Risk factors for medication-related osteonecrosis of the jaw after tooth extraction in patients treated with denosumab

doi:10.12439/kqhm.1005-4979.2026.04.006

Abstract

Abstract:

Objective:

To investigate the factors associated with medication-related osteonecrosis of the jaw (MRONJ) following tooth extraction in patients receiving denosumab, and to evaluate the clinical value of mucoperiosteal flap closure.

Methods:

A single-center prospective cohort study was conducted, including 116 patients receiving denosumab therapy (308 teeth) who underwent tooth extraction at Shanghai Tongji Stomatological Hospital, between February 2024 and September 2025. Clinical data were collected, and patients were divided into a mucoperiosteal flap closure group and a simple suturing group according to the wound management approach. All patients were followed up for 3 months, and healing outcomes were recorded. Generalized estimating equations (GEE) were applied at the tooth level to identify factors influencing post-extraction healing outcomes.

Results:

The incidence of MRONJ was 15.00% in the denosumab high-dose group and 1.04% in the low-dose group. Multivariate analysis showed that uncontrolled inflammation at the surgical site was significantly associated with adverse healing outcomes [adjusted odds ratio (aOR) = 84.86], whereas mucoperiosteal flap closure significantly reduced the risk of poor healing and MRONJ (aOR = 0.27). No significant association was observed between preventive drug discontinuation (≥1 month) and healing outcomes (P>0.05).

Conclusion:

Local inflammatory status is an important factor affecting healing outcomes after tooth extraction in patients receiving denosumab. Mucoperiosteal flap closure may help reduce the risk of adverse postoperative outcomes. When long-term discontinuation is not feasible, a 1-month drug discontinuation before extraction appears to be relatively safe.

Key words: bone-modifying agents, medication-related osteonecrosis of the jaw, mucoperiosteal flap, preventive drug discontinuation

摘要：

目的：

分析地舒单抗用药患者拔牙后发生药物相关性颌骨坏死（medication-related osteonecrosis of the jaw，MRONJ）的影响因素，并评估黏骨膜瓣封闭技术的应用价值。

方法：

采用单中心前瞻性队列研究设计，纳入2024年2月至2025年9月于上海市同济口腔医院就诊的116例地舒单抗用药患者（共308颗患牙）。收集临床资料，根据拔牙创处理方式将患者分为黏骨膜瓣封闭组与简单缝合组，随访3个月，记录愈合结局。采用广义估计方程（generalized estimating equations，GEE）模型在患牙水平筛选影响拔牙后愈合结局的因素。

结果：

地舒单抗高剂量组MRONJ发生率为15.00%，低剂量组为1.04%。多因素分析显示，术区难以控制的炎症与不良愈合结局显著相关[校正后比值比(adjusted odds ratio，aOR)=84.86]；黏骨膜瓣封闭技术可显著降低术后愈合不良及MRONJ发生风险（aOR=0.27）。预防性停药时间(≥1个月)与愈合结局无显著相关性（P>0.05）。

结论：

术区炎症控制情况是影响地舒单抗用药患者拔牙后愈合结局的重要因素；黏骨膜瓣封闭技术有助于降低术后不良结局的发生风险。在无法长期停药的情况下，拔牙前停药1个月是相对安全的。

关键词: 骨改良药物, 药物相关性颌骨坏死, 黏骨膜瓣, 预防性停药

CAO Shaokang, ZHANG Yiyun, LI Haixia, KANG Feiwu, ZHANG Xueming. Risk factors for medication-related osteonecrosis of the jaw after tooth extraction in patients treated with denosumab[J]. Journal of Oral and Maxillofacial Surgery(CN), 2026, 36(4): 307-317.

曹少康, 张逸云, 李海霞, 康非吾, 张雪明. 接受地舒单抗治疗患者拔牙后发生药物相关性颌骨坏死的风险因素分析[J]. 《口腔颌面外科杂志》, 2026, 36(4): 307-317.

