Search

Objective: Experimental studies suggest that lipids affect bone metabolism. We aimed to elucidate whether lipid levels are associated with bone mineral density (BMD) in a cohort of postmenopausal women., Design: A cross-sectional study of participants in the Chronic Ailment Reduction after MENopause (CARMEN) cohort. Women underwent assessment of clinical and analytical parameters, including fasting lipid levels. BMD was assessed at both lumbar spine and hip. Homogeneity in the cohort was optimized by filtering out a series of confounding variables with a known impact on bone., Main Outcome Measures: Association of BMD at lumbar spine and femoral neck with lipid levels., Results: A total of 667 of the 1304 screened women were analyzed. A strong correlation was revealed between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in univariate analysis. Multivariate analysis detected a significant positive association of HDL-C with BMD at both spine (p = 0.007) and femoral neck (p = 0.013). Other independent predictors of spine BMD were years since menopause (ysm, negatively associated), and body mass index (BMI) and estradiol, both positively associated with BMD. The other independent variables in the femoral neck were ysm and glucose (negatively associated) and BMI, estradiol, and phosphate, all positively associated with BMD., Conclusion: Levels of HDL-C, but not TC, LDL-C or triglycerides, were positively associated with BMD at both the lumbar spine and femoral neck in a homogeneous cohort of postmenopausal women., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Compelling data are revealing that the CD40/CD40L system is involved in bone metabolism. Furthermore, we have previously demonstrated that polymorphisms in both genes are associated with bone phenotypes. The aim of this study is to further characterize this association and to identify the causal functional mechanism. We conducted an association study of BMD with 15 SNPs in CD40/CD40L genes in a population of 779 women. In addition, we assessed the functionality of this association through the study of the allele-dependent expression of CD40 and CD40L in peripheral blood leukocytes (PBLs) and in human osteoblasts (OBs) obtained from bone explants by qPCR and by sequencing. When an allelic imbalance (AI) was detected, studies on allele-dependent in vitro transcription rate and on CpG methylation in the gene promoter were also performed. Our results confirm the genetic association between SNP rs116535 (T>C) of CD40L gene with LS-BMD. Regarding CD40 gene, two SNPs showed nominal P-values<0.05 for FN- and LS-BMD (Z-scores), although the association was not significant after correcting for multiple testing. Homozygous TT women for SNP rs1883832 (C>T) of CD40 gene showed a trend to have lower levels of OPG (Q-value=0.059), especially when women of BMD-quartile ends were selected (P<0.05). Regarding functionality, we detected an AI for rs1883832 with the C allele the most expressed in OBs and in PBLs. Since the rs116535 of CD40L gene did not show AI, it was not further analyzed. Finally, we described a differential methylation of CpGs in the CD40 promoter among women of high in comparison to low BMD. Our results suggest that the CD40/CD40L system plays a role in regulating BMD. Effectively, our data suggest that a decreased production of OPG could be the cause of the lower BMD observed in TT women for rs1883832 of the CD40 gene and that the degree of methylation of CpGs in the CD40 promoter could contribute to the acquisition of BMD. One possibility that deserves further study is whether the degree of methylation of the CD40 gene affects the level of CD40 expression and, consequently, the level of OPG., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Changes in bone density and bone markers suggest that pregnancy is associated with deterioration of bone mass in the mother. The metabolism of calcium resets to allow for the needs imposed by the building of the fetal skeleton. The fetus contributes to the process through the output of regulators from the placenta. Understanding of the whole process is limited, but some changes are unambiguous. There is an increase in the circulating levels of vitamin D, but its functional impact is unclear. Fetal parathyroid hormone (PTH) and PTH-related peptide (PTHrp) play an indirect role through support of a calcium gradient that creates hypercalcemia in the fetus. Placental GH, which increases up to the end of pregnancy, may exert some anabolic effects, either directly or through the regulation of the IGF1 production. Other key regulators of bone metabolism, such as estrogens or prolactin, are elevated during pregnancy, but their role is uncertain. An increase in the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) to osteoprotegerin (OPG) acts as an additional pro-resorbing factor in bone. The increase in bone resorption may lead to osteoporosis and fragility fracture, which have been diagnosed, although rarely. However, the condition is transitory as long-term studies do not link the number of pregnancies with osteoporosis. Prevention is limited by the lack of identifiable risk factors. When fractures are diagnosed, rest, analgesics, or, when indicated, orthopedic intervention have demonstrated efficacy. Systemic treatment with anti-osteoporotic drugs is effective, but the potential harm to the fetus imposes caution in their use., (© 2015 European Society of Endocrinology.)

