DataSheet1_Wnt/β-catenin pathway as a potential target for Parkinson’s disease: a cohort study of romosozumab using routinely collected health data in Japan.PDF

IntroductionRomosozumab 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.
MethodsThis 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.
ResultsIn 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.
ConclusionRomosozumab 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.

引言 罗莫单抗（romosozumab）是一款获批用于骨质疏松症的单克隆抗体，其靶向硬化蛋白（sclerostin）——一种Wnt/β-连环蛋白（Wnt/β-catenin）通路的内源性抑制剂。鉴于Wnt/β-连环蛋白通路在多种组织中发挥关键作用，我们假设罗莫单抗治疗可能会对其他疾病产生影响。
方法 本队列研究利用日本电子病历数据库，纳入了2019年1月1日后接受罗莫单抗或甲状旁腺受体（PTHR）激动剂治疗的患者。本研究关注的结局包括自身免疫性疾病、间质性肺炎、心血管事件、阿尔茨海默病、帕金森病（PD）、严重感染以及恶性肿瘤。本研究采用稳定逆概率加权Cox比例风险模型估算风险比，并按年龄和性别进行亚组分析。此外，本研究还基于国际疾病分类第10版（ICD-10）的三位数编码对探索性结局进行了分析。
结果 本研究共纳入罗莫单抗治疗患者2673例，甲状旁腺受体激动剂治疗患者5980例。尽管多数关注结局与罗莫单抗治疗无显著关联，但与甲状旁腺受体激动剂相比，罗莫单抗治疗可降低帕金森病的发病风险（风险比[95%置信区间]：0.37[0.14–0.94]）。在心血管事件方面，整体未观察到显著关联；但按性别进行的亚组分析提示，男性可能是罗莫单抗治疗相关的潜在风险因素。903项探索性结局中仅16项可能受到罗莫单抗治疗的影响。
结论 与甲状旁腺受体激动剂相比，罗莫单抗可降低帕金森病的发病风险。本研究同时凸显了常规收集的健康数据在药物重定位研究中的应用价值。尽管尚需进一步验证，但本研究结果提示Wnt/β-连环蛋白通路有望成为帕金森病的治疗靶点。