Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany.
Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
Cochrane Database Syst Rev. 2022 Jul 12;7(7):CD012432. doi: 10.1002/14651858.CD012432.pub3.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab, and antiangiogenic agents), and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, this adverse drug reaction may occur rarely (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment), or commonly (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat. This is an update of our review first published in 2017.
To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs. To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ.
Cochrane Oral Health's Information Specialist searched four bibliographic databases up to 16 June 2021 and used additional search methods to identify published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention.
Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CIs).
We included 13 RCTs (1668 participants) in this updated review, of which eight were new additions. The studies were clinically diverse and examined very different interventions, so meta-analyses could not be performed. We have low or very low certainty about available evidence on interventions for the prophylaxis or treatment of MRONJ. Prophylaxis of MRONJ Five RCTs examined different interventions to prevent the occurrence of MRONJ. One RCT compared standard care with regular dental examinations at three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ (RR 0.10, 95% CI 0.02 to 0.39, 253 participants). Secondary outcomes were not evaluated. Dentoalveolar surgery is considered a common predisposing event for developing MRONJ and five RCTs tested various preventive measures to reduce the risk of postoperative MRONJ. The studies evaluated plasma rich in growth factors inserted into the postextraction alveolus in addition to standardised medical and surgical care versus standardised medical and surgical care alone (RR 0.08, 95% CI 0.00 to 1.51, 176 participants); delicate surgery and closure by primary intention versus non-traumatic tooth avulsion and closure by secondary intention (no case of postoperative MRONJ in either group); primary closure of the extraction socket with a mucoperiosteal flap versus application of platelet-rich fibrin without primary wound closure (no case of postoperative MRONJ in either group); and subperiosteal wound closure versus epiperiosteal wound closure (RR 0.09, 95% CI 0.00 to 1.56, 132 participants). Treatment of MRONJ Eight RCTs examined different interventions for the treatment of established MRONJ; that is, the effect on MRONJ cure rates. One RCT analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone (at last follow-up: RR 1.56, 95% CI 0.77 to 3.18, 46 participants). Healing rates from MRONJ were not significantly different between autofluorescence-guided bone surgery and conventional bone surgery (RR 1.08, 95% CI 0.85 to 1.37, 30 participants). Another RCT that compared autofluorescence- with tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ found no significant difference (at one-year follow-up: RR 1.05, 95% CI 0.86 to 1.30, 34 participants). Three RCTs investigated the effect of growth factors and autologous platelet concentrates on healing rates of MRONJ: platelet-rich fibrin after bone surgery versus surgery alone (RR 1.05, 95% CI 0.90 to 1.22, 47 participants), bone morphogenetic protein-2 together with platelet-rich fibrin versus platelet-rich fibrin alone (RR 1.10, 95% CI 0.94 to 1.29, 55 participants), and concentrated growth factor and primary wound closure versus primary wound closure only (RR 1.38, 95% CI 0.81 to 2.34, 28 participants). Two RCTs focused on pharmacological treatment with teriparatide: teriparatide 20 μg daily versus placebo in addition to standard care (RR 0.96, 95% CI 0.31 to 2.95, 33 participants) and teriparatide 56.5 μg weekly versus teriparatide 20 μg daily in addition to standard care (RR 1.60, 95% CI 0.25 to 1.44, 12 participants).
Prophylaxis of medication-related osteonecrosis of the jaw One open-label RCT provided some evidence that dental examinations at three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of medication-related osteonecrosis of the jaw (MRONJ) in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be very low. There is insufficient evidence to either claim or refute a benefit of the interventions tested for prophylaxis of MRONJ in patients with antiresorptive therapy undergoing dentoalveolar surgery. Although some interventions suggested a potential large effect, the studies were underpowered to show statistical significance, and replication of the results in larger studies is pending. Treatment of medication-related osteonecrosis of the jaw The available evidence is insufficient to either claim or refute a benefit, in addition to standard care, of any of the interventions studied for the treatment of MRONJ.
