Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigation.

Background: How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death.

Methods: We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men.

Findings: The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass.

Interpretation: These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease.

Funding: The study was supported by funding from the Swedish Research Council (https://www.vr.se; grants No. 2015-03257, 2017-00644, 2017-06100, and 2019-01291 to Karl Michaëlsson) and funding from Olle Engkvist Byggmästares stiftelse (SOEB).