Article

Vitamin D Receptor Gene Polymorphisms Are Associated with the Risk of Fractures in Postmenopausal Women, Independently of Bone Mineral Density

September 2005
The Journal of Clinical Endocrinology and Metabolism 90(8):4829-35

September 2005
90(8):4829-35

DOI:10.1210/jc.2005-0364

Source
PubMed

Authors:

Patrick Garnero

University of Lyon

Elisabeth Sornay-Rendu

French Institute of Health and Medical Research

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Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. A prospective population-based cohort was studied. A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. The study measured incidents of vertebral and nonvertebral fractures. VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.

Vitamin D Receptor Gene Polymorphisms Affect Osteoporosis-Related Traits and Response to Antiresorptive Therapy

Article

Full-text available

Jan 2023

The present study analyzed the effect of vitamin D receptor (VDR) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, raloxifene, and ibandronate) in 356 postmenopausal women from Slovakia. Association analysis revealed a significant effect of BsmI polymorphism on lumbar spine BMD, serum osteocalcin (OC), and β-CrossLaps levels. While ApaI and Cdx2 polymorphisms were associated with OC and alkaline phosphatase, TaqI polymorphism affected all turnover markers. ApaI, TaqI, and BsmI genotypes increased the risk of spinal, radial, or total fractures with odds ratios ranging from 2.03 to 3.17. Each of therapy types evaluated had a beneficial effect on all osteoporosis-related traits; however, the VDR gene affected only ibandronate and raloxifene treatment. ApaI/aa, TaqI/TT, and BsmI/bb genotypes showed a weaker or no response to ibandronate therapy in femoral and spinal BMD. The impact of aforementioned polymorphisms on turnover markers was also genotype dependent. On the contrary, only TaqI and BsmI polymorphisms influenced raloxifene therapy, even only in lumbar spine BMD. These results point to the potential of using the VDR gene in personalized pharmacotherapy of osteoporosis.

Influence of BsmI polymorphism in vitamin D receptor gene on the risk of fracture in Caucasian populations: a meta analysis

Article

Mar 2015
Int J Clin Exp Med

To gain combined risk estimates for the BsmІ polymorphism in vitamin D receptor (VDR) gene associated with the risk of fractures in Caucasian population. We performed a meta-analysis and extracted 15 eligible publications by searching the databases of Medline, EMBASE and CNKI. Summary odds ratio (OR) with 95% confidence interval (CI) was estimated by using fixed-effects model. The inconsistency index (I(2)) was performed to evaluate heterogeneity. Begg's funnel plots and Egger's test were used to assess publication bias. A total of 15 available studies including 5,570 subjects (1,912 cases and 3,658 controls) were included in the meta-analysis. No overall association was observed between the BsmI polymorphism in VDR gene and the susceptibility to fracture under all genetic models. When stratifying by fracture type, we did not find any significant risk, either. But in the subgroup analysis by source of control, the results from population-based groups suggested the BsmI polymorphism was associated with the increased fracture susceptibility (ORBB vs. bb = 1.22, 95% CI = 1.01-1.48, P heterogeneity = 0.912; ORB vs. b = 1.10, 95% CI = 1.00-1.20, P heterogeneity = 0.921). Our meta-analysis provides evidence that the BsmI polymorphism in VDR gene may not be associated with the susceptibility to fracture in Caucasian populations. Our findings need to be further confirmed in future larger and well-designed studies.

[Association of polymorphism TaqI of vitamin de receptor with bone mineral density in young Mexican women]

Article

Full-text available

Oct 2012
NUTR HOSP

Introduction: Osteoporosis is a multifactorial disease characterized by a low bone mineral density (BMD). Osteoporosis and the occurrence of fractures in postmenopausal women have been associated to the TaqI polymorphism in the vitamin D receptor (VDR) gene. Objective: To analyze the association of the different genotypes of TaqI polymorphism of the VDR gene with BMD in young Mexican women. Methods: Dual X-ray absorptiometry was carried out in 150 women aged 19 to 29 years in order to determine their total bone mineral density (tBMD) and dual BMD of the femur (dfBMD). DNA was extracted from peripheral blood to determine the genotype of the TaqI polymorphism in the VDR gene. The data obtained were analyzed by simple linear regression and ANOVA. Results: Mean tBMD was 1.096 ± 0.064 mean dfBMD was 0.960 ± 0.107 g/cm². The frequency of the TaqI polymorphisms was 57% (TT), 37% (Tt) and 6% (tt), the frequency of the alleles was 75% (T) and 25% (t). Ths statistical analysis showed a lack of association between BMD and the genotypes of TaqI polymorphism in the VDR gene. Discussion and conclusions: These results suggest that may exist factors other than the TaqI polymorphism in the VDR gene contributing to BMD in young women from Northern Mexico.

