Background: Sclerostin inhibitors are used to decrease fracture risk in osteoporotic patients. However, some (not all) randomised controlled trials have shown an increase in cardiovascular risk. There is an urgent need for evidence on the causal effects of sclerostin on cardiovascular metabolism.
Objectives: To study the association between sclerostin and cardiovascular health, including biomarkers, risk factors, and outcomes by using Mendelian randomisation (MR) methods.
Methods: We conducted a meta-analysis of three published Genome-Wide Association Studies (GWAS) of circulating sclerostin, and selected 6 single nucleotide polymorphism (SNPs) at the gene coding for sclerostinas genetic instruments for the MR. We used UK Biobank data to study the association between the derived instrument and: positive controls (fracture risk and heel BMD), biomarkers (HDL and LDL cholesterol, triglycerides, apolipoproteins, C-reactive protein, HbA1c, and glucose), risk factors (hypertension, type 2 diabetes (T2DM)), and events (coronary artery disease (CAD), myocardial infarction (MI), and ischaemic stroke (IS)). Outcomes and risk factors were identified from linked medical records, while biomarkers were measured on enrolment to UK Biobank. Odds Ratio (OR) per 1 SD of decrease in genetically predicted sclerostin levels were reported for binary risk factors/outcomes, and beta coefficients for biomarker levels and continuous risk factors.
Results: We included 49,371 European participants in the sclerostin GWAS meta-analysis, and 242,603 in the UK Biobank analysis. MR suggested that lower circulating sclerostin led to reduced fracture risk (OR=0.27; 95%CI=0.23 to 0.33) and increased heel BMD (beta=0.85 [0.67, 1.04]), but also caused changes in most biomarkers: HDL (beta=-0.2 [-0.27, -0.14]), apolipoprotein A (beta=-0.16 [-0.22, -0.09]), lipoprotein A (beta=-0.09 [-0.15, -0.03]) , triglycerides (beta=0.3 [0.23, 0.37]), apolipoprotein B (beta=0.14 [0.09, 0.19]), C-reactive protein (beta=0.03 [-0.01, 0.08]), and glucose (beta=0.1 [0.05, 0.15]). Lower genetically predicted sclerostin levels were also associated with CAD (OR=1.74 [1.48, 2.04]), and MI (OR=1.89 [1.49, 2.41]), but nor IS (OR=0.97 [0.71, 1.33]) or hypertension (OR=1.08 [1, 1.16]).
Conclusions: These findings contribute to a growing body of genetic evidence suggesting that reduced sclerostin levels lead to a higher risk of cardiovascular biomarkers, risk, and outcomes including CAD and MI. These findings replicate previous trials demonstrating that lower sclerostin levels cause better bone health and lower fracture risk. More clinical studies are needed on the benefit-risk of sclerostin inhibitors.