/ / Recommend / Download Citations

URL: https://journal06.magtech.org.cn/Jweb_joms/EN/10.12439/kqhm.1005-4979.2026.04.006

https://journal06.magtech.org.cn/Jweb_joms/EN/Y2026/V36/I4/307

Figures/Tables 9

References 35

[1]	Otto S, Pautke C, Van den Wyngaert T, et al. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases[J]. Cancer Treat Rev, 2018, 69: 177-187.
[2]	何悦, 陈珩, 安金刚, 等. 药物相关性颌骨坏死临床诊疗专家共识[J]. 中国口腔颌面外科杂志, 2023, 21(4): 313-325.
[3]	Ruggiero SL, Dodson TB, Aghaloo T, et al. American association of oral and maxillofacial surgeons' position paper on medication-related osteonecrosis of the jaws—2022 update[J]. J Oral Maxillofac Surg, 2022, 80(5): 920-943.
[4]	Bracchi P, Zecca E, Brunelli C, et al. A real-world study on the prevalence and risk factors of medication related osteonecrosis of the jaw in cancer patients with bone metastases treated with Denosumab[J]. Cancer Med, 2023, 12(17): 18317-18326.
[5]	Watts NB, Grbic JT, Binkley N, et al. Invasive oral procedures and events in postmenopausal women with osteoporosis treated with denosumab for up to 10 years[J]. J Clin Endocrinol Metab, 2019, 104(6): 2443-2452.
[6]	张雪明, 康非吾. 药物相关性颌骨坏死防控策略: 从风险分级到临床实践[J]. 口腔颌面外科杂志, 2026, 36(1): 1-10.
[7]	Avishai G, Muchnik D, Masri D, et al. Minimizing MRONJ after tooth extraction in cancer patients receiving bone-modifying agents[J]. J Clin Med, 2022, 11(7): 1807.
[8]	Bedogni A, Mauceri R, Fusco V, et al. Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ)[J]. Oral Dis, 2024, 30(6): 3679-3709.
[9]	叶立, 曹钰彬, 孙国文, 等. 关于接受地舒单抗治疗患者拔牙围手术期管理的专家共识[J]. 华西口腔医学杂志, 2026, 44(2): 153-172.
[10]	Wang Y, Zhang Y, Li DK, et al. Potential role of the comprehensive tooth extraction procedure in preventing medication related osteonecrosis of the jaw (MRONJ): A prospective cohort study[J]. Orphanet J Rare Dis, 2025, 20(1): 619.
[11]	Matsumoto A, Sasaki M, Schmelzeisen R, et al. Primary wound closure after tooth extraction for prevention of medication-related osteonecrosis of the jaw in patients under denosumab[J]. Clin Oral Investig, 2017, 21(1): 127-134.
[12]	Ristow O, Rückschloß T, Moratin J, et al. Wound closure and alveoplasty after preventive tooth extractions in patients with antiresorptive intake—a randomized pilot trial[J]. Oral Dis, 2021, 27(3): 532-546.
[13]	Hasegawa T, Kawakita A, Ueda N, et al. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: Can primary wound closure and a drug holiday really prevent MRONJ?[J]. Osteoporos Int, 2017, 28(8): 2465-2473.
[14]	Hasegawa T, Ueda N, Yamada S, et al. Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: A multicenter retrospective study[J]. Osteoporos Int, 2021, 32(11): 2323-2333.
[15]	Junquera L, Gallego L. Nonexposed bisphosphonate-related osteonecrosis of the jaws: Another clinical variant?[J]. J Oral Maxillofac Surg, 2008, 66(7): 1516-1517.
[16]	Patel S, Choyee S, Uyanne J, et al. Non-exposed bisphosphonate-related osteonecrosis of the jaw: A critical assessment of current definition, staging, and treatment guidelines[J]. Oral Dis, 2012, 18(7): 625-632.
[17]	Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update[J]. J Oral Maxillofac Surg, 2014, 72(10): 1938-1956.
[18]	Fedele S, Porter SR, D’Aiuto F, et al. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: A case series[J]. Am J Med, 2010, 123(11): 1060-1064.
[19]	Wongratwanich P, Shimabukuro K, Konishi M, et al. Do various imaging modalities provide potential early detection and diagnosis of medication-related osteonecrosis of the jaw? A review[J]. Dentomaxillofac Radiol, 2021, 50(6): 20200417.
[20]	张雪明, 曹少康, 王欣仪, 等. 非暴露型药物相关性颌骨坏死的早期识别与鉴别诊断[J]. 口腔颌面外科杂志, 2026, 36(2): 79-90.
[21]	Otto S, Aljohani S, Fliefel R, et al. Infection as an important factor in medication-related osteonecrosis of the jaw (MRONJ)[J]. Medicina (Kaunas), 2021, 57(5): 463.
[22]	Hallmer F, Andersson G, Götrick B, et al. Prevalence, initiating factor, and treatment outcome of medication-related osteonecrosis of the jaw-a 4-year prospective study[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2018, 126(6): 477-485.
[23]	Beth-Tasdogan NH, Mayer B, Hussein H, et al. Interventions for managing medication-related osteonecrosis of the jaw[J]. Cochrane Database Syst Rev, 2017, 10(10): CD012432.
[24]	Ng TL, Tu MM, Ibrahim MFK, et al. Long-term impact of bone-modifying agents for the treatment of bone metastases: A systematic review[J]. Supportive Care Cancer, 2021, 29(2): 925-943.
[25]	Nguyen QH, Nguyen H, Giap HV, et al. Stage-related changes of bone density and volume in treatment of medication-related osteonecrosis of the jaw[J]. Sci Rep, 2025, 15(1): 45235.
[26]	Ko YY, Yang WF, Leung YY. The role of cone beam computed tomography (CBCT) in the diagnosis and clinical management of medication-related osteonecrosis of the jaw (MRONJ)[J]. Diagnostics (Basel), 2024, 14(16): 1700.
[27]	Ciobanu GA, Mogoantă L, Camen A, et al. Clinical and histopathological aspects of MRONJ in cancer patients[J]. J Clin Med, 2023, 12(10): 3383.
[28]	Zhou Y, Li QX, Huang HY, et al. Clinical efficacy analysis of mucoperiosteal flap combined with perforation technique for tooth extraction in medication-related osteonecrosis of the jaw risk population: A retrospective study[J]. BMC Oral Health, 2025, 25(1): 1740.
[29]	Pippi R, Giuliani U, Tenore G, et al. What is the risk of developing medication-related osteonecrosis in patients with extraction sockets left to heal by secondary intention? A retrospective case series study[J]. J Oral Maxillofac Surg, 2021, 79(10): 2071-2077.
[30]	Hayashida S, Yanamoto S, Fujita S, et al. Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw[J]. J Bone Miner Metab, 2020, 38(1): 126-134.
[31]	Takeda D, Kurita H, Kashima Y, et al. Is withdrawal of antiresorptive agents necessary before and after tooth extraction? A systematic review[J]. Clin Oral Investig, 2023, 28(1): 38.
[32]	Moon C, Kim H, Park JH, et al. High-dose denosumab (Xgeva^®) Associated Medication-Related Osteonecrosis of the Jaws (MRONJ): Incidence and clinical characteristics in a retrospective analysis of 1278 patients[J]. Supportive Care Cancer, 2024, 32(12): 774.
[33]	Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: Systematic review and additional cases[J]. J Bone Mineral Res, 2017, 32(6): 1291-1296.
[34]	Kumar S, Wang M, Kim AS, et al. Denosumab discontinuation in the clinic: Implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures[J]. J Bone Miner Res, 2025, 40(9): 1017-1034.
[35]	李凡, 李健斌, 宋华, 等. 乳腺癌骨转移患者骨改良药物相关颌骨坏死的临床特征及预测模型分析: 单中心14年回顾性研究[J]. 解放军医学院学报, 2025, 46(8): 767-775.

