Decision letter for "The Effect of Plasma Lipids and Lipid‐Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study"

AbstractStatin treatment increases bone mineral density (BMD) and reduces fracture risk, but the underlying mechanism is unclear. We used Mendelian randomization (MR) to assess whether this relation is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels and results from a heel BMD GWAS (derived from quantitative ultrasound) in 426,824 individuals from the UK Biobank. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD. To test whether the effect of statins on BMD was mediated by lowering lipid levels, MR was repeated with and without SNPs in theHMGCRregion, the gene targeted by statins. Univariate MR analyses provided evidence for a causal effect of LDL-C on BMD (β= −0.060; −0.084 to −0.036; P = 4×10-6; standard deviation change in BMD per standard deviation change in LDL-C, with 95% CI), but not HDL or triglycerides. Multivariable MR analysis suggested that the effect of LDL-C on BMD was independent of HDL-C and triglycerides, and sensitivity analyses involving MR Egger and weighted median MR approaches suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in theHMGCRregion showed similar effects on BMD(β= −0.083; −0.132 to −0.034; P = 0.001) to those excluding these SNPs (β= −0.063; −0.090 to −0.036; P = 8×10-6). Bidirectional MR analyses provided some evidence for a causal effect of BMD on plasma LDL-C levels. Our results suggest that effects of statins on BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.

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Correlations of lipid metabolism with bone remodeling

Medic ro ◽

10.26416/med.138.6.2020.3996 ◽

2020 ◽

Vol 6 (1) ◽

pp. 28-30

Author(s):

M. Ciornei ◽

Emese Orban ◽

Remus Şipoş

Keyword(s):

Bone Mineral Density ◽

Bone Marrow ◽

Bone Mineral ◽

Plasma Lipids ◽

Positive Impact ◽

Oxidation Products ◽

Lipid Lowering ◽

Osteoporotic Bone ◽

Mineral Density ◽

Wide Range

Introduction. Both dyslipidemia and osteoporosis are chronic medical problems, and the relationship between these two pathologies is based on common risk factors and pathogenic mechanisms which favour the development of both diseases. Dyslipidemia can be a risk factor for osteoporosis, therefore it is important to understand the mechanisms underlying the relation between these two pathologies. The link between dyslipidemia and osteoporosis. Lipoprotein oxidation products suppress the differentiation of osteoblasts while stimulating the differentiation of adipocytes and their proliferation, a mechanisms that can contribute to the reduction of bone mineralization and the occurrence of inflammatory events. A number of clinical and experimental studies have been performed, these studies suggesting an inverse correlation between the adipose content of the bone marrow and the density of the bone tissue, in other words, in parallel with the osteoporotic bone loss there is an increase of the adipocyte content in the bone marrow. The role of plasma lipids on bone metabolism. Because in clinic patients with dyslipidemia are often diagnosed with osteoporosis, we can say that serum levels of plasma lipids influence both osteoblastic and osteoclastic activity. Cholesterol correlates with low bone mineral density, while triglycerides are associated with a low incidence of vertebral fractures in osteoporotic women. Effects of lipid-lowering medication on bone tissue. Statins, first introduced to treat patients with hyperlipidemia and hypercholesterolemia, have also been shown to be beneficial for osteoporotic patients and have recently been introduced to prevent fractures and treat osteoporosis through their ability to enhance osteogenesis and inhibit osteoclastogenesis. Conclusions.There is a wide range of studies that have shown that statins, widely used as lipid-lowering agents, could also be utilized in the treatment of osteoporosis, through the beneficial effects they have on bone metabolism, effects with a positive impact on bone mineral density.

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Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽

10.3390/nu13061940 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1940

Author(s):

Karl Michaëlsson ◽

Susanna C. Larsson

Keyword(s):

Bone Mineral Density ◽

Confidence Interval ◽

Bone Mineral ◽

Genetic Variants ◽

Mendelian Randomization ◽

Alpha Tocopherol ◽

European Ancestry ◽

Mineral Density ◽

Standard Deviation Increase ◽

A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

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