Gloria Hoi-Yee Li1, Ching-Lung Cheung1,2,3, Philip Chun-Ming Au1, Kathryn Choon-Beng Tan3, Ian Chi-Kei Wong1,4, Pak-Chung Sham2,5. 1. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong. 2. Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong. 3. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Pokfulam, Hong Kong. 4. Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK. 5. Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Abstract
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to bone mineral density (BMD) and assess the effects of LDL-C-lowering drugs on BMD. METHODS: Association between blood lipid levels and BMD was examined by epidemiological observation analyses in a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (GWAS) of blood lipids (n = 188 577), total body BMD (TB-BMD) (n = 66 628) and estimated BMD (eBMD) (n= 142 487), was performed to infer causality between LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs' effects on BMD. RESULTS: In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 - 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 - 0.074]; P = 0.038} and eBMD [0.076 (0.042 - 0.111); P = 1.20x10-5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 - 0.066); P = 0.034]. Statins' LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 - 0.316); P = 9.600x10-3] and eBMD [0.143 (0.062 - 0.223); P = 5.165x10-4]. CONCLUSIONS: Negative causal association exists between LDL-C level and BMD. Statins' LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to bone mineral density (BMD) and assess the effects of LDL-C-lowering drugs on BMD. METHODS: Association between blood lipid levels and BMD was examined by epidemiological observation analyses in a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (GWAS) of blood lipids (n = 188 577), total body BMD (TB-BMD) (n = 66 628) and estimated BMD (eBMD) (n= 142 487), was performed to infer causality between LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs' effects on BMD. RESULTS: In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 - 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 - 0.074]; P = 0.038} and eBMD [0.076 (0.042 - 0.111); P = 1.20x10-5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 - 0.066); P = 0.034]. Statins' LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 - 0.316); P = 9.600x10-3] and eBMD [0.143 (0.062 - 0.223); P = 5.165x10-4]. CONCLUSIONS: Negative causal association exists between LDL-C level and BMD. Statins' LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.
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