Evaluation of Association Studies and an Updated Meta-Analysis of VDR Polymorphisms in Osteoporotic Fracture Risk

Article

Full-text available

Jan 2022

Background: Several studies have examined the association between vitamin D receptor (VDR) polymorphisms and osteoporotic fracture risk; however, the results are not uniform. Furthermore, many new articles have been published, and therefore, an updated meta-analysis was performed to further explore these issues. Objectives: The aim of the study was to investigate the association between VDR, BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and osteoporotic fracture risk. Methods: The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between VDR BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and the risk of osteoporotic fracture. We also used the false-positive reporting probability (FPRP) test and the Venice criteria to evaluate the credibility of the statistically significant associations. Results: Overall, this study found that the VDR ApaI and BsmI polymorphisms significantly increased the risk of osteoporotic fracture in European countries and America, respectively. However, when sensitivity analysis was performed after excluding low-quality and Hardy–Weinberg disequilibrium (HWD) studies, it was found that only individuals with the double-mutated genotype have an increased risk of osteoporotic fracture in European countries. In addition, when the credibility of the positive results was assessed, it was found that the positive results were not credible. Conclusion: This meta-analysis indicates that there may be no significant association among the polymorphisms of VDR BsmI, ApaI, TaqI, FokI, and Cdx2 and the risk of osteoporotic fracture. The increased risk of osteoporotic fracture is most likely due to false-positive results.

Least-detectable and age-related local in vivo bone remodelling assessed by time-lapse HR-pQCT

Article

Full-text available

Jan 2018
PLOS ONE

We previously developed an image analysis approach for the determination of local sites of bone remodelling using time-lapse in vivo HR-pQCT. The involved image filtering for removing noise was chosen rather aggressively, and also removed some effects of the bone remodelling. In this paper, we quantify these filtering settings using ex vivo reproducibility HR-pQCT images, and determine the least-detectable bone remodelling using in vivo reproducibility HR-pQCT images, as well as testing whether the approach is capable of capturing age-related bone remodelling by use of in vivo long-term HR-pQCT images. We found that a threshold value of 225 mg HA/cm³ for the filtering led to acceptable results with falsely determined bone remodelling of less than 0.5%, and that the least-detectable bone formation and bone resorption are 2.0 ± 1.0% and 2.2 ± 0.7% respectively. We also found that age-related local bone remodelling can be captured satisfactorily in postmenopausal women. The latter revealed new insights into the effect of ageing on bone remodelling, and showed that bone remodelling seems to take place through a few small formation packets and many large resorption volumes leading to a net bone loss. We conclude that local in vivo bone remodelling can be successfully assessed with time-lapse in vivo HR-pQCT capable of assessing age-related changes in bone remodelling.

Polymorphism of some genes of bone tissue metabolism (VDR Bsm1 c.IVS7G>A, LCT 13910 T>C, COL1A 12046 G->T) among the representatives of Russian and Buryat nationalities

Article

Full-text available

May 2017

Aim: to study the frequency of genotypes of the polymorphous markers of bone remodeling (vita-min D receptor gene Bsm1 c.IVS7G> A, the lactase gene LCT 13910 T> C and collagen gene COL1A 12046 G-> T) in healthy people and patients with osteopo-rosis (OP) among the indigenous population of Trans-baikalia of Russian and Buryat nationalities. Methods: 97 women with OP were examined: 49 Russian and 48 Buryat women aged from 50 to 80 years. 123 healthy women of the same age group were included in the control group. DNA sam-ples for molecular genetic analysis were taken from peripheral venous blood. Results: The recessive allele A of the VDR – Bsm1c.IVS7G> A polymorphism was accumulated in women of Buryat nationality, but the statistical significance was not observed (OR = 1.04, CI [0 68, 1.6]). C al-lele of LCT -13910 T> C polymorphism was associated with the development of OP among the representa-tives of Buryat nationality. Conclusion: The gene allele VDR Bsm1 c.IVS7G> Aand the LCT -13910 T>C leads to a higher risk of OP in women of Buryat nationality. The genotypes G/Tand T/T of COL1A12046 G-> T are associated with the development of OP in people of both nationalities.

