Unidad de Metabolismo Óseo, HM Universitario de Madrid, HM Hospitales, Madrid, Spain.
Departamento Ciencias Básicas de La Salud, Área de Farmacología Y Nutrición, Facultad de Ciencias de La Salud, High Performance Research Group in Experimental Pharmacology (PHARMAKOM), Universidad Rey Juan Carlos, Unidad Asociada I+D+I Al Instituto de Química Médica (CSIC), 28933, Alcorcón, Madrid, Spain.
Osteoporos Int. 2023 Oct;34(10):1799-1804. doi: 10.1007/s00198-023-06838-z. Epub 2023 Jul 5.
Denosumab is a human monoclonal antibody indicated for patients with osteoporosis and a high risk of fractures. It targets RANKL, the receptor activator of NF-κB (RANK) ligand, blocking RANKL-RANK interaction and leading to rapid osteoclast-mediated bone resorption inhibition. But RANK is widely expressed in neurons, microglia, and astrocytes. RANKL/RANK/NF-κB system can play an important role in the neuroinflammatory response, depressive behavior, memory impairments, and neurotrophism. We present two well-documented case reports of recurrent neuropsychiatric manifestations in patients treated with denosumab and a descriptive review of similar cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database between 2012 and 2022. Only those reported by healthcare professionals, coding denosumab as the only suspected drug, were retained. An 81-year-old woman with pre-existing mild cognitive impairment suffered two acute confusional episodes and another 81-year-old woman with depression in remission suffered two depressive recurrences with anxiety and psychomotor inhibition, in both cases following sequential administrations of denosumab without underlying calcium/phosphate imbalance. Scores on Naranjo Adverse Drug Reaction Probability Scale were 6 and 7, respectively, suggesting a probable causal relationship. Of the 91,151 cases with denosumab exposure reported to FAERS, 5.7% were related to psychiatric/neurological disorders and 23.8% of these corresponded to cognitive impairment, depressive/mood disturbances, or psychomotor retardation. Denosumab may cause transient but severe neuropsychiatric symptoms by several mechanisms involving RANKL blockade and subsequent immuno-inflammatory changes, at least in subjects with pre-existing neurobiological vulnerability. We recommend caution and careful monitoring of these patients following denosumab administrations.
地舒单抗是一种人源化单克隆抗体，适用于骨质疏松症和骨折高风险患者。它靶向 RANKL（核因子-κB 受体激活物配体），阻断 RANKL-RANK 相互作用，导致破骨细胞介导的骨吸收迅速抑制。但是 RANK 在神经元、小胶质细胞和星形胶质细胞中广泛表达。RANKL/RANK/NF-κB 系统在神经炎症反应、抑郁行为、记忆障碍和神经营养作用中发挥重要作用。我们报告了两例接受地舒单抗治疗的患者反复出现神经精神表现的病例，并对 2012 年至 2022 年期间食品和药物管理局不良事件报告系统（FAERS）数据库中报告的类似病例进行了描述性综述。仅保留了由医疗保健专业人员报告的、将地舒单抗编码为唯一可疑药物的病例。一名 81 岁的老年女性患有轻度认知障碍，先后发生了两次急性意识障碍发作；另一名 81 岁的老年女性患有缓解期抑郁症，先后两次复发，伴有焦虑和运动抑制，均在序贯给予地舒单抗治疗后发生，且均无钙/磷失衡的基础。Naranjo 药物不良反应概率量表评分分别为 6 和 7，提示可能存在因果关系。在 FAERS 报告的 91151 例地舒单抗暴露病例中，5.7%与精神/神经障碍有关，其中 23.8%与认知障碍、抑郁/情绪障碍或精神运动迟缓有关。地舒单抗可能通过几种机制引起短暂但严重的神经精神症状，包括 RANKL 阻断和随后的免疫炎症变化，至少在存在预先存在的神经生物学脆弱性的患者中是如此。我们建议在给予地舒单抗后谨慎并仔细监测这些患者。