Gene candidate and genome-wide association studies have revealed tens of loci of susceptibility for osteoporosis. Some limitations such as sample size, use of confounding variables, and control for multiple testing and for population stratification, however, represent common problems in these studies that make replication in independent cohorts desirable and even necessary. The main objective of the present study is to replicate previous data on three functional polymorphisms in a cohort of Spanish women. To that end, we performed an association study of three functional polymorphisms previously associated with bone phenotypes in the LRP5, TNFRSF11B, and FGFBP1 genes with low bone mineral density (BMD) in a cohort of 721 Spanish women, most of them postmenopausal. We detected a strong significant association, even when correcting for multiple comparisons, for polymorphism rs312009 in the LRP5 gene with low BMD at the lumbar-spine site. These were women with the CC genotype, which showed the worst bone parameters. Moreover, these women had a higher risk of osteoporosis (adjusted odds ratio 2.82, P = 0.001) than women with the TT/TC genotype. This association seems to be caused because the rs312009 single nucleotide polymorphism (SNP) is located at a binding site for the transcription factor RUNX2 at the 5' region of the LRP5 gene, and the T allele seems to be a better transcriber than the C allele. Regarding the other two SNPs, only the rs4876869 SNP in the TNFRSF11B gene showed a suggestive trend for both skeletal sites. These results underscore the significance of the LRP5 gene in bone metabolism and emphasize the significance of the replication of previous results in independent cohorts.

RUNX2 is a transcription factor essential for osteoblast differentiation and skeletal morphogenesis. Its mutation creates cleidocranial dysplasia (CCD), a disorder characterized by skeletal abnormalities and bone mineral density (BMD) alterations. The purpose of the present study has been to clarify whether polymorphisms affecting this gene could be associated with changes in BMD in women. To that end, we performed an association study of BMD values from 776 women with two single nucleotide polymorphisms (SNPs) located at P2 promoter (-1025 T>C) and at exon 2 (+198 G>A), and with a deletion polymorphism (17Ala>11Ala), also located at exon 2. We found an association of -1025 T>C SNP with femoral neck BMD (FN-BMD), being the women of TC/CC genotype who have higher BMD than women of TT genotype (P = 0.006). This association was independent of age, weight, menopausal status, or hormone replacement therapy (HRT) use as shown by regression analysis. When women of highest versus lowest quartile of BMD were compared, this association became more evident (P = 0.002), extending also to +198 G>A SNP (GA/AA women with higher FN-BMD; P < 0.05). In addition, we describe herein three novel rare variants in the polyglutamine domain of RUNX2 protein: an in-frame insertion and two deletions in exon 2, resulting in the insertions of 7 and deletions of 7 and 5 glutamines, respectively. These variants do not produce CCD, increased frequency of bone fracture, or BMD alterations. In conclusion, common polymorphisms in Runx2 are associated with FN-BMD. Nevertheless, rare variants that modify the polyglutamine domain of RUNX2 neither have any effect on BMD nor produce the CCD phenotype. These results underscore the significance of polymorphisms in the 5'-region of Runx2 in the determination of FN-BMD.

Osteoporosis is a common skeletal disorder characterized by increased risk of bone fracture (BF) due to fragility. BFs, particularly hip fracture, are a major concern in health care because of the associated morbidity and mortality, mainly in the elderly. Lately the involvement of epigenetic mechanisms in the pathophysiology of many diseases has been recognized. In this context, the identification of microRNAs (miRNAs) specific to BF should represent a substantial step forward in diagnostics and therapeutics. The present study aimed to identify specific miRNAs in osteoporotic BF patients compared to those in osteoarthritic controls. In the profiling stage, total RNA was extracted from serum, two pools were prepared, and then retro-transcribed in triplicate. Levels of 179 serum miRNAs were analyzed by real-time PCR, and 42 of them showed significance (P < 0.05), and 12 passed the false discovery rate test for multiple comparisons. Six miRNAs were selected for the replication stage and individually analyzed in sera from 15 BF patients and 12 controls. Results showed that 3 miRNAs (miR-122-5p, miR-125b-5p, and miR-21-5p) were valuable upregulated biomarkers in BF with respect to controls and, significantly, their levels were not affected by hemolysis. For miR-21-5p, the difference detected between groups was independent of age (P = 0.005) and its levels correlated to those of CTx (r = 0.76; P < 0.00001), a marker of bone resorption. In conclusion, several miRNAs may be biomarkers of BF, particularly miR-21-5p. Further studies are needed in order to better characterize the levels of these miRNAs in other bone diseases and to elucidate the mechanism involved in the association of these three miRNAs with osteoporotic BF. [ABSTRACT FROM AUTHOR]