Higher Hip Bone Mineral Density Research Articles

Factors Affecting Postpartum Bone Mineral Density in a Clinical Trial of Vitamin D Supplementation.

Background: Few studies evaluate the effects of vitamin D status and supplementation on maternal bone mineral density (BMD) during lactation and further lack inclusion of diverse racial/ethnic groups, body mass index (BMI), or physical activity. Objective: Determine the effects of vitamin D treatment/status, feeding type, BMI, race/ethnicity, and physical activity on postpartum women's BMD to 7 months. Methods: Women with singleton pregnancies beginning 4-6 weeks' postpartum were randomized into two treatment groups (400 or 6400 IU vitamin D/day). Participant hip, spine, femoral neck, and whole-body BMD using Dual-energy X-ray absorptiometry (DXA Hologic), serum 25-hydroxyvitamin D [25(OH)D] (RIA; Diasorin), BMI, and physical activity were measured at 1, 4, and 7 months postpartum. A general linear mixed modeling approach was undertaken to assess the effects of vitamin D status [both serum 25(OH)D concentrations and treatment groups], feeding type, race/ethnicity, BMI, and physical activity on BMD in postpartum women. Results: During the 6-month study period, lactating women had 1-3% BMD loss in all regions compared with 1-3% gain in nonlactating women. Higher maternal BMI was associated with less bone loss in femoral neck and hip regions. Black American women had less BMD loss than White/Caucasian or Hispanic lactating women in spine and hip regions. Exclusively breastfeeding women in the 6400 IU vitamin D group had less femoral neck BMD loss than the 400 IU group at 4 months sustained to 7 months. Physical activity was associated with higher hip BMD. Conclusion: While there was BMD loss during lactation to 7 months, the loss rate was less than previously reported, with notable racial/ethnic variation. Breastfeeding was associated with loss in BMD compared with formula-feeding women who gained BMD. Higher BMI and physical activity independently appeared to protect hip BMD, whereas higher vitamin D supplementation appeared protective against femoral neck BMD loss.

Association of dietary carbohydrate and fiber ratio with postmenopausal bone mineral density and prevalence of osteoporosis: A cross-sectional study.

This study aimed to investigate the associations of carbohydrate to dietary fiber ratio with bone mineral density (BMD) and the prevalence of osteoporosis in postmenopausal women. This cross-sectional study retrieved the data of 2829 postmenopausal women from the National Health and Nutrition Examination Survey (NHANES) database. Weighted univariable logistic regression models were used to investigate the correlations of carbohydrate, dietary fiber, or carbohydrate to fiber ratio with osteoporosis. Higher dietary fiber intake was correlated with decreased odds ratio of osteoporosis [odds ratio(OR) = 0.96, 95% confidence interval (CI): 0.93 to 0.99]. The odds ratio of osteoporosis in postmenopausal women was elevated as the increase of carbohydrate to fiber ratio (OR = 1.80, 95%CI: 1.10 to 2.96). Carbohydrate to fiber ratio >17.09 was related to increased odds ratio of osteoporosis (OR = 1.63, 95%CI: 1.04 to 2.56). Compared to the carbohydrate to fiber ratio ≤11.59 group, carbohydrate to fiber ratio >17.09 was associated with decreased total femur BMD (β = -0.015, 95%CI: -0.028 to -0.001) and femur neck BMD (β = -0.020, 95%CI: -0.033 to -0.006) in postmenopausal women. The femur neck BMD in postmenopausal women was decreased with the increase of carbohydrate to fiber ratio (β = -0.015, 95%CI: -0.028 to -0.001). In postmenopausal women, a high carbohydrate/fiber ratio >17.09 is associated with an increased risk of osteoporosis and lower hip BMD and high fiber intake is associated with less osteoporosis and higher hip BMD.

Differentially expressed genes and miRNAs in female osteoporosis patients.

