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

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.

BACKGROUND Aortic Stenosis is a common cause of valvular heart disease in which the valve cusps become progressively calcified. The only available treatment is aortic valve replacement and previous attempts at providing medical therapies to modify the disease process have proved unsuccessful.

Pathophysiology of Aortic Stenosis. The initiating event is believed to be caused by mechanical damage to the cells lining the valve in a process similar to that which occurs in atherosclerosis. However the propagating mechanism is more likely to be that of active calcification. In support of this, a growing body of pre-clinical and clinical data indicates that treatments for osteoporosis, which work by preventing the breakdown of bone and therefore calcium release into the blood, can reduce calcium deposition (calcification) of the blood vessels. These agents therefore hold considerable promise as novel therapies for aortic stenosis.

Denosumab in Aortic Stenosis Denosumab is a drug which prevents bone cells called osteoclasts from breaking down bone and releasing calcium into the blood. For this reason it is used to treat osteoporosis. It works on a specific pathway which we believe to be important in regulating calcium release from bone. Mice engineered with defects within this pathway were found to have increased bone breakdown and blood vessel calcification. Furthermore there have been two studies to assess the role of this pathway in patients with aortic valve disease. Both studies have also demonstrated altered regulation within this pathway

Bisphosphonates in Aortic Stenosis Bisphosphonates are a group of drugs widely used for the treatment of osteoporosis and also prevent bone breakdown by osteoclasts. They have also been shown to have important cardiovascular effects with a consistent reduction in calcification of blood vessels and the aortic valve. This in part appears to be a consequence of their inhibition of bone breakdown but also by reducing the production of key inflammatory substances implicated in the early stages of aortic stenosis. We plan on using alendronic acid which is a bisphosphonate commonly used in the management of osteoporosis.

PET CT scanning in Aortic Stenosis. 18F-NaF (Sodium Fluoride) is biochemical compound which preferentially binds to regions of newly developing calcification and emits radiation. When used in combination with Computed Tomography (CT) it enables it to be localized. This way we are able to identify areas of newly developing calcification on an aortic valve.

In previous studies in our institution, we demonstrated we could quantify 18F-NaF uptake in the aortic valve and that there was a progressive rise in activity with increasing disease severity. We found that at At 1 year, the baseline 18F-NaF uptake emerged as a powerful predictor of the progression in aortic valve calcification. Following analysis of 2 year follow up data, 18F-NaF emerged as an independent predictor of aortic valve replacement and cardiovascular mortality

Therefore these findings have led us to propose that

1. Calcification is the key driver to Aortic Stenosis Progression
2. We want to reduce calcification activity using Denosumab and Biphosphonates
3. We predict that this will reduce the 18F-NaF signal and disease progression on Echocardiography and CT.

STUDY DESIGN This will be a double-blind, randomized, placebo-control trial of denosumab and alendronic acid in patients with aortic stenosis.

Study population and randomization

We aim to recruit 170 patients in total with non-rheumatic calcific aortic stenosis.

20 patients will only participate in scan-rescan reproducibility studies. They will not proceed to the randomization stage.

Of the remaining 150 patients, 75 subjects will be randomized (2:1) to either subcutaneous denosumab 60 mg (n=50) or matched placebo (n=25) every 6 months; and a further 75 will be randomized (2:1) to oral alendronate 70 mg (n=50) or matched placebo (n=25) once weekly

Assessment and follow up

All subjects will undergo a standardized clinical assessment at baseline and every six months. Data will be collected with respect to symptomatic status, the trial safety endpoints, routine biochemical profiling, biomarkers, quality of life questionnaires and electrocardiography.

Aortic stenosis severity will be assessed at baseline and every 6 months by echocardiography performed by a single, dedicated sonographer to maximize reproducibility. Severity will be assessed using the peak and mean aortic valve pressure gradients (this technique is used to monitor aortic stenosis severity; the higher the pressure gradient across the aortic valve the more severe the narrowing). We will also calculate the aortic valve area and calcification score.

PET CT and CT calcium scoring.

Both will be performed using a combined PET and 128-multidetector CT scanner (Biograph 128, Siemens).

CT calcium scoring measures the amount of calcium in the valve and will be assessed at baseline, 6 months and 2 years. It will act as an additional marker of disease severity and progression alongside Echocardiography. Those with a heart rate of \>65 /min will be given heart-slowing medication (beta blockers) if deemed safe. The region of the aortic valve will be then be scanned during a breath hold.

18F-NaF PET uptake will be measured at baseline, and 6 months to assess the early impact of the intervention on valvular calcification activity. PET images on their own are difficult to interpret as they do not tell you where the radiation is coming from. For this reason the PET needs to be performed alongside CT which gives us images of the aortic valve. By superimposing the two images we are able to identify where the 'PET signal' is originating from.

To ensure optimal image quality patients will be required to adhere to a high fat, low carbohydrate diet for 48 hours prior to the scan. The subject will then be cannulated to enable injection of the 18F-NaF tracer. They will then rest in a quiet environment for 60 minutes to enable the tracer to reach the valve before transfer to the imaging suite. Those with a heart rate of \>65 /min will be given beta-blockade if it is deemed suitable and safe. This is routine practice in cardiac CT. A scout CT will be performed to allow optimal alignment of the PET and CT scanners (so we can be sure the radiation we are detecting is coming from the aortic valve). The patient will then be asked to lie still for 30 minutes so that the PET data can be acquired.

Finally a 'CT angiogram' will be performed of the aortic valve. This involves image acquisition following injection of a radio opaque dye into the aorta. This again allows more accurate localization of our PET signal.

The additional twenty patients will only undergo repeat PET/CT imaging within 2 weeks of their baseline scan to investigate scan-rescan reproducibility of the 18F-NaF PET signal. They will not proceed with the trial beyond this stage to avoid facing increased radiation exposure.

Eligibility Criteria:
Inclusion Criteria:

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

Exclusion Criteria:

1. Anticipated or planned aortic valve surgery in the next 6 months,
2. Life expectancy \<2 years,
3. Inability to undergo scanning
4. Treatment for osteoporosis with bisphosphonates or denosumab.
5. Long-term corticosteroid use.
6. Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying,

8) 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