Research assistant Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom
Background: Sclerostin inhibitors have been shown to improve bone mineral density (BMD) in large trials (BMD) and decrease fracture risk. However, regulators like the European Medicines Agency have warned of a possible cardiovascular risk associated with their use, and restricted indication to subjects with no previous cardiovascular history. While observational studies are ongoing, there is a scarcity of information on the causal effects of sclerostin inhibition on cardiovascular risk.
Objectives: To study the effect of sclerostin on cardiovascular health by using Mendelian randomisation.
Methods: We conducted a meta-analysis of three published Genome Wide Association Studies (GWAS) of circulating sclerostin. We extracted single nucleotide polymorphisms (SNPs) significantly correlated with sclerostin (p < 10^(-6)) in the SOST gene and used pruning to discard SNPs in high linkage disequilibrium (LD) (r > 0.8). The remaining SNPs were used as instruments in the two-sample Mendelian randomisation for the study outcomes. Study outcomes included hip fracture (positive control), cardiovascular events (coronary artery disease (CAD), myocardial infarction (MI), ischaemic stroke (IS)) and risk factors (hypertension, type 2 diabetes (T2DM)). A generalized MR model was used to adjust for correlation between variants. MR estimates are reported as odds ratios (OR) per standard deviation decrease in genetically predicted sclerostin levels.
Results: We included 49,371 European participants in the sclerostin GWAS meta-analysis from three different cohorts. 6 SNPs were in low LD with each other and significantly associated with sclerostin in the SOST gene, and were therefore chosen for MR. Two sample MR analyses suggested that lower circulating sclerostin resulted in a reduced hip fracture risk (OR=0.25; 95%CI=0.17 to 0.35), but caused an increased risk of hypertension (OR=1.01; 95%CI=1.01 to 1.02), T2DM (OR=1.51; 95%CI=1.38 to 1.65), MI (OR=1.28; 95%CI=1.18 to 1.38), CAD (OR=1.25; 95%CI=1.15 to 1.35) and IS (OR=1.17; 95%CI=1.08 to 1.25).
Conclusions: Results from this study provide genetic evidence that reduced sclerostin levels lead to a higher risk of T2DM, hypertension, MI, CAD, and IS. Our findings support a protective effect against hip fracture when sclerostin levels are reduced. These findings support the hypothesis that sclerostin inhibition decreases fracture risk but at the cost of increasing cardiovascular risk. More data are urgently needed on the cardiovascular safety of sclerostin inhibitors.