Osteoporosis is characterized by lowing bone mineral density. This study aimed to investigate the genes, miRNAs, pathways, and miRNA-gene interaction pairs involved in the pathogenesis of female osteoporosis. The differentially expressed genes (DEGs, GSE62402), differentially expressed miRNAs (DEmiRNAs, GSE63446), and differentially methylated genes (GSE62588) between females with low- and high-hip bone mineral density were identified. Genes common to DEGs, differentially methylated genes, DEmiRNAs' targets, and osteoporosis-related genes were retained and used to construct the miRNA-mRNA-pathway regulatory network. The expression of hub nodes was validated in microarray datasets (genes in GSE56116 and miRNAs in GSE93883). Thirty-four DEmiRNAs and 179 DEGs with opposite expression-methylation profiles were identified. Functional enrichment analysis showed that DEGs were associated with pathways including "hsa00380:Tryptophan metabolism," "hsa04670:Leukocyte transendothelial migration," "hsa04630:Jak-STAT signaling pathway," and "hsa04062:Chemokine signaling pathway." The miRNA-mRNA-pathway network included 10 DEGs, 9 miRNAs, and 4 osteoporosis-related pathways. The miRNA-gene-pathway axes including hsa-miR-27b-5p/3p-IFNAR1-hsa04630, hsa-miR-30a-5p/3p-IFNAR1-hsa04630, hsa-miR-30a-5p/3p-ALDH2-hsa00380, and hsa-miR-194-5p/3p-NCF2-hsa04670 were included in the network. Microarray validation showed that IFNAR1, NCF2, and ALDH2 were upregulated, and hsa-miR-30a-3p/5p, hsa-miR-194-3p/5p, hsa-miR-27b-3p/5p, and hsa-miR-34a-3p were downregulated in osteoporotic samples compared with control. Axes including hsa-miR-27b/30a-IFNAR1-Jak-STAT signaling pathway, hsa-miR-30a-ALDH2-Tryptophan metabolism, and hsa-miR-194-NCF2-Leukocyte transendothelial migration were involved in osteoporosis pathogenesis.

Is Regular Weight-Bearing Physical Activity Throughout the Lifecourse Associated with Better Bone Health in Late Adulthood?

We considered how weight-bearing physical activity (WBPA) through the lifecourse related to bone health in late adulthood in the Hertfordshire Cohort Study (HCS), a cohort of community dwelling adults born 1931–9, to identify sex-specific differences and periods critical for optimal bone health. Available questionnaire data from 258 participants (128 men and 130 women) included current reported lifestyle factors (including physical activity) and WBPA, coded as participation in WBPA aged < 18 years; aged 18–29 years; aged 30–49 years and aged ≥ 50 years. Responses were recorded as none/once a month/once a week/> once a week. Hip bone mineral density (BMD) was measured using a Lunar Prodigy DXA scanner. The mean age was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men reported significantly higher levels of past WBPA aged < 18 years (p = 0.006) and aged 18–29 years than women (p < 0.001). We observed greater BMD at total hip in women who reported regular WBPA at ages 18–29 years (p = 0.02) and 30–49 years (p = 0.02) compared with those who reported no WBPA (p = 0.019), after adjustment for confounders including current activity levels. In this cohort of older adults, recalled regular WBPA around the time of peak bone mass acquisition was less common in women than men, but associated with higher hip BMD in women in late adulthood.

P132 Does weight-bearing physical activity track through the lifecourse? Findings from the Hertfordshire Cohort Study

