Causal association of 35 biomarkers,including apolipoprotein B,serum phosphate,and calcium,with bone mineral density:A Mendelian randomization analysis
ZHUANG Jianxiong
CHEN Rong
TU Jian
YU Zhengran
ZHENG Xiaoqing
CHANG Yunbing
GU Honglin
Abstract：Objective To investigate the potential causal relationship between 35 blood and urine markers and bone mineral density(BMD)at different skeletal sites using a two-sample Mendelian randomization design.Methods Genetic instruments(single-nucleotide polymorphisms,SNPs)associated with the 35 biomarkers were selected from the UK Biobank(UKB).GWAS aggregate data for bone mineral density were obtained from the Osteoporosis Genetic Factors Consortium(GEFOS).The inverse-variance weighted(IVW)method served as the primary analysis,supplemented by the weighted median,simple median,and MR-Egger methods.Sensitivity analyses,including tests for pleiotropy and heterogeneity,were performed to ensure robustness.Furthermore,the significant findings were validated in independent European GWAS datasets.Results IVW results showed that apolipoprotein B was negatively associated with heel BMD(OR=0.98,95%CI:0.97～1.00,P=0.027).There may be a causal relationship between blood phosphorus and bone mineral density of femoral neck(OR=1.09,95%CI:1.03～1.15,P=0.003);Elevated blood calcium levels were potentially causally linked to reduced BMD in the skull(OR=0.90,95%CI:0.85～0.95,P=1.75×10⁻⁴)and lumbar spine(OR=0.92,95%CI:0.86～0.98,P=0.007).We also found blood urea nitrogen,glomerular filtration rate,apolipoprotein B,triglycerides,and total protein also have potential correlations with bone mineral density,and the P-values are all less than 0.05.MR-Egger regression suggests that the above causal association is not affected by horizontal pleiotropy,and weighted median method and simple median method can obtain results similar to IVW.All these biomarker-BMD associations were replicated in the validation cohort.Conclusions This large-scale two-sample MR study system-atically identifies potential causal effects of specific biomarkers on site-specific BMD.The findings suggest that higher apolipoprotein B may reduce heel BMD,elevated blood phosphorus might help maintain femoral neck BMD,and increased blood calcium could be associated with lower BMD in the skull and lumbar spine.
Keywords：Mendelian randomizationosteoporosisbone densityapolipoprotein Bblood phos-phorusblood calcium
Publication Date：2025-12-25
Online Publishing Date：2026-01-04(First online date of this platform, not the publication date of the document)
Pages：11( 3947-3957 )