Polymorphism of vitamin D3 receptor and its relation to mineral bone density in perimenopausal women

Article

Full-text available

Nov 2014

Postmenopausal osteoporosis is the most common metabolic bone disease with important genetic factors. We evaluated the frequency of polymorphism 283G/A of the vitamin D3 VDR gene receptor. The study included 800 women at the postmenopausal (505) and reproductive (295) age. Statistically significant changes, depending on the genotype, were shown. Postmenopausal osteoporosis is the most common metabolic bone disease of strong genetic origin with population variability determined by the interaction of genetic and environmental factors. Recognition of different genetic variants underlying development of osteoporosis would make it possible to administer individual symptomatic treatment as well as early prophylactics of osteoporosis. The aim of the study was to evaluate the frequency of polymorphism 283G/A of the vitamin D3 VDR gene receptor and assessment of its relations with the clinical parameters of osseous turnover and degree of postmenopausal osteoporosis. The study included 800 women at the postmenopausal (505) and reproductive (295) age throughout the Wielkopolska region in Poland. The postmenopausal group included women with osteoporosis and osteopenia and the healthy ones. Women at the reproductive age were healthy. Frequency of the tested gene polymorphism was evaluated in the group where bone mineral density (BMD) was marked and in the control group. The obtained test results pointed to correlation of polymorphism VDR 283G/A with the BMD scores for the lumbar vertebrae in women with osteopenia and osteoporosis, therefore the ones at risk of fractures. Vitamin D receptor (VDR) polymorphism correlated with reduced BMD values. Polymorphism 283G/A of the vitamin D3 receptor gene has been proved to be the genetic factor of postmenopausal osteoporosis. The polymorphism mentioned above has been proved to be a factor of mineral bone density changes of women.

Desnutrición, Sobrepeso, Obesidad y Osteoporosis. Criterios para el diagnóstico biofísico población adulta.

Book

Full-text available

Jan 2008

Carmen Margarita Santos-Hernández

Guia de Practica Clinica para diagnostico biofisico de la Desnutricion,sobrepeso, obesidad y osteoporosis. El incremento de la esperanza de vida se comporta como un elemento acondicionador del mayor peso en algunas patologías dentro de las cifras de morbimortalidad en el adulto mayor. La pirámide poblacional con un modelo estacionario, sumado a la alta sobre vivencia de los cubanos llevará a uno de los procesos de envejecimiento más rápidos y profundos del continente americano y del mundo. De cada 10 muertes que ocurren en Cuba, casi 8 se producen en personas mayores de 60 años. Este grupo de población ha de ser más del 20 % de la población cubana en el 2015. Las características de la esperanza de vida entre los indicadores de salud y de ingreso y escolarización han llevado a nuestro país a ocupar un lugar dentro de los países de mayor desarrollo según un informe de la Organización de Naciones Unidas. Clinical Practice Guide for biophysical diagnosis of Denutrition, overweight, obesity and osteoporosis. The increase in life expectancy behaves as a conditioning element of greater weight in some pathologies within the figures of morbidity and mortality in the elderly. The population pyramid with a stationary model, added to the high survival rate of Cubans will lead to one of the fastest and deepest aging processes in the Americas and the world. Of every 10 deaths that occur in Cuba, almost 8 occur in people over 60 years old. This population group must be more than 20% of the Cuban population in 2015. The characteristics of life expectancy among the health and income indicators and schooling have led our country to occupy a place within the countries of greater development according to a report by the United Nations.

Composición corporal y masa ósea criterios de referencia para diagnóstico biofísico de desnutrición, obesidad, y osteoporosis población adulta.

