Mapping the role of macro and micronutrients in bone mineral density: a comprehensive Mendelian randomization study

Macro and micronutrients may play an important role in osteoporosis development; however, observational studies have yielded inconsistent results. Clarifying these associations is vital to the development of nutritional recommendations aimed at preventing osteoporosis.

Utilizing the largest available genome-wide association study (GWAS) summary statistics to date, we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of energy-adjusted macronutrient intake (fat, protein, carbohydrate, and sugar) and circulating levels of 20 micronutrients (ten each for vitamins and minerals) on heel estimated bone mineral density (eBMD), a promising marker for osteoporosis risk and fracture susceptibility. Sensitivity, sex-specific, and one-sample MR analyses were applied to further validate and annotate the results.

Among all nutrients, four genetically predicted circulating levels of micronutrients were suggestively associated with eBMD (vitamin A: $\beta$ _IVW = - 0.054, P_IVW = 3.70 × 10^-2; vitamin B12: $\beta$ _IVW = - 0.020, P_IVW = 3.71 × 10^-6; vitamin E: $\beta$ _IVW = 0.277, P_IVW = 3.22 × 10^-2; selenium: $\beta$ _IVW = 0.023, P_IVW = 5.37 × 10^-3; all P_intercept > 0.05). All these results were also considered robust, as sensitivity analyses yielded directionally consistent results. However, only the causal effects of vitamin B12 and selenium on eBMD remained significant after Bonferroni correction and were not confounded by obesity, smoking status, or alcohol consumption. Sex-specific analysis revealed a male-specific causal association between vitamin E and eBMD ( $\beta$ _IVW = 0.275, P_IVW = 9.81 × 10^-14). Additionally, using individuallevel data from the UK Biobank cohort, one-sample MR analysis found no causal relationships between diet-derived nutrient intake and eBMD in the overall population, as well as in the females or the males.

Our findings suggest that appropriate levels of plasma vitamin B12 and adequate levels of serum selenium are crucial for delaying bone loss and promoting bone health, emphasizing the need for nutritional recommendations to maintain optimal levels of these nutrients to promote eBMD and prevent osteoporosis.