Age-specific effects of body size on fracture risk in later life: A lifecourse Mendelian randomization study

Abstract

Musculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites, indicated through previous clinical and epidemiological observational research. However, the association between weight and bone health is complex and sources of bias, induced by confounding factors, may have distorted earlier findings. Employing a lifecourse Mendelian randomization (MR) approach by using genetic instruments to separate effects at different life stages, this investigation aims to explore how prepubertal and adult body size independently influence fracture risk in later life. Using data from a large UK-based prospective cohort, univariable and multivariable MR with inverse variance weighted meta-analysis were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n=453,169) on the odds of fracture in later life (n=416,795). A two-step MR framework was additionally applied to elucidate potential mediators. Univariable and multivariable MR indicated strong evidence that higher body size in childhood reduced fracture risk in later life (OR, 95% CI: 0.89, 0.82 to 0.96, P=0.005 and OR, 95% CI: 0.76, 0.69 to 0.85, P=1x10-6, respectively). Conversely, higher body size in adulthood increased fracture risk (OR, 95% CI: 1.08, 1.01 to 1.16, P=0.023 and OR, 95% CI: 1.26, 1.14 to 1.38, P=2x10-6, respectively). Two-step MR analyses suggested that the effect of higher body size in childhood on reduced fracture risk was mediated by its influence on higher estimated bone mineral density (eBMD) in adulthood. This investigation provides novel evidence that higher body size in childhood has a direct effect on reduced fracture risk in later life through its influence on increased eBMD. Results indicate that higher body size in adulthood is a risk factor for fractures, opposing findings from earlier research. Protective effect estimates previously observed are likely attributed to childhood effects.

Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study

“…The results of MR analyses could be interpreted as the average effects of blood pressure and plasma proteins over a lifetime, representing the cumulative impact of exposure levels from conception and throughout the course of life. 76 Conversely, in prospective observational studies based on individuallevel data, assessing the lifetime effects requires measuring blood pressure (exposures), plasma proteins (mediators), and CMR traits/heart failure (outcomes) at separate and consecutive time points, with sufficient follow-up time for repeated measurements. In such scenarios, the timing of measurements becomes crucial for estimating both direct and indirect effects.…”

A Guide for Understanding and Designing Mendelian Randomization Studies in the Musculoskeletal Field

“…( 83 ) Conversely, a greater body size in later life appeared to increase fracture risk. ( 83 ) Two‐step MR was then employed to identify mediators of the effect of childhood body size on later life fracture risk, providing evidence to suggest that adulthood BMD (estimated from heel ultrasound) mediated the effect of childhood body size on later life fracture risk. ( 83 )…”

“…(81) Multivariable MR can also be employed in lifecourse analyses to disentangle the timing at which the exposure influences a later life outcome. (82)(83)(84) For example, a recent multivariable MR analysis identified a direct influence of childhood body size on later life fracture risk, with a higher body size in childhood being protective against fractures, independent of later life body size. (83) Conversely, a greater body size in later life appeared to increase fracture risk.…”

“…(82)(83)(84) For example, a recent multivariable MR analysis identified a direct influence of childhood body size on later life fracture risk, with a higher body size in childhood being protective against fractures, independent of later life body size. (83) Conversely, a greater body size in later life appeared to increase fracture risk. (83) Two-step MR was then employed to identify mediators of the effect of childhood body size on later life fracture risk, providing evidence to suggest that adulthood BMD (estimated from heel ultrasound) mediated the effect of childhood body size on later life fracture risk.…”

“…(83) Two-step MR was then employed to identify mediators of the effect of childhood body size on later life fracture risk, providing evidence to suggest that adulthood BMD (estimated from heel ultrasound) mediated the effect of childhood body size on later life fracture risk. (83) Novel methods for overlapping samples Although there is now evidence to suggest that the bias due to sample overlap is minimal in most scenarios, (22) the bias toward the observational estimate is greater when instruments are weak, (21) for example, using instruments identified in a GWAS where winner's curse is likely to be present (ie, an unreplicated GWAS). (22) This is an issue given that many of the publicly available GWAS, available through the data sources described in Software and Data Sources, were performed in UK Biobank.…”