Book

Jan 2012

Carmen Margarita Santos-Hernández

Introduction and objectives. The objectives of the work are to build a reference to assess the nutritional status in the diagnosis of malnutrition, obesity, osteopenia and osteoporosis from densitometry tools in four anatomical sites and total bodies of a selected population of 1397 women and 549 healthy men among the ages from 20 to 70 years, obtained during the years 1998 to 2007 in the City of Havana. Material and methods. Measurements of densitometry of x-ray of double beam of photons are made by DEXA Lunar equipment bone densitometer of x-ray DPX-IQ, version 4.6 ba: lumbar vertebrae (anterior-posterior), neck of femur, triangle of Ward, trochanter and total body . Comparative analysis of bone density (gm / cm2), declination (%), relative ratios according to height of the measurement day, bone mineral concentration, lean mass (Kg.) Fatty tissue (Kg.) And adiposity ratio (fatty tissue / lean mass) and the body mass index (BMI) according to age, sex, ancestral affinity1, variance and percentile distributions and differences with some reference populations. The frequency of malnutrition, obesity and osteoporosis risk is evaluated according to the criteria of the World Health Organization and cut-off sites identified in the indigenous young female and male population, presenting limits of distribution and normality in percentiles, means and standard deviation, as a whole and subdivided according to ancestral origin. * The safety and risk criteria are applied in 707 patients treated in hospitals of the City of Havana, during that period. The data was processed by the SPSS Software Package version 13.0 for Windows

Differences in Chronic Low-Grade Inflammation and Metabolic Disturbances between VDR Genotypes in an Ethnically Homogenous Postmenopausal Female Population from Poland

Article

Full-text available

Jun 2023

(1) Vitamin D deficiency and changes in the endocrine system may stimulate systemic inflammation. VDR expression and the vitamin D concentration decrease with age, which is important in postmenopausal women for whom estrogen deficiency causes rapid bone loss. This group is, moreover, particularly at risk of developing atherosclerosis and its adverse consequences, such as chronic inflammation. The aim of this study was to assess the differentiation by the VDR genotype of the risk factors for so-called chronic low-grade inflammation and metabolic disorders. (2) We studied the differences between the anthropometric, metabolic, and inflammation parameters of VDR genotypes for Apa-I, Bsm-I, Fok-I, and Taq-I in a sample of 321 women aged 50–60 from an ethnically homogeneous urban population in Poland. (3) The TT Taq-I genotype presented a significantly higher rate of insulin resistance (HOMA) and lower serum levels of adiponectin than the other two genotypes. The AA genotype of the Bsm-I polymorphism was associated with a more atherogenic serum profile and significantly higher LDL and LDL/HDL values and Castelli Index. (4) Chronic low-grade inflammation was associated with the TT Taq-I genotype and presented a higher rate of insulin resistance. The AA genotype of the Bsm-I polymorphism presented a more atherogenic serum lipid profile and, therefore, a higher risk of developing cardiovascular disease.

The Effect of Caffeine on Calcitriol-Inducible Vitamin D Receptor-Controlled Gene Expression in Intestinal and Osteoblastic Cells

Article

Full-text available

Dec 2019
CALCIFIED TISSUE INT

Some epidemiological studies suggested caffeine consumption as the cause for bone mineral density loss. Certain genes involved in this process are regulated by vitamin D receptor (VDR). Therefore, we investigated if caffeine can affect inducible expression of VDR-regulated genes, some of them being involved in bone mineralization process. By employing reporter gene assay, polymerase chain reaction, and western blotting, we monitored the VDR activity and expression in cell cultures of intestinal (LS180), osteosarcoma (HOS), and normal human osteoblasts in vitro. While caffeine stimulated calcitriol-inducible VDR-dependent nanoluciferase activity in stable reporter cell line IZ-VDRE (derived from LS180), it rather modulated mRNA levels of target genes, like CYP24A1, BGLAP, SPP1, and TNSF11 in LS180 and HOS cells. However, caffeine significantly decreased calcitriol-inducible CYP24A1, TNSF11, and SPP1 transcripts in osteoblasts. This decrease had non-linear U-shaped profile. Our in vitro data demonstrate biphasic action of caffeine on the expression of certain calcitriol-inducible VDR-regulated genes in normal human osteoblasts.