Abstract Background/Aims Physical activity is known to be beneficial for musculoskeletal health across the lifecourse. We have previously demonstrated that regular participation in weight-bearing physical activity (WBPA) at the time of peak bone mass acquisition is associated with higher hip bone mineral density in late adulthood in women. Understanding how WBPA tracks across the lifecourse may help us develop interventions to promote WBPA for musculoskeletal benefit; we consider these relationships here. Methods The study population consisted of 128 men and 130 women from the Hertfordshire Cohort Study. Questionnaire data on participation in sports and leisure time exercise involving WBPA e.g. running, racquet sports, football, rugby, hockey and dancing, but not walking, cycling or swimming were collected for the following age bands: &amp;lt;18 years; ages 18-29 years; ages 30-49 years; and ≥50 years. Responses were coded as none/ once a month/ once a week/ ≥once a week. Data on current lifestyle and physical activity levels were also collected. Results The mean age of participants was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men tended to report higher levels of past WBPA throughout the lifecourse, with significant differences in WBPA up to the age of 18 years (p = 0.006) and 18-29 years (p &amp;lt; 0.001). Table 1 shows kappa statistics of relationships between reported WBPA levels at different ages. These decreased over time, and while broadly similar, the tracking was generally stronger in women than men. For example, we observed that participants who were active at 30-49 years were more likely to remain active in late adulthood with kappa in men 0.393 (95%CI: 0.295-0.442) and kappa in women 0.492 (95% CI: 0.400-0.555). Conclusion WBPA decreased with advancing age in both sexes, though was generally higher in men than women in this retrospective cohort study. The correlation between WBPA at different stages of the lifecourse weakened as time between the measurements increased in both sexes. Our results highlight the need for further work to understand the drivers to encourage WBPA at different stages in the lifecourse and to facilitate development of appropriate interventions to promote WBPA for musculoskeletal benefit. Disclosure J. Zhang: None. K. Jameson: None. L. Westbury: None. N. Fuggle: None. K. Ward: None. C. Cooper: None. E. Dennison: None.

Screening of Important Markers in Peripheral Blood Mononuclear Cells to Predict Female Osteoporosis Risk Using LASSO Regression Algorithm and SVM Method.

Background:Osteoporosis is a bone disease that increases the patient’s risk of fracture. We aimed to identify robust marker genes related to osteoporosis based on different bioinformatic methods and multiple datasets.Methods:Three datasets from Gene Expression Omnibus (GEO) were utilized for analysis separately. Significantly differentially expressed genes (DEGs) from comparing high hip and low hip low bone mineral density (BMD) groups in the first dataset were identified for Gene Ontology (GO), Gene set enrichment analysis (GSEA) and Kyoto encyclopedia of genes and genomes (KEGG) to investigate the discrepantly enriched biological processes between high hip and low hip group. Last absolute shrinkage and selection operator (LASSO), SVM model and protein-protein interaction (PPI) regulatory network were performed and generated robust marker genes for downstream TF-target and miRNA-target prediction.Results:Several DEGs between high hip BMD group and low hip BMD group were obtained. And the metabolism-related pathways such as metabolic pathways, carbon metabolism, glyoxylate and dicarboxylate metabolism shown enrichment in these DEGs. Integration with LASSO regression analysis, 8 differential expression genes (SH3BP1, NARF, ANKRD34B, RNF40, ZNF473, AKT1, SHMT1, and VASH1) in GSE62402 were identified as the optimal differential genes combination. Moreover, the SVM validation analysis in GSE56814 and GSE56815 datasets showed that the characteristic gene combinations presented high diagnostic effects, and the model AUC areas for GSE56814 was 0.899 and for GSE56815 was 0.921. Furthermore, the subcellular localization analysis of the 8 genes revealed that 4 proteins were located in the cytoplasm, 3 proteins were located in the nucleus, and 1 protein was located in the mitochondria. Additionally, the related TFs and miRNAs by performing TF-target and miRNA-target prediction for 5 genes (AKT1, SHMT1, ZNF473, RNF40 and VASH1) were investigated from PPI network.Conclusion:The optimal differential genes combination (SH3BP1, NARF, ANKRD34B, RNF40, ZNF473, AKT1, SHMT1, and VASH1) presented high diagnostic effect for osteoporosis risk.