变量	愈合类型			P值
变量	愈合（n=106）	愈合不良（n=6）	MRONJ（n=4）	P值
年龄/岁	70(64.00,76.00)	64(60.00,71.00)	67(64.75,72.25)	0.286
性别				0.276
男	10(83.34)	1(8.33)	1(8.33)
女	96(92.31)	5(4.81)	3(2.88)
地舒单抗剂量				0.008
低剂量	91(94.79)	4(4.17)	1(1.04)
高剂量	15(75.00)	2(10.00)	3(15.00)
合并其他用药史				0.277
否	71(93.42)	4(5.26)	1(1.32)
是	35(87.50)	2(5.00)	3(7.50)
特征性影像学表现				0.013
无	76(93.83)	5(6.17)	0(0)
有	30(85.71)	1(2.86)	4(11.43)
预防性停药时间/月				0.503
1~2	20(86.96)	1(4.35)	2(8.69)
3~6	64(92.75)	3(4.35)	2(2.90)
>6	22(91.67)	2(8.33)	0(0)

变量	愈合类型			P值
变量	愈合（n=106）	愈合不良（n=6）	MRONJ（n=4）	P值
年龄/岁	70(64.00,76.00)	64(60.00,71.00)	67(64.75,72.25)	0.286
性别				0.276
男	10(83.34)	1(8.33)	1(8.33)
女	96(92.31)	5(4.81)	3(2.88)
地舒单抗剂量				0.008
低剂量	91(94.79)	4(4.17)	1(1.04)
高剂量	15(75.00)	2(10.00)	3(15.00)
合并其他用药史				0.277
否	71(93.42)	4(5.26)	1(1.32)
是	35(87.50)	2(5.00)	3(7.50)
特征性影像学表现				0.013
无	76(93.83)	5(6.17)	0(0)
有	30(85.71)	1(2.86)	4(11.43)
预防性停药时间/月				0.503
1~2	20(86.96)	1(4.35)	2(8.69)
3~6	64(92.75)	3(4.35)	2(2.90)
>6	22(91.67)	2(8.33)	0(0)

