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

Grace Marion Power*, Jonathan H Tobias, Timothy Frayling, Jess Tyrrell, April E Hartley, Jon E Heron, George Davey Smith, Tom G Richardson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)


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. However, sources of bias induced by confounding factors, may have distorted previous findings. Employing a lifecourse Mendelian randomisation (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 prospective cohort, univariable and multivariable MR were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n=453,169) on fracture risk (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 (OR, 95% CI: 0.89, 0.82 to 0.96, P=0.005 and 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 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 reduces fracture risk in later life through its influence on increased eBMD. From a public health perspective, this relationship is complex since obesity in adulthood remains a major risk factor for co-morbidities. Results additionally indicate that higher body size in adulthood is a risk factor for fractures. Protective effect estimates previously observed are likely attributed to childhood effects.
Original languageEnglish
Pages (from-to)795-807
Number of pages13
JournalEuropean Journal of Epidemiology
Issue number7
Early online date3 May 2023
Publication statusE-pub ahead of print - 3 May 2023

Bibliographical note

Funding Information:
This work was in part supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). GDS conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. GMP is supported by the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI (MR/N0137941/1). TGR was a UKRI Innovation Research Fellow whilst contributing to this study (MR/S003886/1). TMF has received funding from the Medical Research Council (MR/T002239/1) EU-IMI SOPHIA and GSK. JT is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s).

Structured keywords

  • Bristol Population Health Science Institute


  • bone health
  • fracture risk
  • weight
  • body size
  • Mendelian randomisation
  • lifecourse


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