良事件的信息。尽管研究结果表明辅助高压氧治疗可改善BRONJ，但证据质量非常低，因为唯一的这项研究样本量不足，且由于缺乏盲法、组间参与者交叉以及极高的失访率（本研究设计的预期随访时间为24个月，12个月时失访率为50%，18个月时为80%）而存在高偏倚风险。
缺乏来自随机对照试验的证据来指导双膦酸盐相关颌骨骨坏死（BRONJ）的治疗。一项存在高偏倚风险的小型试验评估了高压氧治疗（HBO）作为“标准”治疗的辅助手段，但无法证实或反驳HBO的有效性。有两项正在进行的关于特立帕肽治疗BRONJ的试验。我们未发现任何其他BRONJ治疗方法的随机对照试验。需要高质量的随机对照试验。我们为其重点和设计提供了建议。
