Letter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial”

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HomeCirculationVol. 144, No. 22Letter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBLetter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial” Wilko Spiering, MD, PhD, Willem P. Mali, MD, PhD and Pim A. de Jong, MD, PhD Wilko SpieringWilko Spiering https://orcid.org/0000-0002-2493-6407 Departments of Vascular Medicine (W.S.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author , Willem P. MaliWillem P. Mali Radiology (W.P.M., P.A.d.J.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author and Pim A. de JongPim A. de Jong Radiology (W.P.M., P.A.d.J.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author Originally published29 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.055622Circulation. 2021;144:e334To the Editor:We read with interest the article by Pawade et al1 on the effects of denosumab or alendronate on the progression of aortic stenosis. The authors conclude from this randomized, controlled trial that both drugs did not affect progression of aortic valve calcification in patients with calcific aortic stenosis. They call for a search to find alternative pathways and mechanisms to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. We think that this trial does not justify abandoning bisphosphonate therapy as a potential treatment, but that it would have been better if the authors had chosen etidronate as the comparator instead of alendronate.Mineralization in soft tissues such as arteries and valves is controlled by endogenous inhibitors of hydroxyapatite formation, of which inorganic pyrophosphate is the most important. Bisphosphonates are nonhydrolyzable analogs of inorganic pyrophosphate, and cumulating evidence shows that they can inhibit vascular calcification. Nonnitrogenous bisphosphonates, like etidronate, are potent inhibitors of ectopic calcification, whereas nitrogenous bisphosphonates, like alendronate, have a high affinity for bone and are more potent inhibitors of osteoclasts. In an ex vivo model of calcification in intact aortic valves, it was shown that etidronate completely prevented aortic valve leaflet calcification at already very low concentrations.2Pseudoxanthoma elasticum is a heritable ectopic mineralization disorder with increased medial arterial calcification. In an animal model of pseudoxanthoma elasticum, etidronate, but not alendronate, significantly reduced calcification, indicating that the inhibiting effect on ectopic calcification of bisphosphonates is not just a class effect.3 In a double-blind, placebo-controlled, randomized, controlled trial in patients with pseudoxanthoma elasticum, we showed that etidronate reduced arterial calcification.4 However, in a randomized, controlled trial in patients with chronic kidney disease, alendronate did not decrease the progression of vascular calcification.5We think that the absence of any effect of alendronate on the progression of aortic stenosis seen in the study of Pawade et al is in line with earlier findings that alendronate with its low affinity for soft tissues is not the ideal bisphosphonate for inhibiting ectopic calcification.We would like to know why, with cumulating evidence that etidronate is very efficacious in inhibiting soft tissue calcification, the authors decided to choose alendronate and not etidronate in their clinical trial.Article InformationDisclosuresNone.FootnotesCirculation is available at www.ahajournals.org/journal/circ