Purpose: Multiple risk factors have been suggested to play crucial roles in the development of osteoporosis. This study aimed to examine the potential causal associations between serum nutritional factors and bone mineral density (BMD).

Methods: Each nutritional factor included in this study was identified independently from genome-wide association studies (GWAS) based on the European population. Outcomes included BMD at forearm (FA), femoral neck (FN), lumbar spine (LS) and heel (HL) (n = 8143, 32735, 28498 and 394929, respectively), and BMD in men and women (n = 206496). Two-sample Mendelian randomization (MR) approach was used to estimate causal associations between serum nutritional factors and BMD.

Results: Six nutritional factors were selected. A positive causal association was found between serum selenium levels and FA BMD (95% CI, 0.01 to 1.31) in MR analysis. Serum calcium levels were observed to be inversely associated with LS BMD. And positive associations were found between serum retinol (95% CI, 0.04 to 0.23), selenium (95% CI, 0.10 to 0.33) and vitamin E (95% CI, 0.07 to 0.50) levels and HL BMD. Also, we found sex-specific causal effects of serum retinol (95% CI, 0.09 to 0.53) and vitamin E (95% CI, 0.07 to 0.48) levels on BMD in men.

Main conclusions: BMD is causally influenced by serum calcium, selenium, retinol and vitamin E levels at specific skeletal sites. And sex-specific associations were observed between serum retinol and vitamin E levels and BMD in men, suggesting that these nutritional factors may play crucial roles in bone metabolism and osteoporosis.