low-BMD Group Research Articles

Osteoporosis and Endplate Damage Correlation Using a Combined Approach of Hounsfield Unit Values and Total Endplate Scores: A Retrospective Cross-Sectional Study.

PurposeOsteoporosis and endplate damage, two primary orthopedic disorders that have adverse effects on the quality of life of older adults, may have some previously unknown relationship. The purpose of this study was to determine the potential association between osteoporosis and endplate damage with two specific imaging scoring systems and analyze the underlying mechanisms.Patients and MethodsA cross-sectional study including 156 patients with degenerative disc disease (DDD) who visited our department in 2018 was performed. Data including age, sex, body mass index, Hounsfield unit (HU) values utilizing computed tomography (CT), and total endplate scores (TEPSs) using magnetic resonance imaging (MRI) of all patients were retrospectively collected and analyzed. The average HU value and TEPS of L1–L4 were used to represent the degrees of bone mineral density (BMD) and endplate damage, respectively. Patients with an HU value < 110 were defined as having osteoporosis and placed in the low-BMD group; otherwise, they were placed in the normal-BMD group. Multivariate logistic regression models were used to determine the independent factors of endplate damage.ResultsThe TEPSs in the low-BMD group were significantly higher (6.4 ± 1.6 vs 5.0 ± 0.9, p < 0.001) overall and in every segment of L1–L4 (p < 0.01). A significant negative correlation was found between TEPS and HU values (p < 0.001). The HU value (odds ratio [OR] 0.221; 95% confidence interval [CI], 0.148–0.295, p < 0.001), age (OR 0.047; 95% CI, 0.029–0.224, p < 0.001), and BMD (OR 3.796; 95% CI, 2.11–7.382, p < 0.05) were independent factors influencing endplate damage.ConclusionA significantly positive correlation was observed between osteoporosis and endplate damage, indicating the requirement for a more comprehensive therapeutic regimen for treating patients with DDD complicated with osteoporosis.

Impact of serum magnesium and bone mineral density on systemic fractures in chronic hemodialysis patients.

IntroductionBone mineral density (BMD) measured with dual-energy X-ray absorptiometry (DXA) can be used to predict fractures, but its clinical utility has not been fully established in chronic kidney disease (CKD) patients. Magnesium is an essential trace element. Although magnesium is associated with the risk of fractures in non-CKD populations, the relationship is unknown in CKD patients.MethodsBMD and serum magnesium levels were measured in 358 stable outpatients undergoing maintenance hemodialysis therapy. The primary outcome was fragility fracture. Patients were divided into groups according to the median level of magnesium and the normal threshold value of lumbar spine BMD.ResultsDuring the median follow-up period of 36 months, 36 (10.0%) fractures occurred. The cumulative incidence rates of fractures were 17.6% and 5.2% [adjusted hazard ratio (aHR) 2.31, 95% confidence interval (CI) 1.03–5.17, P = 0.030] in the lower (<2.6 mg/dL) and higher (≥2.6 mg/dL) magnesium (Mg) groups, respectively, and 21.2% and 7.3% (aHR 2.59, 95% CI 1.09–6.16, P = 0.027) in the low- and high-BMD groups, respectively. The lower-Mg and low-BMD group had a 9.21-fold higher risk of fractures (95% CI; 2.35–47.00; P = 0.0010) than the higher-Mg and high-BMD group. Furthermore, adding both magnesium levels and lumbar spine BMD levels to the established risk factors significantly improved the prediction of fractures (C-index: 0.784 to 0.830, p = 0.041).Discussion/ConclusionsThe combination of serum magnesium and lumbar spine BMD can be used for fracture risk stratification and synergistically improves the prediction of fractures in CKD patients.

Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic.

This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range. Data were collected from February 2016 to October 2018 for 41 patients (n=20 in the HPP group, n=21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging. Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43IU/L or less and PLP level of 120nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases. This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.

Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women

IntroductionWe investigated the relationship between gut microbiota composition and osteoporosis/fracture risk in Japanese postmenopausal women using 16S rRNA gene sequencing, FRAX, bone mineral density, biochemical bone parameters, and a self-administered questionnaire. Variation in abundance of specific microbiota was found to be significantly associated with fracture risk and vitamin K levels.Gut microbiota data with respect to bone metabolism and fracture risk is limited. Vitamin K is produced by certain intestinal bacteria and has been reported to play a role in maintaining bone quality.PurposeWe investigated relationships among gut microbiota composition, bone metabolism, and fracture risk in postmenopausal Japanese women.MethodsBone mineral density (BMD) was evaluated in 38 postmenopausal women (mean age 62.9 years) using forearm dual-energy X-ray absorptiometry. We collected and analyzed serum bone turnover markers (vitamin K fraction and tartrate-resistant acid phosphatase 5b; TRACP-5b), gut microbiota profiling (16S rRNA gene sequencing), and self-administered questionnaire data, including fracture history and vitamin K intake. Vitamin K2, BMD, and TRACP-5b data were divided into high- and low-level groups using cutoff values of 0.06 ng/mL, 87.05%, and 420 mU/dL, respectively; the proportions of bacteria were analyzed. Fracture incidence and relative risk were investigated for each bacterium.ResultsThe genus Bacteroides was predominant in the high vitamin K2 group (29.73% vs 21.58%, P = 0.022). Fracture incidence was significantly higher in the low Bacteroides group, with a 5.6-times higher risk ratio of fracture history.The family Rikenellaceae was more abundant in the low BMD group and more abundant in the high TRACP-5b group (2.15% vs 0.82%, P = 0.004; 2.38% vs 1.12%, P = 0.013, respectively).ConclusionBacteroides and Rikenellaceae may be involved in bone metabolism and fracture risk. Further investigations of the underlying microbiota-related pathways in bone metabolism may reveal treatment strategies, and facilitate the prevention of osteoporosis.

A Multi-Omic Analysis for Low Bone Mineral Density in Postmenopausal Women Suggests a RELATIONSHIP between Diet, Metabolites, and Microbiota.

The effect of microbiota composition and its health on bone tissue is a novel field for research. However, their associations with bone mineral density (BMD) have not been established in postmenopausal women. The present study investigates the relation of diet, the microbiota composition, and the serum metabolic profile in postmenopausal women with normal-BMD or with low-BMD. Ninety-two Mexican postmenopausal women were classified into normal-BMD (n = 34) and low-BMD (n = 58). The V4 hypervariable region was sequenced using the Miseq platform. Serum vitamin D was determined by chemiluminescence immunoassay. Serum concentrations of acyl-carnitines and amino acids were determined by electrospray tandem mass spectrometry. Diet was assessed by a food frequency questionnaire. The low-BMD group had fewer observed species, higher abundance of γ-Proteobacteria, lower consumption of lycopene, and lower concentrations of leucine, valine, and tyrosine compared with the normal-BMD group. These amino acids correlated positively with the abundance of Bacteroides. Lycopene consumption positively correlated with Oscillospira and negatively correlated with Pantoea genus abundance. Finally, the intestinal microbiota of women with vitamin D deficiency was related to Erysipelotrichaceae and Veillonellaceae abundance compared to the vitamin D non-deficient group. Associations mediated by the gut microbiota between diet and circulating metabolites with low-BMD were identified.

Association Between Serum Ferritin Levels and Low Bone Mineral Density in Postmenopausal Osteoporosis Women

