Inokuchi Shoichiro, Shimamoto Koji
Research and Analytics Department, Real World Data Co., Ltd., Kyoto, Japan.
Front Pharmacol. 2024 Jul 22;15:1411285. doi: 10.3389/fphar.2024.1411285. eCollection 2024.
Romosozumab is a monoclonal antibody approved for osteoporosis which targets sclerostin, an endogenous inhibitor of Wnt/β-catenin pathway. Given the essential roles of the Wnt/β-catenin pathway in various tissues, we hypothesized romosozumab treatment may influence other conditions.
This cohort study included patients prescribed romosozumab or parathyroid receptor (PTHR) agonists after 1 January 2019, using a Japanese electronic medical record database. The outcomes of interest included autoimmune disease, interstitial pneumonia, cardiovascular outcome, Alzheimer's disease, Parkinson's disease (PD), serious infections, and malignancies. A stabilized inverse probability-weighted Cox proportional hazard model was used to estimate the hazard ratios. Age- and gender-based subgroup analyses were conducted. Exploratory outcomes based on three-digit International Classification of Diseases 10th Revision-based were also examined.
In total, 2,673 patients treated with romosozumab and 5,980 treated with PTHR agonists were identified, respectively. While most outcomes of interest showed no association with romosozumab, the risk of PD decreased with romosozumab (hazard ratio [95% confidence interval], 0.37 [0.14-0.94]) compared with PTHR agonist. Regarding the cardiovascular outcome, no notable association was identified overall; however, gender-based subgroup analysis suggested that male sex may be a potential risk factor with romosozumab treatment. Only 16 of 903 exploratory outcomes were potentially influenced by romosozumab.
Romosozumab lowered the risk of PD development compared with PTHR agonist. The study also highlights the utility of routinely collected health data for drug repositioning. While further validation is warranted, the findings suggest that the Wnt-β-catenin pathway holds promise as a therapeutic target for PD.
罗莫索单抗是一种被批准用于治疗骨质疏松症的单克隆抗体，其作用靶点是硬化蛋白，这是一种Wnt/β-连环蛋白信号通路的内源性抑制剂。鉴于Wnt/β-连环蛋白信号通路在各种组织中发挥着重要作用，我们推测罗莫索单抗治疗可能会影响其他疾病。
本队列研究利用日本电子病历数据库，纳入了2019年1月1日后开具罗莫索单抗或甲状旁腺受体（PTHR）激动剂处方的患者。感兴趣的结局包括自身免疫性疾病、间质性肺炎、心血管结局、阿尔茨海默病、帕金森病（PD）、严重感染和恶性肿瘤。采用稳定的逆概率加权Cox比例风险模型来估计风险比。进行了基于年龄和性别的亚组分析。还检查了基于国际疾病分类第十版三位数编码的探索性结局。
分别确定了2673例接受罗莫索单抗治疗的患者和5980例接受PTHR激动剂治疗的患者。虽然大多数感兴趣的结局与罗莫索单抗无关，但与PTHR激动剂相比，罗莫索单抗降低了PD的发病风险（风险比[95%置信区间]，0.37[0.14 - 0.94]）。关于心血管结局，总体上未发现显著关联；然而，基于性别的亚组分析表明，男性可能是罗莫索单抗治疗的潜在风险因素。在903项探索性结局中，只有16项可能受到罗莫索单抗的影响。
与PTHR激动剂相比，罗莫索单抗降低了PD的发病风险。该研究还强调了常规收集的健康数据在药物重新定位方面的作用。虽然需要进一步验证，但研究结果表明Wnt-β-连环蛋白信号通路有望成为PD的治疗靶点。