变量	愈合类型			P值
变量	愈合（n=295）	愈合不良（n=7）	MRONJ（n=6）	P值
年龄/岁	70(64.00,76.00)	63(61.00,69.00)	67(64.00,68.75)	0.026
性别				0.641
男	44(93.62)	1(2.13)	2(4.25)
女	251(96.17)	6(2.30)	4(1.53)
地舒单抗剂量				0.065
低剂量	218(97.32)	5(2.23)	1(0.45)
高剂量	77(91.67)	2(2.38)	5(5.95)
合并其他用药史				0.397
否	188(96.91)	5(2.58)	1(0.52)
是	107(93.86)	2(1.75)	5(4.39)
预防性停药时间分组/月
1~2	54(93.10)	1(1.72)	3(5.17)
3~6	175(96.15)	4(2.20)	3(1.65)	0.377
>6	66(97.06)	2(2.94)	0(0)	0.324
预防性停药时间/月	4(2.00,6.00)	3(2.00,9.00)	2(1.00,3.00)	0.605
拔牙牙根数
单根	199(95.22)	4(1.91)	6(2.87)
双根	58(96.67)	2(3.33)	0(0)	0.616
三根	38(97.44)	1(2.56)	0(0)	0.572
患牙位置				0.637
上颌	140(96.55)	3(2.07)	2(1.38)
下颌	155(95.10)	4(2.45)	4(2.45)
术区难以控制的炎症				<0.001
无	285(98.62)	3(1.04)	1(0.35)
有	10(52.63)	4(21.05)	5(26.32)
特征性影像学表现				0.117
无	206(97.17)	6(2.83)	0(0)
有	89(92.71)	1(1.04)	6(6.25)
拔牙创处理方式				0.068
简单缝合组	175(94.60)	7(3.78)	3(1.62)
黏骨膜瓣封闭组	120(97.56)	0(0)	3(2.44)

变量	愈合类型			P值
变量	愈合（n=295）	愈合不良（n=7）	MRONJ（n=6）	P值
年龄/岁	70(64.00,76.00)	63(61.00,69.00)	67(64.00,68.75)	0.026
性别				0.641
男	44(93.62)	1(2.13)	2(4.25)
女	251(96.17)	6(2.30)	4(1.53)
地舒单抗剂量				0.065
低剂量	218(97.32)	5(2.23)	1(0.45)
高剂量	77(91.67)	2(2.38)	5(5.95)
合并其他用药史				0.397
否	188(96.91)	5(2.58)	1(0.52)
是	107(93.86)	2(1.75)	5(4.39)
预防性停药时间分组/月
1~2	54(93.10)	1(1.72)	3(5.17)
3~6	175(96.15)	4(2.20)	3(1.65)	0.377
>6	66(97.06)	2(2.94)	0(0)	0.324
预防性停药时间/月	4(2.00,6.00)	3(2.00,9.00)	2(1.00,3.00)	0.605
拔牙牙根数
单根	199(95.22)	4(1.91)	6(2.87)
双根	58(96.67)	2(3.33)	0(0)	0.616
三根	38(97.44)	1(2.56)	0(0)	0.572
患牙位置				0.637
上颌	140(96.55)	3(2.07)	2(1.38)
下颌	155(95.10)	4(2.45)	4(2.45)
术区难以控制的炎症				<0.001
无	285(98.62)	3(1.04)	1(0.35)
有	10(52.63)	4(21.05)	5(26.32)
特征性影像学表现				0.117
无	206(97.17)	6(2.83)	0(0)
有	89(92.71)	1(1.04)	6(6.25)
拔牙创处理方式				0.068
简单缝合组	175(94.60)	7(3.78)	3(1.62)
黏骨膜瓣封闭组	120(97.56)	0(0)	3(2.44)

变量	aOR	95%CI	P值
年龄（每增加1岁）	0.99	0.91~1.07	0.770
地舒单抗剂量（高vs低）	1.67	0.39~7.05	0.487
术区难以控制的炎症（有vs无）	84.86	10.29~700.15	<0.001
拔牙创处理方式（黏骨膜瓣封闭技术vs简单缝合）	0.27	0.12~0.62	0.002
预防性停药时间（每增加1个月）	1.08	0.96~1.21	0.188
特征性影像学表现（有vs无）	1.05	0.28~3.93	0.938

Please choose a citation manager

Content to export