British Heart Foundation Centre for Cardiovascular Science (T.A.P., M.K.D., R.B., A.C.W., M.C.W., P.D.A., J.P.M.A., T.R.G.C., W.S.A.J., M.S., T.F., N.B., D.E.N., M.R.D.), University of Edinburgh, United Kingdom.
Edinburgh Clinical Trials Unit (L.F.), University of Edinburgh, United Kingdom.
Circulation. 2021 Jun 22;143(25):2418-2427. doi: 10.1161/CIRCULATIONAHA.121.053708. Epub 2021 Apr 29.
Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.
In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.
A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; =0.49). Similarly, there were no differences in change in peak aortic jet velocity or F-sodium fluoride aortic valve uptake.
Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
瓣叶钙化是主动脉瓣狭窄发病和进展的核心，临床前和观察性研究表明，骨转换和瓣膜间质细胞成骨分化是重要的促成机制。我们旨在确定用 denosumab 或 alendronic acid 抑制这些途径是否可以减少主动脉瓣狭窄的疾病进展。
在一项单中心、平行分组、双盲随机对照试验中，年龄大于 50 岁、有钙化性主动脉瓣狭窄（峰值主动脉射流速度＞2.5 m/s）的患者以 2:1:2:1 的比例随机分为 denosumab（每 6 个月 60mg）组、安慰剂注射组、alendronic acid（每周 70mg）组或安慰剂胶囊组。参与者接受多普勒超声心动图、计算机断层扫描主动脉瓣钙评分、F-氟酸钠正电子发射断层扫描和计算机断层扫描的连续评估。主要终点是计算的 24 个月主动脉瓣钙评分变化。
共纳入 150 名（平均年龄 72±8 岁；21%为女性）有钙化性主动脉瓣狭窄（峰值主动脉射流速度 3.36 m/s [2.93-3.82 m/s]；主动脉瓣钙评分 1152 AU [655-2065 AU]）的患者，进行了随机分组并接受了分配的试验干预：denosumab（n=49）、alendronic acid（n=51）和安慰剂（注射 n=25，胶囊 n=25；合并分析）。denosumab（0.23 [0.18-0.33 µg/L] 至 0.11 µg/L [0.08-0.17 µg/L]）和 alendronic acid（0.20 [0.14-0.28 µg/L] 至 0.09 µg/L [0.08-0.13 µg/L]）的血清 C 端肽水平从基线到 6 个月时减半，但安慰剂组（0.23 [0.17-0.30 µg/L] 至 0.26 µg/L [0.16-0.31 µg/L]）无变化。denosumab 与安慰剂（343 [198-804 AU] 与 354 AU [76-675 AU]；P=0.41）或 alendronic acid 与安慰剂（326 [138-813 AU] 与 354 AU [76-675 AU]；P=0.49）相比，24 个月时主动脉瓣钙评分变化无差异。同样，峰值主动脉射流速度或 F-氟酸钠主动脉瓣摄取的变化也无差异。
denosumab 或 alendronic acid 均未影响钙化性主动脉瓣狭窄患者主动脉瓣钙化的进展。需要探索替代途径和机制，以确定针对这一潜在致命疾病的潜在疾病修饰治疗方法。
