Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis.

Summary

Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it. The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. This is on the basis that studies have suggested that altered regulation of calcium metabolism may be an important mechanism perpetuating the disease. Both drugs work by reducing calcium release into the bloodstream from bones and therefore calcification of the aortic valve. 150 patients will therefore be randomly allocated to either of the trial drugs which are denosumab,the bisphosphonate (alendronic acid), or a placebo. Positron Emission Tomography (PET) scanning is a technique where biochemically active molecules are injected and are taken up at sites of ongoing calcification activity where they emit radiation and can be detected by the PET scanner. We have previously shown that this technique can demonstrate areas of newly developing calcification on an aortic valve. We therefore propose that patients receiving bisphosphonates or denosumab will have reduced evidence of active calcification and slower progression of their disease at two years as assessed by Echocardiography (ultrasound) and a change in their calcium score (quantity of calcium on the aortic valve measured using Computed Tomography \[CT\] ). The data from this study will then be used to design a larger trial.

Timeline

Start

2014-11-12

Primary completion

2019-11-28

Completion

2019-11-28

Publications

• Background Dweck MR, Jenkins WS, Vesey AT, Pringle MA, Chin CW, Malley TS, Cowie WJ, Tsampasian V, Richardson H, Fletcher A, Wallace WA, Pessotto R, van Beek EJ, Boon NA, Rudd JH, Newby DE. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging. 2014 Mar;7(2):371-8. doi: 10.1161/CIRCIMAGING.113.001508. Epub 2014 Feb 7.
• Background Dweck MR, Khaw HJ, Sng GK, Luo EL, Baird A, Williams MC, Makiello P, Mirsadraee S, Joshi NV, van Beek EJ, Boon NA, Rudd JH, Newby DE. Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation? Eur Heart J. 2013 Jun;34(21):1567-74. doi: 10.1093/eurheartj/eht034. Epub 2013 Feb 7.
• Background Dweck MR, Joshi FR, Newby DE, Rudd JH. Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial (1)(8)F-sodium fluoride uptake as a marker of plaque biology. Expert Rev Cardiovasc Ther. 2012 Sep;10(9):1075-7. doi: 10.1586/erc.12.104. No abstract available.
• Background Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, Marsden M, Pessotto R, Clark JC, Wallace WA, Salter DM, McKillop G, van Beek EJ, Boon NA, Rudd JH, Newby DE. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012 Jan 3;125(1):76-86. doi: 10.1161/CIRCULATIONAHA.111.051052. Epub 2011 Nov 16.
• Oikonomou EK, Craig NJ, Holste G, Vasisht Shankar S, White AC, Mahendran M, Newby DE, Dweck MR, Khera R. Artificial Intelligence-Enabled Echocardiography as a Surrogate for Multimodality Aortic Stenosis Imaging: Post Hoc Analysis of a Clinical Trial. Circ Cardiovasc Imaging. 2026 Feb;19(2):e018353. doi: 10.1161/CIRCIMAGING.125.018353. Epub 2025 Dec 31.
• Geers J, Manral N, Razipour A, Park C, Tomasino GF, Xing E, Grodecki K, Kwiecinski J, Pawade T, Doris MK, Bing R, White AC, Droogmans S, Cosyns B, Slomka PJ, Newby DE, Dweck MR, Dey D. Epicardial adipose tissue, myocardial remodelling and adverse outcomes in asymptomatic aortic stenosis: a post hoc analysis of a randomised controlled trial. Heart. 2025 Jun 26;111(14):686-694. doi: 10.1136/heartjnl-2024-324925.
• Geers J, Bing R, Pawade TA, Doris MK, Daghem M, Fletcher AJ, White AC, Forsyth L, Evans E, Kwiecinski J, Williams MC, van Beek EJR, Kwak S, Peeters FECM, Tzolos E, Slomka PJ, Lucatelli C, Ralston SH, Prendergast B, Newby DE, Dweck MR. Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial. J Am Heart Assoc. 2024 Sep 17;13(18):e032571. doi: 10.1161/JAHA.123.032571. Epub 2024 Sep 9.
• Pawade TA, Doris MK, Bing R, White AC, Forsyth L, Evans E, Graham C, Williams MC, van Beek EJR, Fletcher A, Adamson PD, Andrews JPM, Cartlidge TRG, Jenkins WSA, Syed M, Fujisawa T, Lucatelli C, Fraser W, Ralston SH, Boon N, Prendergast B, Newby DE, Dweck MR. Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial. Circulation. 2021 Jun 22;143(25):2418-2427. doi: 10.1161/CIRCULATIONAHA.121.053708. Epub 2021 Apr 29.
• Pawade T, Clavel MA, Tribouilloy C, Dreyfus J, Mathieu T, Tastet L, Renard C, Gun M, Jenkins WSA, Macron L, Sechrist JW, Lacomis JM, Nguyen V, Galian Gay L, Cuellar Calabria H, Ntalas I, Cartlidge TRG, Prendergast B, Rajani R, Evangelista A, Cavalcante JL, Newby DE, Pibarot P, Messika Zeitoun D, Dweck MR. Computed Tomography Aortic Valve Calcium Scoring in Patients With Aortic Stenosis. Circ Cardiovasc Imaging. 2018 Mar;11(3):e007146. doi: 10.1161/CIRCIMAGING.117.007146.
• Pawade TA, Cartlidge TR, Jenkins WS, Adamson PD, Robson P, Lucatelli C, Van Beek EJ, Prendergast B, Denison AR, Forsyth L, Rudd JH, Fayad ZA, Fletcher A, Tuck S, Newby DE, Dweck MR. Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis. Circ Cardiovasc Imaging. 2016 Oct;9(10):e005131. doi: 10.1161/CIRCIMAGING.116.005131.
• Pawade TA, Newby DE, Dweck MR. Calcification in Aortic Stenosis: The Skeleton Key. J Am Coll Cardiol. 2015 Aug 4;66(5):561-77. doi: 10.1016/j.jacc.2015.05.066.
• Pawade TA, Newby DE. Treating aortic stenosis: arresting the snowball effect. Expert Rev Cardiovasc Ther. 2015 May;13(5):461-3. doi: 10.1586/14779072.2015.1037284. Epub 2015 Apr 16.

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