Addressing Bone Quality and Bone Density After Renal Transplantation. A Prospective Evaluation of the Evolution of Trabecular Bone Score and Bone Mineral Density over the first five years following renal transplantation in Asian Patients

Article

Full-text available

Jul 2019

Trabecular Bone Score (TBS) and Bone Mineral Density (BMD) evolution over the 1st 5‐years after renal transplantation was prospectively evaluated in 164 patients. Dual Energy X‐Ray Absorptiometry (DXA) scans were performed at 0, 6, 12, 24 and 60 months. Cumulative steroid dose, serum 25(OH)D, calcium, parathyroid hormone, and total ALP levels at these time points were checked. Incident fractures were identified from X‐rays/Vertebral Fracture Assessments. Mean(SD) Age, TBS and Lumbar Spine BMD at baseline were 47.11(9.53), 1.424(0.097) and 0.935(0.183) gm/cm2 respectively. Baseline TBS was lower in tertiary (1.38(0.07) vs secondary hyperparathyroidism (1.43(0.01) vs post parathyroidectomy (1.46(0.11); p=0.035. TBS and BMD significantly decreased from baseline‐>6 months, changes after that at consecutive time‐points were non‐significant. 11% had incident fractures during the follow‐up period, majority being metatarsal with no vertebral or hip fractures noted. This first prospective evaluation of TBS and BMD evolution at multiple time‐points over 5‐years suggest that microarchitectural and bone density deteriorations post‐renal transplantation stabilize after 6 months. Stabilization of these parameters could partially account for the absence of major fractures noted in this Asian population. Possible genetic and ethnic differences in fracture‐risk between Asian and Caucasian renal transplant patients have to be explored through large population‐based studies. This article is protected by copyright. All rights reserved.

Clinical characteristics associated with bone mineral density improvement after 1-year alendronate/vitamin d3 or calcitriol treatment: Exploratory results from a phase 3, randomized, controlled trial on postmenopausal osteoporotic women in China

Article

Full-text available

Aug 2018

Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO). In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis. In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (β = −0.00084, P < .01), dietary calcium (β = −0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (β = −0.000469, P = .0016), but positively with body mass index (BMI) (β = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (β = 0.0023, P = .02), baseline P1NP (β = 0.00035, P = .0067), history of prior vertebral fracture(s) (β = 0.034, P < .0001) and baseline serum 25(OH)D level (β = −0.00083, P = .02). The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.

Associations between VDR Gene Polymorphisms and Osteoporosis Risk and Bone Mineral Density in Postmenopausal Women: A systematic review and Meta-Analysis

Article

Full-text available

Jan 2018

Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDR ApaI, VDR FokI and PMOP susceptibility. Subgroup analysis showed that VDR ApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDR BsmI and VDR FokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying the ApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women with FokI Ff genotype. PMOP women with the Cdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.

Study of Vitamin D Receptor Gene Polymorphisms in Egyptian Patients with Primary Osteoporosis

Article

Full-text available

Jan 2015

Osteoporosis is a common skeletal disease characterized by a generalized reduction in bone mineral density (BMD), architectural deterioration of bone tissue and increased risk of fracture. Primary osteoporosis is the most common type and is more frequent in postmenopausal women caused by severe decrease in serum estrogen levels after cessation of the ovarian function. A genetic contribution to the pathogenesis of osteoporosis has been recognized. One of the first genes to be studied for its association with osteoporosis is that for the Vitamin D receptor (VDR). To investigate the association of four polymorphisms (TaqI, ApaI, BsmI, FokI); characterized by the ability to distinguish between different polymorphisms by digestion with the restriction endonucleases; of VDR gene to BMD and to estimate the frequencies of those different polymorphic genotypes in a study population. In a pilot study, sixty five Egyptian women with primary osteoporosis were selected according to measurements of DEXA test. In addition, thirty women who did not suffer of any skeletal disorder were also included in the study as control subjects. Genomic DNA was extracted from peripheral blood leukocytes using the salting out procedure. Polymerase chain reaction –restriction fragment length polymorphism (PCR-RFLP) was performed to identify the VDR genotype of the four chosen polymorphic loci. We found a close association of specific genotypes of the four studied polymorphisms in the VDR gene with low BMD in Egyptian patients with primary osteoporosis. Based on the data obtained in this study as well as several other community-specific profiles, the four selected polymorphisms of the VDR gene were proved to be reliable, simple, cheap and non-invasive markers to detect susceptibility to osteoporosis, thus lead to better management of primary osteoporosis cases and reduce or delay the pathogenic consequences of the disease.