As women go through menopause, serum estrogen decreases, and ferritin increases. Ferritin is an essential component of the body, but many studies have stated that ferritin, which exceeds the normal physiological range, may potentially cause health problems in women. The aim of this study is to investigate the relationship between bone mineral density and serum ferritin levels in post-menopausal women and to evaluate serum ferritin levels as a potential biomarker for postmenopausal osteoporosis. Serum ferritin levels were measured in 62 postmenopausal women with low bone mineral density, and in 18 postmenopausal healthy control women using a standardized Enzyme-Linked Immune Sorbent Assay (ELISA) kit. Bone mineral density BMD was assessed at the lumbar spine and femoral neck. The mean serum ferritin level was significantly higher in the postmenopausal women with low BMD group (group 1) than in the normal control group (group 2), respectively (mean=262.69 vs. 181.44 ng/ml, (P&lt;0.05), and serum ferritin level was negatively correlated with BMD among low BMD postmenopausal women's group (R= -0.628, P=0.0001), and in the healthy postmenopausal group (R= -0.052, P=0.838). A comparison of the BMD between spine and femur neck sites shows that the frequency of low BMD in the spine site is higher than the femur neck site. Our findings show that increased serum ferritin levels were associated with low bone mineral density in postmenopausal osteoporosis.

Low selenium levels are associated with decreased bone mineral densities

PurposeOsteoporosis has a high worldwide prevalence and detrimental consequences (e.g., increased fracture risk). The amount of bone mineral in bone tissue (i.e., bone mineral density [BMD]) is most widely used indicator of osteoporosis in clinical medicine. Selenium is an essential micronutrient for animals and humans. It is a cofactor for antioxidant enzyme reduction (e.g., glutathione peroxidase). It also enhances immune surveillance and modulates cell proliferation. Study findings on the associations between BMD and selenium levels are inadequate and contradictory. The purpose of this study was to examine the associations between hair selenium levels and lumbar spine and femur BMD values. MethodsUsing a cross-sectional study design, we assessed the associations between hair selenium levels and BMD values in 1,167 Korean adults who underwent a health check-up. Each subject was assigned to one of two groups based on BMD (normal group [T-score ≥ -1.0] or low BMD group [T-score < -1.0]). The associations between hair selenium levels and the risk for low BMD were estimated using multivariate logistic regression models. ResultsStudy participants with lower hair selenium levels were older and had higher phosphorous, alkaline phosphatase, and osteocalcin levels. They also had lower BMDs, corrected serum calcium levels, uric acid levels, and creatinine clearance. Participants with low BMDs had significantly lower hair selenium levels (P < 0.001). After adjusting for osteoporosis-related risk factors, the risk of a low BMD was significantly greater for the lower hair selenium quartile groups (P = 0.045). ConclusionIn conclusion, this study found that lower hair selenium levels were associated with low BMD values, independent of the other osteoporosis risk factors examined. Further prospective studies are warranted to determine the role of selenium in the development of osteoporosis.

Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS).

ABSTRACTWorldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture‐related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI‐adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD (N = 98) and highest adjusted BMD (N = 110) were chosen for exome sequencing. Controls (N = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low‐ or high‐BMD subjects with controls for single‐gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers‐Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single‐gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low‐BMD subjects compared with controls (p = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low‐BMD subjects compared with controls (p = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene‐panel approach to screen for multivariant associations in larger cohorts. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Gut microbiota composition and bone mineral loss-epidemiologic evidence from individuals in Wuhan, China.

Gut microbiota plays important roles in human health and associates with a number of diseases. However, few studies explored its association with bone mineral loss in human. We collected 102 fecal samples from each eligible individual belonging to low-BMD and control groups for high-throughput 16S rRNA gene sequencing. The low-BMD individuals had a smaller number of OTUs and bacterial taxa at each level. At the phylum level, Bacteroidetes were more abundant in the low-BMD group; Firmicutes were enriched in the control group; Firmicutes and Actinobacteria positively correlated and Bacteroidetes negatively correlated with the BMD and T-score in all subjects. At the family level, the abundance of Lachnospiraceae in low-BMD individuals reduced and positively correlated with BMD and T-score; meanwhile, BMD increased with increasing Bifidobacteriaceae. At the genus level, low-BMD individuals had decreased proportions of Roseburia compared with control ones (P < 0.05). Roseburia, Bifidobacterium, and Lactobacillus positively correlated with BMD and T-score. Furthermore, BMD increased with rising abundance of Bifidobacterium. Functional prediction revealed that 93 metabolic pathways significantly differed between the two groups (FDR-corrected P < 0.05). Most pathways, especially pathways related to LPS biosynthesis, were more abundant in low-BMD individuals than in control ones. Several taxa with altered abundance and specific functional pathways were discovered in low-BMD individuals. Our findings provide novel epidemiologic evidence to elucidate the underlying microbiota-relevant mechanism in bone mineral loss and osteoporosis.

