基于FAERS数据库对唑来膦酸和地舒单抗药物不良反应的信号挖掘与分析

Signal Mining and Analysis of Adverse Drug Reactions of Zoledronic Acid and Denosumab Based on FAERS Database

摘要

目的 基于美国食品药品监督管理局不良事件报告系统（Food and Drug Administration Adverse Event Reporting System，FAERS）数据库，挖掘抗骨吸收药物唑来膦酸和地舒单抗的药物不良反应（adverse drug reaction，ADR）风险信号，为临床安全用药提供参考依据。方法 提取FAERS系统中2004年1月至2024年9月唑来膦酸和地舒单抗的药物不良事件（adverse drug event，ADE）报告，采用报告比值比法和比例报告比值比法挖掘ADE信号。结果 共识别212 622份与上述2种常用抗骨吸收药物相关的ADE报告，其中唑来膦酸ADE阳性信号1 311个，地舒单抗683个。2种药物ADE信号存在较大差异。颌骨外露、死骨等与唑来膦酸相关性最强；而骨巨细胞瘤、恶性骨巨细胞瘤等与地舒单抗相关性较强。唑来膦酸主要累及各种肌肉骨骼及结缔组织疾病、全身性疾病及给药部位各种反应；地舒单抗则涉及各类损伤、中毒及操作并发症和各种肌肉骨骼与结缔组织疾病。研究还发现多个新ADE，如骨骼疾病、颌骨疾病等。结论 检索到唑来膦酸和地舒单抗ADE信号基本与说明书一致。在临床应用时，除了要关注死亡、颌骨坏死等相关不良反应外，对药物说明书中未提及的新的潜在不良反应信号，如各种肌肉骨骼及结缔组织疾病等也需多加关注。

Abstract

Objective Based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, this study aims to detect adverse drug reaction (ADR) risk signals of two antiresorptive drugs, zoledronic acid and denosumab, so as to provide reference for clinical safe medication. Methods Adverse drug event (ADE) reports of zoledronic acid and denosumab in the FAERS database from January 2004 to September 2024 were extracted, and the reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods were adopted for ADE signal mining. Results A total of 212 622 ADE reports related to the two commonly used antiresorptive drugs were identified, including 1 311 positive ADE signals for zoledronic acid and 683 for denosumab. There were significant differences in ADE signal profiles between the two drugs. Exposed mandibular bone and bone sequestrum showed the strongest correlation with zoledronic acid, while giant cell tumor of bone and malignant giant cell tumor of bone were strongly associated with denosumab. The ADEs of zoledronic acid mainly involved musculoskeletal and connective tissue disorders, systemic disorders, and administration site reactions; while those of denosumab mainly involved injuries, poisoning and procedural complications, as well as musculoskeletal and connective tissue disorders. Several new ADE signals were also identified in this study, such as skeletal disorders and mandibular disorders.Conclusion The ADE signals of zoledronic acid and denosumab detected in this study are generally consistent with those recorded in the package inserts. In clinical practice, in addition to focusing on known adverse reactions such as death and osteonecrosis of the jaw, close attention should also be paid to new potential adverse reaction signals not mentioned in the package inserts, including various musculoskeletal and connective tissue disorders.

关键词

唑来膦酸 / 地舒单抗 / FAERS数据库 / 药物不良事件 / 信号挖掘

Key words

zoledronic acid / denosumab / FAERS database / adverse drug event / signal mining

参考文献

[1] Fornetti J, Welm A L, Stewart S A. Understanding the bone in cancer metastasis[J].J Bone Miner Res, 2018, 33(12): 2099-2113.

[2] 李宁, 肖国有. 前列腺癌骨转移治疗的研究进展[J].肿瘤防治研究, 2020, 47(8): 641-646.

[3] Bernstein Z S, Kim E B, Raje N. Bone disease in multiple myeloma: biologic and clinical implications[J]. Cells, 2022, 11(15): 2308.

[4] Huang X L, Huang L Y, Cheng Y T,et al. Zoledronic acid inhibits osteoclast differentiation and function through the regulation of NF—κB and JNK signalling pathways[J].Int J Mol Med, 2019, 44(2): 582-592.

[5] Stopeck A T, Lipton A, Body J J,et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double—blind study[J].J Clin Oncol, 2010, 28(35): 5132-5139.

[6] Kendler D L, Cosman F, Stad R K,et al. Denosumab in the treatment of osteoporosis: 10 years later: a narrative review[J].Adv Ther, 2022, 39(1): 58-74.

[7] Kowalski M L, Makowska J S, Blanca M,et al. Hypersensitivity to nonsteroidal anti—inflammatory drugs (NSAIDs)—classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA[J].Allergy, 2011, 66(7): 818-829.

[8] 李云, 张科, 袁恒杰, 等. 基于FAERS分析比较英夫利昔单抗、乌司奴单抗和维得利珠单抗用于炎症性肠病治疗的安全性[J].中国现代应用药学, 2024, 41(19): 2694-2703.

[9] Kim Y, Paik M, Khan C,et al. Real—world safety evaluation of musculoskeletal adverse events associated with Korean pediatric fluoroquinolone use: a nationwide longitudinal retrospective cohort study[J].Sci Rep, 2019, 9(1): 20156.

[10] Omar N E, Fahmy Soliman A I, Eshra M,et al. Postmarketing safety of anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS)[J].ESMO Open, 2021, 6(6): 100315.

[11] 宋再伟, 李欣亚, 门鹏, 等. 基于FAERS数据库的维泊妥珠单抗不良反应信号挖掘[J].中国临床药理学与治疗学, 2024, 29(7): 752-761.

[12] 高鹍, 程峰. 基于FAERS数据库挖掘开展的药物安全性研究进展[J].中国医院药学杂志, 2023, 43(3): 337-340.

[13] Vargas—Franco J W, Castaneda B, Rédiní F,et al. Paradoxical side effects of bisphosphonates on the skeleton: what do we know and what can we do?[J].J Cell Physiol, 2018, 233(8): 5696-5715.

[14] Limones A, Sáez—Alcaide L, Díaz—Parreño S,et al. Medication—related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: a systematic review and meta—analysis[J].Med Oral, 2020: e326-e336.

[15] Boonen S, Sellmeyer D E, Lippuner K,et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women[J].Kidney Int, 2008, 74(5): 641-648.

[16] Cummings S R, Martin J S, McClung M R,et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis[J].N Engl J Med, 2009, 361(8): 756-765.

[17] Black D M, Reid I R, Napoli N,et al. The interaction of acute—phase reaction and efficacy for osteoporosis after zoledronic acid: horizon pivotal fracture trial[J].J Bone Miner Res, 2022, 37(1): 21-28.

[18] 戴梦飞, 丁海樱, 潘利斌, 等. 基于FAERS的益生菌制剂相关不良事件信号挖掘与分析[J].中国现代应用药学, 2024, 41(21): 2966-2970.

基金资助

云南省科技人才与平台计划(202305AC160016)