Abstract：
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.
摘要：
Denosumab是一种人类单克隆抗体，适用于骨质疏松症和骨折高风险患者。它的目标是RANKL,NF-κB受体激活剂（RANK）配体，阻断RANKL-RANK相互作用并导致快速破骨细胞介导的骨吸收抑制。但是RANK在神经元中广泛表达，小胶质细胞,和星形胶质细胞。RANKL/RANK/NF-κB系统在神经炎症反应中发挥重要作用,抑郁行为，记忆障碍，和神经营养。我们在2012年至2022年期间，提供了两份记录良好的Denosumab治疗患者复发神经精神表现的病例报告，并对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审查。只有医疗保健专业人员报告的，将denosumab编码为唯一的可疑药物，被保留。一名患有轻度认知障碍的81岁女性患有两次急性混乱发作，另一名患有抑郁症缓解期的81岁女性患有两次抑郁复发，伴有焦虑和精神运动抑制，在这两种情况下，连续服用地诺塞马后，没有潜在的钙/磷酸盐失衡。Naranjo药品不良反应概率量表评分分别为6分和7分,表明可能的因果关系。在FAERS报告的91,151例Denosumab暴露病例中，5.7%与精神/神经系统疾病有关，其中23.8%与认知障碍有关，抑郁/情绪障碍，或者精神运动迟钝.Denosumab可能通过涉及RANKL阻断和随后的免疫炎症变化的几种机制引起短暂但严重的神经精神症状。至少在预先存在神经生物学脆弱性的受试者中。我们建议在denosumab给药后谨慎并仔细监测这些患者。
