Associations of visceral adipose tissue with bone mineral density and fracture: observational and Mendelian randomization studies

Abstract

Background The associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses. Methods UK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40–69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis. Results In 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10−16) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10−15) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10−136, P for VAT^-sex interaction = 8.4 × 10−51). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10−4 for total fractures; 1.5 × 10−4 for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10−31 for heel BMD; 2.7 × 10−4 for total fractures; 5.7 × 10−3 for hip fractures; 6.8 × 10−3 for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures. Conclusions These novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding.

Relationship between visceral and subcutaneous fat and bone health in American adults: a cross-sectional study

“…Our study, involving adults aged 20-59 years, revealed a non-linear (U-shaped) relationship between VMI and Lumbar BMD T-score. This nding is consistent with the association between VAT and total fracture risk as reported in observational and Mendelian randomization studies 22 . Furthermore, a meta-analysis 23 showed that a low BMI is associated with a higher risk of fractures, but the connection changes when a high BMI is contrasted with a normal BMI, becoming non-linear (U-shaped).…”

Effect of BMI-Discordant Abdominal Tissue Thickness on Fracture Probability: A Registry-Based Study

“…( 18 ) In the UK Biobank, visceral adipose tissue (VAT), estimated from a prediction model, showed an inverted U‐shaped association with heel ultrasound in men ( p for nonlinearity <0.001) but a monotonic increase in women ( p for nonlinearity 0.28) when adjusted for lean mass from bioelectrical impedance and other covariates. ( 19 ) Estimated VAT was associated with lower (not greater) risk of hip fracture in men and women; total fractures showed no significant relationship with VAT in women but a bimodal effect in men that increased above and below 1.25 kg ( p for nonlinearity <0.001). Significant VAT‐BMI interactions were found in men but not women.…”

“…(10)(11)(12) However, the effects of abdominal obesity on BMD and fracture risk have been inconsistent. (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) Importantly, none of the previous studies specifically examined clinical implications for FRAX or adjusted for competing mortality, which is increased by central obesity in both women and men even after adjusting for BMI. (23) The current analysis was performed to evaluate the effect of abdominal tissue thickness that deviates from BMI-predicted abdominal tissue thickness on performance of FRAX for MOF and hip fracture prediction.…”

“…( 10‐12 ) However, the effects of abdominal obesity on BMD and fracture risk have been inconsistent. ( 13‐22 ) Importantly, none of the previous studies specifically examined clinical implications for FRAX or adjusted for competing mortality, which is increased by central obesity in both women and men even after adjusting for BMI. ( 23 )…”

Chronic airway disease as a major risk factor for fractures in osteopenic women: Nationwide cohort study

“…However, the effect of obesity on the risk of fractures is controversial (37). In a recent UK Biobank study, an inverted U-shaped association was observed between visceral adipose tissue and risk of fractures in men but not in women (38) which could be attenuated in women due to the differences in the visceral fat distribution and estrogen levels. This partly explains the neutral results observed in this study.…”