The Association of Protein Intake and Bone Outcomes in Midwestern Post-menopausal Women

Abstract Objectives Determine the extent to which baseline protein and amino acid intake is independently associated with measures of baseline bone outcomes in a cohort of post-menopausal women. Methods This study was a secondary analysis of participants in the Heartland Osteoporosis Prevention Study (HOPS) randomized controlled trial evaluating the effect of different osteoporosis interventions on post-menopausal women in the Midwest. Diets were evaluated via a Harvard Willett Semi-quantitative Food Frequency Questionnaire (FFQ) at baseline. Dual energy x-ray absorptiometry (DXA) scans were used to collect bone mineral density (BMD) and trabecular bone score (TBS) measurements. Single and multivariate linear regression of total protein intake (g/d and g/kg/d), proline (g), and lysine (g) with BMD and TBS locations were conducted. Student T-tests were used to compare the bone outcome differences between groups with protein intake above and below 1.2g/kg. Results There were 249 participants available for analysis. Mean total protein intake was 82.7 g with 62% consuming &amp;lt; 1.2/kg/d. After adjustment, for every additional gram intake of protein, lysine and proline, Hip BMD increased (Protein: β = 0.0005, P = 0.047; Lysine: β = 0.006, P = 0.04; Proline: β = 0.008, P = 0.04). Whole body BMD and TBS-1 were significantly associated with proline intake (Whole body BMD: β = 0.008, P = 0.04; TBS-1: β = −0.007, P = 0.02). After adjustment, women who consumed protein above 1.2 g/kg, had a Hip BMD 0.03 g/cm2 higher than those who consume protein below 1.2 g/kg (β = 0.03, P = 0.046). Lumbar BMD, Total L1-L4 BMD, TBS-2, TBS-3, TBS-4, and Total TBS were not significantly associated with protein or amino acid intakes after adjustment of covariates. Conclusions Higher protein intakes were associated with higher Hip BMD. Proline may play a controversial role in bone outcomes. Future research should investigate the role of dietary factors on BMD vs TBS. Funding Sources The original research was funded by the National Institute of Nursing Research of the National Institutes of Health under award number R01NR015029. No additional funding was used for the secondary analysis.

Comprehensive Analysis of lncRNA and miRNA Expression Profiles and ceRNA Network Construction in Osteoporosis.

Multiple profiling studies have identified a number of non-coding RNAs associated with the pathogenesis of human diseases. However, the exact regulatory mechanisms and functions of these non-coding RNAs in the development of osteoporosis have not yet been explored. Transcriptome gene expression and miRNA microarray data from peripheral blood monocytes of five high hip bone mineral density (BMD) subjects and five low hip BMD subjects were analyzed. Differentially expressed mRNAs, lncRNAs, and miRNAs were identified and subjected to functional enrichment analysis. Additionally, protein-protein interaction (PPI), lncRNA-mRNA, and mRNA-lncRNA-miRNA competing endogenous RNA (ceRNA) networks were constructed. Differential analysis revealed that 297 mRNAs, 151 lncRNAs, and 38 miRNAs were significantly differentially expressed between peripheral blood monocytes from high and low hip BMD subjects. Key genes including ACLY, HSPA5, and AKT1 were subsequently identified in the PPI network. Additionally, differentially expressed lncRNAs were primarily enriched in the citrate cycle (TCA cycle), biosynthesis of antibiotics, and carbon metabolism pathways. Finally, the mRNA-lncRNA-miRNA network revealed several key ceRNA regulatory relationships among the transcripts and non-coding RNAs. Key mRNAs and non-coding RNAs identified in the networks represent potential biomarkers or targets in the diagnosis and management of osteoporosis. Our findings represent a resource for further functional research on the ceRNA regulation mechanism of non-coding RNA in osteoporosis.