Functional relevance for associations between osteoporosis and genetic variants.

Osteoporosis is characterized by increased bone loss and deterioration of bone microarchitecture, which will lead to reduced bone strength and increased risk of fragility fractures. Previous studies have identified many genetic loci associated with osteoporosis, but functional mechanisms underlying the associations have rarely been explored. In order to explore the potential molecular functional mechanisms underlying the associations for osteoporosis, we performed integrative analyses by using the publically available datasets and resources. We searched 128 identified osteoporosis associated SNPs (P<10−6), and 8 SNPs exert cis-regulation effects on 11 eQTL target genes. Among the 8 SNPs, 2 SNPs (RPL31 rs2278729 and LRP5 rs3736228) were confirmed to impact the expression of 3 genes (RPL31, CPT1A and MTL5) that were differentially expressed between human subjects of high BMD group and low BMD group. All of the functional evidence suggested the important functional mechanisms underlying the associations of the 2 SNPs (rs2278729 and rs3736228) and 3 genes (RPL31, CPT1A and MTL5) with osteoporosis. This study may provide novel insights into the functional mechanisms underlying the osteoporosis associated genetic variants, which will help us to comprehend the potential mechanisms underlying the genetic association for osteoporosis.

A serum metabolomics-based profile in low bone mineral density postmenopausal women

Osteoporosis is characterized as a metabolic disorder of bone tissue, and various metabolic markers are now available to support its diagnosis and evaluate treatment effects. Substances produced as end products of metabolomic activities are the correlated factors to the biological or metabolic status, and thus, metabolites are considered highly sensitive markers of particular pathological states, including osteoporosis. Here we undertook comprehensive serum metabolomics analysis in postmenopausal women with or without low bone mineral density (low BMD vs controls) for the first time using capillary electrophoresis/mass spectrometry. Among the metabolites tested, 57 were detected in sera. Levels of hydroxyproline, Gly-Gly and cystine, differed significantly between groups, with Gly-Gly and cystine significantly lower in the low BMD group and hydroxyproline, a reported marker of osteoporosis, significantly higher. Levels of TRACP5b, a bone resorption marker, were significantly higher in the low BMD group, supporting the study's validity. Taken together, our findings represent novel metabolomic profiling in low BMD in postmenopausal women.

Increased migration of uncemented acetabular cups in female total hip arthroplasty patients with low systemic bone mineral density

Background and purpose — Low bone mineral density (BMD) may jeopardize the initial component stability and delay osseointegration of uncemented acetabular cups in total hip arthroplasty (THA). We measured the migration of uncemented cups in women with low or normal BMD.Patients and methods — We used radiostereometric analysis (RSA) to measure the migration of hydroxyapatite-coated titanium alloy cups with alumina-on-alumina bearings in THA of 34 female patients with a median age of 64 (41–78) years. 10 patients had normal BMD and 24 patients had low systemic BMD (T-score ≤ −1) based on dual-energy X-ray absorptiometry (DXA). Cup migration was followed with RSA for 2 years. Radiographic follow-up was done at a median of 8 (2–10) years.Results — Patients with normal BMD did not show a statistically significant cup migration after the settling period of 3 months, while patients with low BMD had a continuous proximal migration between 3 and 12 months (p = 0.03). These differences in cup migration persisted at 24 months. Based on the perceived risk of cup revision, 14 of the 24 cases were “at risk” (proximal translation of 0.2 to 1.0 mm) in the low-BMD group and 2 of the10 cases were “at risk” in the normal-BMD group (odds ratio (OR) = 8.0, 95% CI: 1.3–48). The radiographic follow-up showed no radiolucent lines or osteolysis. 2 cups have been revised for fractures of the ceramic bearings, but none for loosening.Interpretation — Low BMD contributed to cup migration beyond the settling period of 3 months, but the migrating cups appeared to osseointegrate eventually.

