Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis

Objective: This analysis assessed the putative causal association between genetically predicted percent body fat and areal bone mineral density (aBMD) and, more specifically, the association between genetically predicted metabolically “favorable adiposity” (MFA) and aBMD at clinically relevant bone sites. Methods: Mendelian randomization was used to assess the relationship of MFA and percent body fat with whole-body, lumbar spine, femoral neck, and forearm aBMD. Sex-stratified and age-stratified exploratory analyses were conducted. Results: In all MR analyses, genetically predicted MFA was inversely associated with aBMD for the whole body (β = −0.053, p = 0.0002), lumbar spine (β = −0.075; p = 0.0001), femoral neck (β = −0.045; p = 0.008), and forearm (β = −0.115; p = 0.001). This negative relationship was strongest in older individuals and did not differ by sex. The relationship between genetically predicted percent body fat and aBMD was nonsignificant across all Mendelian randomization analyses. Several loci that were associated at a genome-wide significance level (p < 5 × 10⁻⁸) in opposite directions with body fat and aBMD measures were also identified. Conclusions: This study did not support the hypothesis that MFA protects against low aBMD. Instead, it showed that MFA may result in lower aBMD. Further research is needed to understand how MFA affects aBMD and other components of bone health such as bone turnover, bone architecture, and osteoporotic fractures.