Fasting glucose, bone area and bone mineral density: a Mendelian randomisation study

Adam Mitchell,Karl Michaëlsson,Liisa Byberg,Tove Fall,Håkan Melhus,Susanna C Larsson

doi:10.1007/s00125-021-05410-w

Abstract

Aims/hypothesisObservational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip.MethodsWe selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10−8) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men.ResultsIn a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (−0.67 cm2 [95% CI −1.30, −0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm2 [95% CI −0.00, 0.07; p = 0.060]).Conclusions/interpretationFasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.Graphical abstract

Highlights

Observational studies have shown type 2 diabetes mellitus to be associated with a greater risk for hip fracture [1, 2], despite being associated with a greater bone mineral density (BMD) [3]
The mean weight, height, bone area and BMD were higher in both PIVUS and ULSAM compared with SMCC, as men were present in these cohorts, whereas SMCC comprised only women
Fasting glucose levels were higher in PIVUS and ULSAM which may be explained by the older age in these cohorts compared with SMCC

Summary

Introduction

Observational studies have shown type 2 diabetes mellitus to be associated with a greater risk for hip fracture [1, 2], despite being associated with a greater bone mineral density (BMD) [3]. Potential mechanisms include weakened bone structure [4], diminished levels of bone turnover with greater bone loss [5], an increased risk of falling [6], or smaller bone area [7]. We measured the total hip bone area, but others have shown smaller bone area at the tibia [12] and radius [7] in those with type 2 diabetes. It is unclear which particular aspects of type 2 diabetes are responsible for the damaging effects on bone, as it is a complex disease characterised by both high blood glucose and complications with insulin action or secretion. In addition to type 2 diabetes, we showed in our previous study that fasting glucose levels were inversely associated with bone area in a dose-dependent pattern [11]

Methods

Results

Conclusion