Metabolomic profiles associated with bone mineral density in US Caucasian women

BackgroundIndividuals’ peak bone mineral density (BMD) achieved and maintained at ages 20–40 years is the most powerful predictor of low bone mass and osteoporotic fractures later in life. The aim of this study was to identify metabolomic factors associated with peak BMD variation in US Caucasian women.MethodsA total of 136 women aged 20–40 years, including 65 subjects with low and 71 with high hip BMD, were enrolled. The serum metabolites were assessed using a liquid chromatography-mass spectrometry (LC-MS) method. The partial least-squares discriminant analysis (PLS-DA) method and logistic regression models were used, respectively, to examine the associations of metabolomic profiles and individual metabolites with BMD.ResultsThe low and high BMD groups could be differentiated by the detected serum metabolites using PLS-DA (Ppermutation = 0.008). A total of 14 metabolites, including seven amino acids and amino acid derivatives, five lipids (including three bile acids), and two organic acids, were significantly associated with the risk for low BMD. Most of these metabolites are novel in that they have never been linked with BMD in humans earlier. The prediction model including the newly identified metabolites significantly improved the classification of the groups with low and high BMD. The area under the receiver operating characteristic curve without and with metabolites were 0.88 (95% CI: 0.83–0.94) and 0.97 (95% CI: 0.94–0.99), respectively (P for the difference = 0.0004).ConclusionMetabolomic profiling may improve the risk prediction of osteoporosis among Caucasian women. Our findings also suggest the potential importance of the metabolism of amino acids and bile acids in bone health.

Transcriptomic Data Identified Key Transcription Factors for Osteoporosis in Caucasian Women.

Osteoporosis is a prevalent bone metabolic disease, mainly caused by excessive bone resorption (by osteoclasts) over bone formation (by osteoblasts). Identifying the key transcription factors and understanding the regulatory network influencing osteoclastogenesis will be helpful to explore the potential biological mechanism for osteoporosis. In our study, peripheral blood monocyte (PBM) was used as a cell model for bone mineral density (BMD) research. PBMs serve as progenitors of osteoclasts and produce important cytokines for osteoclastogenesis. In our study, via exon arrays, gene expression profiles of PBMs were analyzed between high versus low hip BMD groups. Transcription factors for differentially expressed genes were then predicted based on the enrichment analysis. We found that 591 genes were differentially expressed between the two BMD groups (nominally significant, raw p value < 0.05). For high BMD subjects, 482 genes were up-regulated and 109 genes were down-regulated. We then found 29 potential transcription factors for up-regulated genes and nine transcription factors for down-regulated genes. Among these transcription factors, HMGA1 and NFKB2 were differentially expressed between high versus low BMD groups. In addition, their regulation types with their target genes were consistent with the information from public databases. Our findings of key transcription factors and their target genes for osteoporosis were further validated by GWAS analysis. Overall, we predicted important transcription factors for osteoporosis. We were also able to infer the regulatory mechanism that exists between transcription factors and target genes in bone metabolism.

Plasma gelsolin is associated with hip BMD in Chinese postmenopausal women.

Gelsolin (GSN) protein, expressed in circulating monocytes, was previously reported to be associated with osteoporosis in both Chinese and Caucasian women. This study aims to test if plasma GSN protein level is associated with hip bone mineral density (BMD) in Chinese population. Based on two study Groups containing 6,308 old Chinese, we adopted extreme sampling scheme and selected 3 independent samples (Subgroups 1–3) for discovery, replication, and validation purposes. We tested plasma GSN concentration, and analyzed whether plasma GSN level differs between subjects with extremely low vs. high hip BMD. In Group 1 (N = 1,860), the plasma GSN level increased in the female with low BMD, which was discovered in the Subgroup 1 (N = 42, p = 0.093) and replicated in the Subgroup 2 (N = 39, p = 0.095). With more extreme sampling for the Subgroup 3 from the Group 2 (N = 4,448), the difference of plasma GSN level in the female with low BMD vs. high BMD is more significant (N = 45, p = 0.037). After the subjects were pooled from Subgroups 2 and 3, the difference in plasma GSN between low and high BMD subjects became even more significant (p = 0.016). The plasma GSN level was negatively correlated with total hip BMD (r = -0.26, p = 0.033). We concluded that plasma GSN was associated with hip BMD in Chinese postmenopausal women and plasma GSN might be a potential risk biomarker for osteoporosis.

