Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial

Abstract

Background: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment.

Methods and results: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups.

Conclusions: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis.

Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Keywords: alendronate; computed tomography; denosumab; positron emission tomography; vascular calcification.

Figure 1. Change in coronary artery calcium score and 18F‐sodium fluoride uptake.

A, Calculated change in 24‐month coronary artery calcium score (P=0.24 for denosumab vs placebo; P=0.99 for alendronic acid vs placebo). B, Calculated change in 12‐month coronary artery microcalcification activity (P=0.47 for denosumab vs placebo; P=0.28 for alendronic acid vs placebo). AU indicates Agatston units.

Figure 2. Change in aortic calcium score and 18F‐sodium fluoride uptake.

A, Calculated change in 12‐month total thoracic aorta calcium score (P=0.75 for denosumab vs placebo; P=0.62 for alendronic acid vs placebo). B, Calculated change in 12‐month total aortic microcalcification activity (P=0.18 for denosumab vs placebo; P=0.24 for alendronic acid vs placebo). AU indicates Agatston units.

Figure 3. No effect of treatment with denosumab or alendronic acid on either aortic or coronary calcification in asymptomatic patients with aortic stenosis.

Asymptomatic patients with calcific aortic stenosis were randomized to treatment with placebo, denosumab or alendronic acid. Vascular calcification in the coronary arteries was monitored by CT calcium scoring at baseline and 24‐month follow‐up; vascular calcification in the thoracic aorta was measured on attenuation correction CT scans at baseline and 12‐month follow‐up; coronary and aortic microcalcification activity were monitored by 18F‐NaF PET at baseline and 12‐month follow‐up. There were no effects of either drug on calcium scores or microcalcification activity in either the aorta or coronary arteries, indicating no effect on either the burden of calcific atherosclerosis or vascular calcification activity. 18F‐NaF PET indicates 18F‐sodium fluoride positron emission tomography; AMA, aortic microcalcification activity; CMA, coronary microcalcification activity; and CT: computed tomography.