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

NCT02132026 | Completed Phase 2

• 1 other identifier: SALTIRE2-2014
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Calcific Aortic Stenosis

Keywords

Aortic Stenosis; Denosumab; Alendronic Acid; Osteoporosis

Outcome Measures

Primary Outcomes (1)

• Change in aortic valve calcium score

  The change in calcium score will be assessed using computed tomography and is an assessment of disease severity.

  Measured at Baseline, 6 months and 2 years

Secondary Outcomes (5)

• Change in aortic valve 18F-NaF uptake

  Measured at baseline and 6 months

• Change in aortic-jet velocity

  Measured at baseline, 6, 12, 18 and 24 months

• Change in thoracic aortic and coronary artery calcium score

  Measured at baseline and 2 years

• Change in thoracic spine bone mineral density

  Measured at baseline and 2 years

• Change in quality of life determined by Short Form 36 Questionnaire

  Measured at baseline and 2 years

Study Arms (4)

Alendronic Acid

ACTIVE COMPARATOR

50 patients will receive once weekly Alendronic Acid tablets (70mg).

Drug: Alendronic Acid

Alendronic Acid placebo

PLACEBO COMPARATOR

25 patients will receive alendronic acid placebo tablets.

Drug: Alendronic Acid Placebo

Denosumab

ACTIVE COMPARATOR

50 patients will receive 6 monthly denosumab injections

Drug: Denosumab

Denosumab Placebo

PLACEBO COMPARATOR

25 patients will receive a 6 monthly placebo injection.

Drug: Denosumab Placebo

Interventions

Denosumab DRUG

Also known as: Prolia, Marketing Authorisation Number : EU/1/11/703/003, ATC number M05BX04

Denosumab

Alendronic Acid DRUG

Also known as: Marketing Authorisation Number PL 30306/0032, ATC codes M05B A04

Alendronic Acid

Denosumab Placebo DRUG

subcutaneous injection of 0.9%Saline at baseline, 6 months, 12 months and 18 months

Denosumab Placebo

Alendronic Acid Placebo DRUG

Inert Capsule containing lactose monohydrate manufactured and labelled by Investigational Supplies Group (ISG) University of Edinburgh.

Alendronic Acid placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age \>50 years
• peak aortic jet velocity of \>2.5 m/s on Doppler echocardiography
• grade 2-4 calcification of the aortic valve on echocardiography

You may not qualify if:

• Anticipated or planned aortic valve surgery in the next 6 months,
• Life expectancy \<2 years,
• Inability to undergo scanning
• Treatment for osteoporosis with bisphosphonates or denosumab.
• Long-term corticosteroid use.
• Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying,
• \) Inability to sit or stand for at least 30 minutes, 9) Known allergy or intolerance to alendronate or denosumab, or any of their excipients, 10) Hypocalcaemia, 11) Maintenance calcium supplementation, 12) Dental extraction within 6 months, 13) History of osteonecrosis of the jaw, 14) Major or untreated cancers, 15) Poor dental hygiene, 16) Women of child-bearing potential who have experienced menarche, are pre-menopausal, have not been sterilised or who are currently pregnant, 17) Women who are breastfeeding, 18) Renal failure (estimated glomerular filtration rate of \<30 mL/min), 19) Allergy or contraindication to iodinated contrast, 20) Inability or unwilling to give informed consent, 21) Likelihood of non-compliance to treatment allocation or study protocol

Sponsors & Collaborators

• University of Edinburgh: lead
• British Heart Foundation: collaborator
• NHS Lothian: collaborator

Study Sites (1)

Clinical Research Facility University of Edinburgh

Edinburgh, EH16 4SA, United Kingdom

Location

Related Publications (12)

• 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.

  PMID: 24508669 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.

  PMID: 23391586 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.

  PMID: 23098140 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.

  PMID: 22090163 BACKGROUND

• Oikonomou EK, Craig NJ, Holste G, Vasisht Shankar S, White A, 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. 2025 Dec 31:e018353. doi: 10.1161/CIRCIMAGING.125.018353. Online ahead of print.

  PMID: 41473954 DERIVED

• 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.

  PMID: 40050004 DERIVED

• 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.

  PMID: 39248270 DERIVED

• 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.

  PMID: 33913339 DERIVED

• 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.

  PMID: 29555836 DERIVED

• 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.

  PMID: 27733431 DERIVED

• 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.

  PMID: 26227196 DERIVED

• 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.

  PMID: 25882205 DERIVED

MeSH Terms

Conditions

Aortic Valve, Calcification of; Aortic Valve Stenosis; Osteoporosis

Interventions

Denosumab; Alendronate

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Officials

• Rong Bing, MbChB

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

• David E Newby, BA BSc PhD BM DM FRCP DSc FRSE

  University of Edinburgh

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 2, 2014
• First Posted: May 6, 2014
• Study Start: November 12, 2014
• Primary Completion: November 28, 2019
• Study Completion: November 28, 2019
• Last Updated: October 14, 2021

Record last verified: 2020-03

Locations

GB (1)