Association of Plasma Irisin with Bone Mineral Density in a Large Chinese Population Using an Extreme Sampling Design

Irisin, a myokine produced by skeletal muscle in response to physical exercise, promotes trans-differentiation of white adipose tissue into brown adipose tissue. Recent evidences suggested that irisin also plays an important role in the control of bone metabolism. This study aimed to ascertain the relationship between plasma irisin and bone mineral density (BMD) in Chinese population by adoption of an extreme sampling method. Based on a large and screened Chinese elderly population (N = 6308), two subgroups with extremely high and low hip BMD were selected for discovery (N = 80, high vs. low BMD = 44:36) and validation (N = 60, high vs. low BMD = 30:30), respectively. Plasma irisin, P1NP, and β-CTx were measured using commercially available ELISA kits. Other metabolic parameters (e.g., blood glucose, total cholesterol and triglycerides) were collected. Student's t test and Spearman correlation analyses were conducted in SPSS. Significant difference was discovered for plasma irisin between females and age-matched males (N = 80, male vs. female = 42:38, P = 0.002). The plasma irisin levels were significantly higher in high BMD subjects than in low BMD subjects, which was observed in both discovery (P = 0.012) and validation samples (P = 0.022). However, such observation was limited to males only. Further correlation analyses in males showed that plasma irisin was correlated with BMD (r = 0.362, P = 0.025) and triglyceride (r = - 0.354, P = 0.032). Plasma irisin levels were associated with hip BMD in Chinese elderly men. This study represented the first effort of investigating the relationship of plasma irisin and BMD in elderly population. The positive correlation between plasma irisin and BMD hints intrinsic communication between muscle and bone.

Anxa2 attenuates osteoblast growth and is associated with hip BMD and osteoporotic fracture in Chinese elderly.

Low bone mineral density (BMD) is a risk factor of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. It was known that PBM-expressed Anxa2 protein is associated with BMD, and extracellular Anxa2 protein promotes osteoclastogenesis. This study aimed to test 1) whether Anxa2 protein level in PBM differs significantly between subjects with OF and without fracture history (NF); 2) whether Anxa2 level in plasma is associated with BMD; 3) how Anxa2 protein at various concentrations would affect osteoblastic activity in vitro. All the study subjects were Chinese Han elderly. Firstly, Anxa2 protein in PBM was identified and quantitated by LC-MS/MS and compared between 45 OF cases and 42 healthy controls. Secondly, plasma Anxa2 protein level was quantitated by ELISA and compared between unrelated subjects with extremely low vs. high hip BMD (0.63±0.10 vs. 1.05±0.10 g/cm2, n = 75). Furthermore, in vitro functional assay was utilized to test the effects of extracellular Anxa2 protein on osteoblastic growth. We found that Anxa2 protein expression in PBM was significantly up-regulated in OF vs. NF subjects (fold change [FC)] = 1.16, P<0.05). Plasma Anxa2 protein concentration (range: 31.69–227.35ng/ml) was significantly elevated in low vs. high BMD subjects (84.85 vs. 66.15ng/ml, FC = 1.28, P<0.05). Cellular dynamical monitoring demonstrated that the general shape of dose-response relationship is the inverse U-shaped curve. Specifically, lower dose of Anxa2 protein may promote osteoblast growth and the optimal concentration for osteoblastic growth was around 50ng/ml, but even higher concentration could attenuate hFOB1.19 osteoprogenitor cell growth. We concluded that Anxa2 protein could attenuate osteoblast growth and be associated with hip BMD and OF in Chinese elderly.

Cytosolic proteome profiling of monocytes for male osteoporosis.

