Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial

Tania A Pawade, Mhairi K Doris, Rong Bing, Audrey C White, Laura Forsyth, Emily Evans, Catriona Graham, Michelle C Williams, Edwin J R van Beek, Alison Fletcher, Philip D Adamson, Jack P M Andrews, Timothy R G Cartlidge, William S A Jenkins, Maaz Syed, Takeshi Fujisawa, Christophe Lucatelli, William Fraser, Stuart H Ralston, Nicholas Boon, Bernard Prendergast, David E Newby, Marc R Dweck, Tania A Pawade, Mhairi K Doris, Rong Bing, Audrey C White, Laura Forsyth, Emily Evans, Catriona Graham, Michelle C Williams, Edwin J R van Beek, Alison Fletcher, Philip D Adamson, Jack P M Andrews, Timothy R G Cartlidge, William S A Jenkins, Maaz Syed, Takeshi Fujisawa, Christophe Lucatelli, William Fraser, Stuart H Ralston, Nicholas Boon, Bernard Prendergast, David E Newby, Marc R Dweck

Abstract

Background: 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.

Methods: 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 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.

Results: 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]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake.

Conclusions: 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.

Keywords: alendronate; aortic stenosis; calcium signaling; computed tomography, X-ray; denosumab.

Figures

Figure 1.
Figure 1.
CONSORT diagram. The primary end point (24-month change in aortic valve calcium score) was calculated from a daily rate of change based on the difference between baseline and final aortic valve calcium score, whether this was at 12 months or 24 months. AVR indicates aortic valve replacement.
Figure 2.
Figure 2.
C-terminal telopeptide concentrations.A, C-terminal telopeptide concentrations at baseline and 6 months for each trial arm (placebo: P>0.5, denosumab: P<0.001, alendronic acid: P<0.001; Wilcoxon rank-sum test). B, Six-month change in C-terminal telopeptide for each trial arm (P<0.001 for both denosumab and alendronic acid compared to placebo; Wilcoxon rank-sum test).
Figure 3.
Figure 3.
Primary and key secondary end points.A, Calculated change in 24-month aortic valve calcium score (P=0.41 for denosumab versus placebo; P=0.49 for alendronic acid versus placebo; Wilcoxon rank-sum test). B, Calculated change in 24-month peak aortic jet velocity (P=0.21 for denosumab versus placebo; P=0.74 for alendronic acid versus placebo; Wilcoxon rank-sum test). C, Calculated change in 12-month aortic valve maximum target to background ratio (P=0.61 for denosumab versus placebo; P=0.15 for alendronic acid versus placebo; Wilcoxon rank-sum test).

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