Metabolites affecting body composition associate with hip fracture risk in elderly women : A large-scale metabolome-wide association study

• Hip fracture is the most devastating fragility fracture and a major threat to individual health. It is known that body composition and changes therein influence hip fracture occurrence but the molecular mechanisms are not fully understood. Few studies have investigated whether circulating metabolites can impact body composition in the context of hip fracture risk. Here, we used untargeted metabolomics to unveil the metabolic interrelationships among bone, muscle, and fat tissues in a cohort of 4886 women (mean age 68 ± 7 years). We discovered and replicated circulating metabolites associated with bone mineral density (BMD), fat and lean mass measured by dual-energy X-ray absorptiometry. Importantly, pyrrolidine and its ethanol derivative, kynurenic acid (KYNA), 3,12-dioxochol-4-en-24-oic acid, and a predicted steroid (ST 22:1;O3;S) were associated with all three measures. The association between leucine or KYNA and body composition was consistent with previous findings. In total 23 metabolites reflecting BMD, fat or lean mass were associated with hip fracture risk; we found the most pronounced association with ST 22:1;O3;S (hazard ratio 0.55 per 1 SD higher level; 95% CI, 0.36 to 0.84). Strong interplay among the three body composition compartments via lysoglycerophospholipids and amino acid derivatives were illustrated by network analysis. The strongest correlations of bone-related clinical biomarkers including circulating 25-hydroxyvitamin D, parathyroid hormone, CrossLaps, osteocalcin and C-reactive protein were found with lipids. Using two-sample Mendelian randomization analysis, genetically-predicted levels of LPC 20:3, gamma-glutamylleucine, leucine and KYNA were causally associated with multiple outcomes, including BMD and 25-hydroxyvitamin D. Our work reveals the importance of several lysoglycerophospholipids and amino acid metabolites in body composition crosstalk and provides potential actionable targets of sarcopenia, osteoporosis, and fracture prevention.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Ortopedi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Orthopaedics (hsv//eng)

Nyckelord

Metabolomics

body composition

DXA

hip fracture

population-based cohort

Mendelian randomization

Bioinformatik

Bioinformatics

Medicinsk vetenskap

Medical Science

Epidemiologi

Epidemiology

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)