Osteoporosis is a serious public health problem, leading to significant mortality not only in aging females but also in males. Peripheral blood monocytes (PBMs) play important roles in bone metabolism by acting as precursors of osteoclasts and producing cytokines important for osteoclast development. The first cytosolic sub-proteome profiling analysis was performed in male PBMs to identify differentially expressed proteins (DEPs) that are associated with BMDs and risk of osteoporosis. Here, we conducted a comparative proteomics analysis in PBMs from Caucasian male subjects with discordant hip BMD (29 low BMD vs. 30 high BMD). To decrease the proteome complexity and expand the coverage range of the cellular proteome, we separated the PBM proteome into several subcellular compartments and focused on the cytosolic fractions, which are involved in a wide range of fundamental biochemical processes. Of the total of 3796 detected cytosolic proteins, we identified 16 significant (P<0.05) and an additional 22 suggestive (P<0.1) DEPs between samples with low vs. high hip BMDs. Some of the genes for DEPs, including ALDOA, MYH14, and Rap1B, showed an association with BMD in multiple omics studies (proteomic, transcriptomic, and genomic). Further bioinformatics analysis revealed the enrichment of DEPs in functional terms for monocyte proliferation, differentiation, and migration. The combination strategy of subcellular separation and proteome profiling allows an in-depth and refined investigation into the composition and functions of cytosolic proteome, which may shed light on the monocyte-mediated pathogenic mechanisms of osteoporosis.

Integrative Analysis of Transcriptomic and Epigenomic Data to Reveal Regulation Patterns for BMD Variation

Integration of multiple profiling data and construction of functional gene networks may provide additional insights into the molecular mechanisms of complex diseases. Osteoporosis is a worldwide public health problem, but the complex gene-gene interactions, post-transcriptional modifications and regulation of functional networks are still unclear. To gain a comprehensive understanding of osteoporosis etiology, transcriptome gene expression microarray, epigenomic miRNA microarray and methylome sequencing were performed simultaneously in 5 high hip BMD (Bone Mineral Density) subjects and 5 low hip BMD subjects. SPIA (Signaling Pathway Impact Analysis) and PCST (Prize Collecting Steiner Tree) algorithm were used to perform pathway-enrichment analysis and construct the interaction networks. Through integrating the transcriptomic and epigenomic data, firstly we identified 3 genes (FAM50A, ZNF473 and TMEM55B) and one miRNA (hsa-mir-4291) which showed the consistent association evidence from both gene expression and methylation data; secondly in network analysis we identified an interaction network module with 12 genes and 11 miRNAs including AKT1, STAT3, STAT5A, FLT3, hsa-mir-141 and hsa-mir-34a which have been associated with BMD in previous studies. This module revealed the crosstalk among miRNAs, mRNAs and DNA methylation and showed four potential regulatory patterns of gene expression to influence the BMD status. In conclusion, the integration of multiple layers of omics can yield in-depth results than analysis of individual omics data respectively. Integrative analysis from transcriptomics and epigenomic data improves our ability to identify causal genetic factors, and more importantly uncover functional regulation pattern of multi-omics for osteoporosis etiology.

Bone and Nutrition. Nutritional management of osteoporosis

Calcium intake was negatively associated with bone resorption marker such as DPD, NTX, and P1NP in Japanese postmenopausal osteoporotic patients. Not only to suppress bone resorption but also to keep higher hip bone mineral density were observed in the patients with higher intake of calcium than 800mg/day and higher vitamin D condition (more than 50nmol/L of serum 25 (OH) D). Higher calcium intake than 800mg/day from dairy and Tofu products, higher intake of vitamin D than 10μg/day from fish, and higher intake of vitamin K from vegetables should be recommended in Japanese postmenopausal osteoporotic patients. We should also pay attention to their losing weight and excess intake of these nutrients from supplements.

Association of Serum Uric Acid and Incident Nonspine Fractures in Elderly Men: The Osteoporotic Fractures in Men (MrOS) Study

Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case-cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case-cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71-0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49-0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD.