Targeted Next Generation Sequencing of the Entire Vitamin D Receptor Gene Reveals Polymorphisms Correlated with Vitamin D Deficiency among Older Filipino Women With and Without Fragility Fracture

Article

Dec 2016

This study aimed to discover genetic variants in the entire 101 kB vitamin D receptor (VDR) gene for vitamin D deficiency in a group of post-menopausal Filipino women using targeted next generation sequencing (TNGS) approach in a case–control study design. A total of fifty women with and without osteoporotic fracture seen at the Philippine Orthopedic Center were included. Blood samples were collected for determination of serum vitamin D, calcium, phosphorus, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and as primary source for targeted VDR gene sequencing using the Ion Torrent Personal Genome Machine. The variant calling was based on the GATK best practice workflow and annotated using Annovar tool. A total of 1496 unique variants in the whole 101 kb VDR gene were identified. Novel sequence variations not registered in the dbSNP database were found among cases and controls at a rate of 23.1% and 16.6% of total discovered variants, respectively. One disease-associated enhancer showed statistically significant association to low serum 25-hydroxy vitamin D levels (Pearson chi square p-value=0.009). The transcription factor binding site prediction program PROMO predicted the disruption of three transcription factor binding sites in this enhancer region. These findings show the power of TNGS in identifying sequence variations in a very large gene and the surprising results obtained in this study greatly expand the catalogue of known VDR sequence variants that may represent an important clue in the emergence of vitamin D deficiency. Such information will also provide the additional guidance toward a personalized nutritional advice to reach a sufficient vitamin D status.

Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women

Article

Full-text available

Feb 2016

Introduction: Many studies have suggested that the vitamin D receptor polymorphism BsmI might be associated with the risk of osteoporosis development in post-menopausal women. However, the results have been inconsistent. The aim of this meta-analysis was to derive a more precise evaluation of the relationship. Material and methods: Published literature from PubMed, EMBASE and the CNKI database was searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association. Results: Ten case-control studies were included with a total of 1,403 osteoporosis cases and 2,144 healthy controls. In the overall analysis, no significant association was found between BsmI polymorphism and osteoporosis risk (BB vs. bb: OR = 0.76, 95% CI = 0.39-1.48; BB vs. Bb: OR = 0.90, 95% CI = 0.71-1.15; dominant model: OR = 1.20, 95% CI = 0.74-1.93; recessive model: OR = 0.83, 95% CI = 0.53-1.30). In the subgroup analysis by ethnicity, the results showed similar result that BsmI polymorphism m had no association with osteoporosis. Conclusions: Results from the current meta-analysis suggest that vitamin D receptor BsmI polymorphism may not be a risk factor for osteoporosis in post-menopausal women.

Pharmacogenomics of Osteoporosis-Related Bone Fractures

Chapter

Aug 2013

Osteoporosis is a systemic skeletal disease characterised by low bone mass and deterioration in the microstructure of bone tissue, which causes bone fragility and consequent increase in fracture risk. The lifetime fracture risk of a patient with osteoporosis is as high as 40 %, and fractures most commonly occur in the hip, spine or wrist. From a patient’s perspective, a fracture and the subsequent loss of mobility and autonomy often represent a major drop in the quality of life. Additionally, osteoporotic fractures of the hip and spine carry a 12-month excess mortality of up to 20 %, because they require hospitalisation and they subsequently present enhanced risk of other complications, such as pneumonia or thromboembolic disease due to chronic immobilisation.

Erdal 2008 Turk J Med Sci VDR

Data

Full-text available

Sep 2015

Erdal 2008 Turk J Med Sci VDR

Data

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Aug 2015

Vitamin D Receptor (VDR) Gene Polymorphisms (FokI, BsmI) and their Relation to Vitamin D Status in Pediatrics βeta Thalassemia Major

Article

Full-text available

May 2015

Vitamin D is critical for calcium, phosphate homeostasis and for mineralization of the skeleton, especially during periods of rapid growth. Vitamin D Deficiency leads to rickets (in children) and osteomalacia (in adults). Expression and activation of the vitamin D receptor (VDR) are necessary for the effects of vitamin D, in which several single nucleotide polymorphisms have been identified especially (FokI, BsmI). In this study serum 25 (OH) vitamin D3 levels were estimated by Enzyme Linked Immunosorbent Assay [ELISA], VDR (FokI, BsmI) gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism assay [PCR–RFLP].Serum levels of calcium, phosphorus, alkaline phosphatase and ferritin were determined in 50 Pediatrics beta thalassemia major patients and 60 controls. Patients had significantly lower serum calcium (p

