Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors.

Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterise relationships between sclerostin and CVD and related risk factors in more detail, by examining these in two large cohorts, LURIC (34% female, mean 63.0 years) and ALSPAC mothers (mean 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analysed, adjusted for age, sex (LURIC), BMI, smoking, social deprivation and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) [1.25 (1.12, 1.37)], risk of elevated fasting glucose [1.15 (1.04, 1.26)], and triglyceride levels [0.03 (0.00, 0.06)]. Conversely, higher sclerostin was associated with lower eGFR [-0.20 (-0.38, -0.02)], HDL cholesterol [-0.05 (-0.10, -0.01)], and Apolopoprotein A-I [-0.05 (-0.08, -0.02)] (odds ratio/ difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow up [HR 1.13 (1.03, 1.23)], and with severity of coronary artery disease on angiogram as reflected by Friesinger score [0.05 (0.01, 0.09)]. Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR and Apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with CAD severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. This article is protected by copyright. All rights reserved.