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

Frysz, Monika; Gergei, Ingrid; Scharnagl, Hubert; Smith, George Davey; Zheng, Jie; Lawlor, Deborah A.; Herrmann, Markus; Maerz, Winfried; Tobias, Jon H.

Affiliations

¹Musculoskeletal Research Unit, University of Bristol, Bristol, UK

²MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK

³Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

⁴Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany

⁵Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

⁶Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK

⁷SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany

Abstract and keywords

Romosozumab 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 3 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 characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (β 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (β −0.20; CI −0.38, −0.02), HDL cholesterol (β −0.05; CI −0.10, −0.01), and apolipoprotein A-I (β −0.05; CI −0.08, −0.02) (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 (hazard ratio [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 coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors.

Keywords: LURIC; ALSPAC; CVD; SCLEROSTIN; DIABETES MELLITUS; HDL CHOLESTEROL

Links

DOI: 10.1002/jbmr.4467

PubMed: 34738659

WoS: 000728315400001

History

Received: 2021-05-26

Revised: 2021-10-11

Accepted: 2021-10-20

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