Background: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with pre-clinical 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-centre parallel group double-blind randomized controlled trial, patients over 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 endpoint was the calculated 24-month change in aortic valve calcium score. Results: One-hundred and fifty patients (mean age 72±8 years; 21% female) with calcific aortic stenosis (peak aortic jet velocity 3.36 [2.93 to 3.82] m/s; aortic valve calcium score 1152 [655 to 2065] Agatston Units) 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 to 0.33] to 0.11 [0.08 to 0.17] µg/L) and alendronic acid (0.20 [0.14 to 0.28] to 0.09 [0.08 to 0.13] µg/L) but was unchanged with placebo (0.23 [0.17 to 0.30] to 0.26 [0.16 to 0.31] µg/L). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198 to 804] AU versus 354 [76 to 675] AU, p=0.41), or alendronic acid and placebo (326 [138 to 813] AU versus 354 [76 to 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. Clinical Trial Registration: https://www.clinicaltrials.gov Unique Identifier: NCT02132026.

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.

Apologies -this was a typo that is now corrected. The correct presentation of the study is 'MA 3 RS' and we do not believe this will cause problems with the reader interpreting the superscript as a reference.