药物相关性颌骨坏死（MRONJ）是某些人在接受某些治疗癌症和骨质疏松症的药物（如双膦酸盐、地舒单抗和抗血管生成药物）时出现的一种严重不良反应，涉及下颌骨或上颌骨的骨进行性破坏。根据药物、其剂量和暴露时间的不同，这种药物不良反应可能很少发生（例如，口服双膦酸盐或地舒单抗治疗骨质疏松症，或抗血管生成药物靶向癌症治疗），也可能很常见（例如，静脉内双膦酸盐治疗癌症）。MRONJ 会导致严重的发病率，影响生活质量（QoL），并且难以治疗。这是我们在 2017 年首次发表的综述的更新。
评估抗吸收或抗血管生成药物暴露者预防 MRONJ 的干预措施与不治疗、安慰剂或阳性对照的效果。评估非手术或手术干预（单独或联合使用）与不治疗、安慰剂或阳性对照在有明显 MRONJ 患者中的治疗效果。
Cochrane 口腔健康信息专家检索了截至 2021 年 6 月 16 日的四个文献数据库，并使用了其他检索方法来确定已发表、未发表和正在进行的研究。
我们纳入了比较一种干预措施与另一种干预措施预防或治疗 MRONJ 的随机对照试验（RCT）。对于“MRONJ 的预防”，主要结局是 MRONJ 的发生率；次要结局是 QoL、时间事件、干预的并发症和副作用的发生率。对于“已建立的 MRONJ 的治疗”，主要结局是 MRONJ 的愈合；次要结局是 QoL、复发、干预的并发症和副作用的发生率。
两名综述作者独立筛选检索结果、提取数据，并评估纳入研究的偏倚风险。对于二分类结局，我们报告风险比（RR）（或率比）和 95%置信区间（CI）。
我们在本次更新的综述中纳入了 13 项 RCT（1668 名参与者），其中 8 项是新增的。这些研究在临床方面存在差异，研究了非常不同的干预措施，因此无法进行荟萃分析。我们对干预措施预防或治疗 MRONJ 的证据的确定性评价为低或极低。
MRONJ 的预防：五项 RCT 研究了不同的干预措施以预防 MRONJ 的发生。一项 RCT 比较了标准护理与每三个月一次的常规牙科检查以及预防性治疗（包括在接受唑来膦酸治疗转移性前列腺癌的男性中进行牙提取前使用抗生素和使用避免骨暴露和污染的伤口闭合技术）在接受唑来膦酸治疗转移性前列腺癌的男性中的作用。该干预措施似乎降低了 MRONJ 的风险（RR 0.10，95%CI 0.02 至 0.39，253 名参与者）。次要结局未进行评估。牙牙槽外科被认为是发生 MRONJ 的常见诱发事件，五项 RCT 研究了各种预防措施以降低术后 MRONJ 的风险。这些研究评估了在标准护理的基础上加用富含生长因子的血浆插入拔牙窝中与标准护理的单独使用（RR 0.08，95%CI 0.00 至 1.51，176 名参与者）；精细手术和一期缝合与非创伤性牙拔除和二期缝合（两组均无术后 MRONJ）；拔牙窝一期缝合黏膜骨瓣与不一期缝合应用富血小板纤维蛋白（两组均无术后 MRONJ）；骨膜下伤口闭合与骨膜上伤口闭合（RR 0.09，95%CI 0.00 至 1.56，132 名参与者）。
MRONJ 的治疗：八项 RCT 研究了已建立的 MRONJ 的不同干预措施的治疗效果；即，MRONJ 治愈率的影响。一项 RCT 分析了高压氧（HBO）治疗联合标准护理（消毒冲洗、抗生素和手术）与单独标准护理（末次随访：RR 1.56，95%CI 0.77 至 3.18，46 名参与者）的效果。MRONJ 的愈合率在自体荧光引导骨手术和传统骨手术之间无显著差异（RR 1.08，95%CI 0.85 至 1.37，30 名参与者）。另一项 RCT 比较了自体荧光与四环素荧光引导的清创术治疗 MRONJ，发现无显著差异（在 1 年随访时：RR 1.05，95%CI 0.86 至 1.30，34 名参与者）。三项 RCT 研究了生长因子和自体血小板浓缩物对 MRONJ 愈合率的影响：骨手术后富血小板纤维蛋白与单独手术（RR 1.05，95%CI 0.90 至 1.22，47 名参与者）、骨形态发生蛋白-2 与富血小板纤维蛋白（RR 1.10，95%CI 0.94 至 1.29，55 名参与者）和浓缩生长因子与一期伤口闭合与仅一期伤口闭合（RR 1.38，95%CI 0.81 至 2.34，28 名参与者）。两项 RCT 专注于药物治疗：特立帕肽 20 μg 每日与安慰剂联合标准护理（RR 0.96，95%CI 0.31 至 2.95，33 名参与者）和特立帕肽 56.5 μg 每周与特立帕肽 20 μg 每日联合标准护理（RR 1.60，95%CI 0.25 至 1.44，12 名参与者）。
MRONJ 的预防：一项开放标签 RCT 提供了一些证据，表明每三个月进行一次牙科检查和预防性治疗可能比标准护理更能降低接受静脉内双膦酸盐治疗晚期癌症的患者发生 MRONJ 的发生率。我们评估证据的确定性为非常低。目前尚没有足够的证据来证明或反驳接受抗吸收治疗的患者在接受牙牙槽外科手术时，干预措施预防 MRONJ 的获益。尽管一些干预措施表明可能有较大的效果，但这些研究的效力不足，无法显示统计学意义，需要在更大的研究中进行复制。MRONJ 的治疗：目前的证据不足以证明或反驳除标准护理外，任何研究中治疗 MRONJ 的干预措施都有获益。