MiR-422a as a potential cellular microRNA biomarker for postmenopausal osteoporosis.

BackgroundMicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis.Methodology/Principal FindingsWe used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression.Conclusions/SignificanceOur study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis.

성인 남성에서 5년간의 골밀도 변화 관찰

성인 남성들이 2002년부터 2006년 까지 건강검진을 받기위해 대학병원을 내원한 성인 남성 80명을 개인별 골밀도를 5년간 관찰하여 분석하였다. 연구 대상자 성인 남성 80명의 평균연령은 <TEX>$43.15{\pm}4.82$</TEX>세였다. 대퇴경부의 골밀도는 1차 측정에서 -0.61에 비하여 4차 및 5차 측정에서 유의하게 감소하였으며, 척추 골밀도는 1차 측정 -0.67에서 2차 측정에서 유의한 감소를 나타냈지만 3~5차 측정에서 유의한 차이를 보이지 않았다. 생활습관에 따른 음주, 흡연, 운동, 식습관에 따른 군 간의 대퇴경부 및 척추 골밀도 변화 값의 차이는 보이지 않았다. 1차 측정에서의 대퇴경부 골밀도를 기준으로 골밀도 상(<TEX>$0{\leqq}BMD$</TEX>), 중(<TEX>$-1.0{\leqq}BMD</TEX><TEX><</TEX><TEX>0$</TEX>), 하(BMD < -1.0) 집단에서 1차 측정과 5차 측정 골밀도의 차이를 비교하였을 때, 상 집단에서 대퇴경부 골밀도가 1차 <TEX>$0.67{\pm}0.76$</TEX>에서 <TEX>$0.42{\pm}0.93$</TEX>로 유의하게 감소하였다. 다른 집단에서는 전후 비교에서 유의한 차이를 보이지 않았다. 대상자들의 나이에 관계없이 젊어서부터 골밀도가 낮은 사람들은 대퇴경부 및 척추의 골밀도가 낮아 있었으며, 골밀도가 높은 사람들은 1차 측정 때부터 5차 측정 때까지 높았다. 대퇴경의 골밀도는 1차 측정에 비해 5차에서 유의한 감소를 나타내어 척추보다는 대퇴경부의 골밀도에 주의하도록 한다. To investigate the decrease of BMD by age and the risk factor of osteoporosis in Korean men. We describe the study of a five-years retrospective observational study with male patients. Eighty Korean men who visited hospital for health screening were assessed for this study from 2002 to 2006. We evaluated the BMD of the femoral neck and L-spine, and the preferences and habits in the life. The data were collected for 5 years, and we analysed the five-years change of BMD and the relations between BMD and other factors. Subjects were divided into 3 group by 1st assessment of femoral neck BMD, and were compared with each other. The age of subjects was <TEX>$43.15{\pm}4.82$</TEX> and BMD of femoral neck was <TEX>$-0.61{\pm}0.97$</TEX> and BMD of L-spine was <TEX>$-0.67{\pm}1.10$</TEX> in the first year assessment. The femoral neck BMD of 4th and 5th assessment was decreased significantly compared to that of 1st assessment. The L-spine BMD of 2nd assessment was decreased significantly compared to the 1st assessment. There was no significant correlation between the changes of BMD and preferences or habits-drinking, smoking, eating habit, exercise. The femoral neck BMD of 5th assessment was decreased significantly compared to that of 1st assessment in the high femoral neck BMD group. And there was no significant change of femoral BMD and L-spine BMD in other groups. Low BMD group in the 1st assessment showed lowest BMD in the 5th assessment and high BMD group in the 1st assessment showed highest BMD in the 5th assessment. We can guess that the young men who has low BMD could have high risk of osteoporosis when he became older. And the femoral BMD should be considered important in anticipating the changes of BMD in middle aged men.

Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data

Bone mineral density (BMD) is influenced by a complex network of gene interactions; therefore, elucidating the relationships between genes and how those genes, in turn, influence BMD is critical for developing a comprehensive understanding of osteoporosis. To investigate the role of transcriptional networks in the regulation of BMD, we performed a weighted gene coexpression network analysis (WGCNA) using microarray expression data on monocytes from young individuals with low or high BMD. WGCNA groups genes into modules based on patterns of gene coexpression. and our analysis identified 11 gene modules. We observed that the overall expression of one module (referred to as module 9) was significantly higher in the low-BMD group (p = .03). Module 9 was highly enriched for genes belonging to the immune system-related gene ontology (GO) category "response to virus" (p = 7.6 × 10(-11)). Using publically available genome-wide association study data, we independently validated the importance of module 9 by demonstrating that highly connected module 9 hubs were more likely, relative to less highly connected genes, to be genetically associated with BMD. This study highlights the advantages of systems-level analyses to uncover coexpression modules associated with bone mass and suggests that particular monocyte expression patterns may mediate differences in BMD.

In Vivo Genome-Wide Expression Study on Human Circulating B Cells Suggests a Novel ESR1 and MAPK3 Network for Postmenopausal Osteoporosis

Osteoporosis is characterized by low BMD. Studies have shown that B cells may participate in osteoclastogenesis through expression of osteoclast-related factors, such as RANKL, transforming growth factor beta (TGFB), and osteoprotegerin (OPG). However, the in vivo significance of B cells in human bone metabolism and osteoporosis is still largely unknown, particularly at the systematic gene expression level. In this study, Affymetrix HG-U133A GeneChip arrays were used to identify genes differentially expressed in B cells between 10 low and 10 high BMD postmenopausal women. Significance of differential expression was tested by t-test and adjusted for multiple testing with the Benjamini and Hochberg (BH) procedure (adjusted p </= 0.05). Twenty-nine genes were downregulated in the low versus high BMD group. These genes were further analyzed using Ingenuity Pathways Analysis (Ingenuity Systems). A network involving estrogen receptor 1 (ESR1) and mitogen activated protein kinase 3 (MAPK3) was identified. Real-time RT-PCR confirmed differential expression of eight genes, including ESR1, MAPK3, methyl CpG binding protein 2 (MECP2), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), Scr-like-adaptor (SLA), serine/threonine kinase 11 (STK11), WNK lysine-deficient protein kinase 1 (WNK1), and zinc finger protein 446 (ZNF446). This is the first in vivo genome-wide expression study on human B cells in relation to osteoporosis. Our results highlight the significance of B cells in the etiology of osteoporosis and suggest a novel mechanism for postmenopausal osteoporosis (i.e., that downregulation of ESR1 and MAPK3 in B cells regulates secretion of factors, leading to increased osteoclastogenesis or decreased osteoblastogenesis).

Serum and urine markers of bone metabolism during the year after hip fracture.

As part of a larger study to describe indices of recovery during the year after hip fracture, the current prospective study investigated longitudinal changes in serum and urine markers of bone metabolism for the year after hip fracture and related them to bone mineral density (BMD). A representative subset of participants provided serum and urine samples and had bone density measured at 3, 10, 60, 180, and 365 days postfracture. Two Baltimore hospitals. The subjects were 205 community-dwelling, white women age 65 and older with fresh proximal femur fractures. Samples were assayed for specific bone-related proteins and bone turnover markers, including serum osteocalcin (OC), procollagen type 1 carboxy-terminal extension peptide (PICP), bone-specific alkaline phosphatase (BAP), and urinary deoxypyridinoline (DPD) cross-links. Selected hormonal regulators of bone metabolism, including parathyroid hormone (PTH), calcitonin (CT), 1,25-dihydroxy vitamin D(3) (1,25 (OH)(2)D), and estrone (E(1)) were measured from serum samples. Repeated measures analyses were used to evaluate postfracture changes in each of the markers. BAP, OC, and PICP were most active during the early postfracture period (3-60 days). BAP and OC remained elevated at 365 days compared with 3 days. DPD rose 48% from 3 days to 60 days, but this difference was not statistically significant. PTH and 1,25 (OH)(2)D increased steadily and significantly from 3 to 365 days. E(1) was highest at baseline and decreased at each time point, whereas CT showed no significant changes. When subjects were stratified into high-, medium-, and low-BMD groups based on their measurement at 3 days, both osteoclastic and osteoblastic markers in the low-BMD group displayed exaggerated and different patterns over time compared with the other groups. Currently, the standard treatment of care for hip fractures still results in high morbidity and mortality and failure to regain prefracture quality of life. Gaining an understanding of bone cell activity in these patients after hip fracture, derived by measuring markers longitudinally during recovery, provides a baseline by which to measure the effectiveness of new interventions to improve recovery from hip fracture.

