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

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

doi:10.1161/circulationaha.121.053708

Cited by 93 publications

(57 citation statements)

References 45 publications

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“…The negative findings from our study, in addition to the ones from a recent randomized trial demonstrating that neither denosumab nor alendronic acid was able to prevent the progression of AVC in patients with aortic stenosis, 22 emphasize the great complexity of this process, and warrant further research.…”

Section: Discussioncontrasting

confidence: 64%

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

et al. 2022

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Background: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. Methods: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 μg MK-7 plus 25 μg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. Results: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). Conclusions: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression.

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Section: Discussioncontrasting

confidence: 64%

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

et al. 2022

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“…Given the protective properties of OPG against cardiovascular calcification, denosumab has raised interest in the prevention of CAVD and has been shown to inhibit porcine aortic VIC calcification in vitro ( 183 ). The SALTIRE2 trial randomised 150 non-osteoporotic patients with moderate calcific AS to either denosumab, the bisphosphonate agent alendronate or placebo, and found no significant difference detected in the progression of CAVD as assessed by computerised tomography (CT) calcium scoring, doppler echocardiography and 18F-sodium fluoride positron emission tomography ( 184 , 185 ).…”

Section: The Unsolved Quest For Medical Therapy Of Aortic Stenosismentioning

confidence: 99%

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Dayawansa

Baratchi

Peter

2022

Front. Cardiovasc. Med.

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Calcific aortic valve disease (CAVD) is a common acquired valvulopathy, which carries a high burden of mortality. Chronic inflammation has been postulated as the predominant pathophysiological process underlying CAVD. So far, no effective medical therapies exist to halt the progression of CAVD. This review aims to outline the known pathways of inflammation and calcification in CAVD, focussing on the critical roles of mechanical stress and mechanosensing in the perpetuation of valvular inflammation. Following initiation of valvular inflammation, dysregulation of proinflammatory and osteoregulatory signalling pathways stimulates endothelial-mesenchymal transition of valvular endothelial cells (VECs) and differentiation of valvular interstitial cells (VICs) into active myofibroblastic and osteoblastic phenotypes, which in turn mediate valvular extracellular matrix remodelling and calcification. Mechanosensitive signalling pathways convert mechanical forces experienced by valve leaflets and circulating cells into biochemical signals and may provide the positive feedback loop that promotes acceleration of disease progression in the advanced stages of CAVD. Mechanosensing is implicated in multiple aspects of CAVD pathophysiology. The mechanosensitive RhoA/ROCK and YAP/TAZ systems are implicated in aortic valve leaflet mineralisation in response to increased substrate stiffness. Exposure of aortic valve leaflets, endothelial cells and platelets to high shear stress results in increased expression of mediators of VIC differentiation. Upregulation of the Piezo1 mechanoreceptor has been demonstrated to promote inflammation in CAVD, which normalises following transcatheter valve replacement. Genetic variants and inhibition of Notch signalling accentuate VIC responses to altered mechanical stresses. The study of mechanosensing pathways has revealed promising insights into the mechanisms that perpetuate inflammation and calcification in CAVD. Mechanotransduction of altered mechanical stresses may provide the sought-after coupling link that drives a vicious cycle of chronic inflammation in CAVD. Mechanosensing pathways may yield promising targets for therapeutic interventions and prognostic biomarkers with the potential to improve the management of CAVD.

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“…In contrast, in aortic stenosis patients, denosumab is not effective in reducing the progression of aortic valve calcification. [119].…”

Section: Treatment Of Hyperphosphatemic Medial Vascular Calcificationmentioning

confidence: 99%

Cardiac Calcifications: Phenotypes, Mechanisms, Clinical and Prognostic Implications

Sega

Fortini

Severi

et al. 2022

Biology

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There is a growing interest in arterial and heart valve calcifications, as these contribute to cardiovascular outcome, and are leading predictors of cardiovascular and kidney diseases. Cardiovascular calcifications are often considered as one disease, but, in effect, they represent multifaced disorders, occurring in different milieus and biological phenotypes, following different pathways. Herein, we explore each different molecular process, its relative link with the specific clinical condition, and the current therapeutic approaches to counteract calcifications. Thus, first, we explore the peculiarities between vascular and valvular calcium deposition, as this occurs in different tissues, responds differently to shear stress, has specific etiology and time courses to calcification. Then, we differentiate the mechanisms and pathways leading to hyperphosphatemic calcification, typical of the media layer of the vessel and mainly related to chronic kidney diseases, to those of inflammation, typical of the intima vascular calcification, which predominantly occur in atherosclerotic vascular diseases. Finally, we examine calcifications secondary to rheumatic valve disease or other bacterial lesions and those occurring in autoimmune diseases. The underlying clinical conditions of each of the biological calcification phenotypes and the specific opportunities of therapeutic intervention are also considered and discussed.

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

Cited by 93 publications

References 45 publications

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Cardiac Calcifications: Phenotypes, Mechanisms, Clinical and Prognostic Implications

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