Magnesium intake is associated with greater bone mineral density but not protective against fractures in the Women's Health Initiative Observational Study (WHI‐OS)

Magnesium (Mg) is a component of healthy bone but the relation of Mg to fracture risk is unclear. The aim of this study was to examine Mg intake as a risk factor for osteoporotic fractures as well as altered bone mineral density (BMD).This prospective cohort study included 73,684 postmenopausal women from the WHI‐OS. Mg intake was estimated from baseline food frequency questionnaires plus supplement use. Hip fractures were confirmed by medical record review; other fractures were self‐reported.Incidences and relative risks of hip and total fractures were not significantly different across quintiles (Q) of Mg intake. However, risk of lower arm/wrist fractures increased with increasing Mg [multi‐variate adjusted hazard ratios (HR) Q4: 1.15 (95% CI 1.01, 1.32) and Q5: 1.23 (95% CI 1.07, 1.42); p for trend 0.048]. Additionally, women in Q4 and Q5 were more physically active and were at higher risk for falls (HR Q4: 1.11; 95% CI 1.06, 1.16; and Q5: 1.15; 95% CI 1.10, 1.20; p for trend &lt;0.001). There was a 3% higher hip BMD, and a 2% higher whole body BMD in women consuming &gt;;422.5 mg/d of Mg versus &lt;206.5 mg/d (p &lt;0.001).In conclusion, lower BMD of the hip and whole body were associated with lower Mg intake but this did not translate into increased risk of fractures. Mg consumption slightly greater than the RDA was associated with increased falls and lower arm/wrist fractures, possibly related to more physical activity in this group of women.

Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density

Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. Although an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high versus low hip BMD (20% tails of the distributions), in two independent U.S. Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 versus ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two single-nucleotide polymorphisms (SNPs), rs6549904 and rs7640046, both of which had significant interactions with an SNP, rs4891159, located on ZNF516 (p = 7.04 × 10(-11) and 1.03 × 10(-10) ). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 versus ZNF516, was successfully replicated in the Caucasian sample (p = 8.07 × 10(-3) and 2.91 × 10(-3) ). For the African sample, a significant interaction was also detected (p = 0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineates the genetic architecture of osteoporosis.

Bone Turnover and Bone Mineral Density Are Independently Related to Selenium Status in Healthy Euthyroid Postmenopausal Women

Selenium status may have direct effects on bone and indirect effects through changes in thyroid hormone sensitivity. We hypothesized that variation in selenium status in healthy euthyroid postmenopausal women is associated with differences in bone turnover, bone mineral density (BMD) and fracture susceptibility. The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. The study was comprised of a population-based cohort from five European cities. A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1144. There were no interventions. We measured selenium (micrograms per liter); selenoprotein P (milligrams per liter); free T(4) (picomoles per liter); free T(3) (picomoles per liter); TSH (milliunits per liter); bone turnover markers; BMD; and vertebral, hip, and nonvertebral fractures. Higher selenium levels were associated with higher hip BMD at study entry (β = 0.072, P = 0.004) and lower levels of bone formation (osteocalcin: β = -0.101, P < 0.001; procollagen type 1 N-terminal propeptide: β = -0.074, P = 0.013) and resorption markers (C-telopeptide of type 1 collagen: β = -0.058, P = 0.050; N-telopeptide of type 1 collagen: β = -0.095, P = 0.002). Higher selenoprotein P was associated with higher hip (β = 0.113, P < 0.001) and lumbar spine BMD (β = 0.088, P = 0.003) at study entry, higher hip BMD after the 6-yr follow-up (β = 0.106, P = 0.001) and lower osteocalcin (β = -0.077, P = 0.009), C-telopeptide of type 1 collagen (β = -0.075, P = 0.012), and N-telopeptide of type 1 collagen (β = -0.110, P < 0.001). Selenium status is inversely related to bone turnover and positively correlated with BMD in healthy euthyroid postmenopausal women independent of thyroid status.