Serum and urine markers of type I collagen metabolism in elderly women with high and low bone mineral density.

The serum markers of bone formation (carboxy-terminal propeptide of type I collagen, PICP) and resorption (pyridinoline cross-links containing telopeptide of type I collagen, ICTP), as well as urinary resorption markers, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), were studied in 78-year-old women with high (n = 18) and low (n = 17) bone mineral density (BMD) measured from the calcaneus and tibia. The low-BMD group had higher values for PICP (P = 0 center dot 025), Pyr (P = 0 center dot 001) and Dpyr (P < 0 center dot 001) than the high-BMD group. No inverse relationship between these markers and BMD was, however, observed within the study groups. ICTP, Pyr and Dpyr correlated with each other in both groups and with PICP in the high-BMD group. Higher levels of both the formation and resorption markers of type I collagen suggest an increased rate of bone turnover and remodelling in osteopenic elderly women.

Estimation of structural and geometrical properties of cortical bone by computerized tomography in 78-year-old women

The structural and geometrical properties of the tibia shaft were investigated at two sections by means of computerized tomography (CT) in 78-year-old women with high (n = 19) and low (n = 17) calcaneal bone mineral density (BMD, g/cm3) previously measured by 125I-photon absorption. The high BMD group had a 20-21% higher tibial BMD and 9-12% higher bone cross-sectional area than was observed in the low BMD group. The distribution of bone mass indicated that the low BMD group had lost bone mainly from the endosteal surface, especially in the anterior part of the tibia. However, both groups had a similar basic pattern of mass distribution at the measured sections. The high BMD group had higher moments of inertia at the upper section than the low BMD group. The differences between the groups were more pronounced when only the high density areas were included. At the lower section, the differences between the groups also appeared significant at the high density levels. There were no group differences in the area moments of inertia. The results suggest that the true distribution of bone mass should be taken into account in determining the moments of inertia. In the tibia, determination of the cross-sectional mass distribution of bone combined with BMD should have a better discriminatory capability than BMD only in studying bone strength and fracture risk.

Bone mineral density in postmenopausal elderly women with type 2 diabetes

We measured lumbar bone mineral density (L2-4 MBMD) in the postmenopausal elderly diabetic women and made comparisons with age-matched controls in terms of the age, body mass index (BMI) and % BMD of age-matched. In addition we evaluated the correlation between BMD and menarche age, menopause age, HbA1c, serum calcium, serum phosphate, serum alkaline phosphatase (S-Alp) and the ratio of urine calcium to urine creatinine (UCa/Cr). Moreover we divided non-insulin dependent diabetic patients (NIDDM) into two groups; the high BMD group and the low BMD group. Serum Alp and the ratio of UCa/Cr were compared in these two groups. The relationships between regimen of therapy and BMD were also analyzed in female NIDDM. There were no significant differences of BMD and background factors between controls and NIDDM. The ratio of UCa/Cr in the high BMD group were significantly less than that in low BMD group (p < 0.05). BMD in NIDDM with retinopathy was lower, but not significantly, than that in NIDDM without retinopathy. The methods of therapy for NIDDM such as diet alone, an oral hypoglycemic agent and insulin did not influence BMD in elderly postmenopausal diabetics. These results indicated that BMD in elderly postmenopausal diabetics are dependent on UCa/Cr and retinopathy.