Odnos polimorfizma gena za vitamin-D receptor, alfa-1 lanac kolagena I i estrogeni receptor i koštane mase u bolesnika s hipertireozom [The association of polymorphisms of the vitamin-D receptor gene, collagen type I alpha-1 gene and estrogen receptor gene and bone mineral density in patients with hyperthyroidism]

Article

Full-text available

Jun 2008

Jozo Jelcic

A Polymorphism at the Translation Start Site of the Vitamin D Receptor Gene Is Associated with the Response to Anti-Osteoporotic Therapy in Postmenopausal Women from Southern Italy

Article

Full-text available

Mar 2015
INT J MOL SCI

The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized.

Relationship of the Vitamin D Receptor and Collagen Iα1 Gene Polymorphisms with Low Bone Mineral Density and Vertebral Fractures in Postmenopausal Turkish Women

Article

Dec 2011

Aytün Efesoy

Objectives: This study aims to investigate (i) the frequencies of the vitamin D receptor (VDR) gene and collagen Iα1 (COL Iα1) gene polymorphisms and (ii) whether there is a relation between the Bsm1 polymorphisms in the VDR gene, and the Sp1 polymorphisms in the COL Iα1 gene and low bone mineral density (BMD), and vertebral fractures in postmenopausal Turkish women. Patients and methods: A hundred postmenopausal Turkish women (mean age 63.4±8.7 years; range 48 to 86 years) who were admitted to our polyclinic for the diagnosis or treatment of osteoporosis were included in this study. The study population was divided into three groups according to the T score value based on BMD measurements. Patients with a T score of >-1.0 formed the control group (n=30). In addition, patients with a T score of <-1.0−>-2.5 formed the osteopenic group (n=30), and those with a T score of <-2.5 formed the osteoporotic group (n=40). The Bsm1 (B/b) polymorphism in the VDR gene and the Sp1 (S/s) polymorphism in the COL Iα1 gene were detected by two parallel polymerase chain reactions and subsequent hybridization. Bone mineral density of the lumbar spine and femur were measured by dual-energy X-ray absorptiometry. Results: The genotype frequencies of the Bsm I (B/b) polymorphism in the VDR gene and the Sp1 (S/s) polymorphism in the COL Iα1 gene were not statistically different among the three study groups. Additionally, no significant difference was found between the patients with vertebral fracture and the patients without fracture in terms of the BB, Bb, and bb genotypes of the VDR gene or in terms of the SS, Ss, and ss genotypes of the COL Iα1 gene. Conclusion: Our findings showed that the Bsm1 polymorphism of the VDR gene and the Sp1 polymorphism of the COL Iα1 gene were not associated with low BMD or vertebral fractures in postmenopausal Turkish women.

Association of vitamin D receptor BsmI gene polymorphism with risk of low bone mineral density in post-menopausal women: A meta-analysis

Article

Oct 2014
GENET MOL RES

The vitamin D receptor BsmI gene polymorphism is reportedly associated with low bone mineral density (BMD) in postmenopausal women, but results from previous studies are conflicting. In the present study, we investigated the association between this polymorphism and the risk of low BMD through a meta-analysis of published studies. A literature search of the Pubmed, Embase, and CNKI databases from inception through July 2013 was conducted. The meta-analysis was performed using the STATA 12.0 software. Crude odds ratios with 95% confidence intervals were used to assess the strength of any association. Eleven case-control studies were included for a total of 1468 low BMD cases and 2177 healthy controls. No significant variation in low BMD risk was detected in any of the genetic models. Further stratified analyses were performed to examine the effect of ethnicity. In the subgroup analysis, no significant association was found in Caucasians and in Asians. The meta-analysis results suggest that the BsmI polymorphism is not associated with low BMD risk in postmenopausal women.

Osteoporosis and Oxidative Stress – Role of Antioxidants

Chapter

Full-text available

Jun 2014

Osteoporosis is a systemic metabolic bone disorder characterized by a decrease of bone strength with fragility fracture. There are only a few studies performed on oxidative stress as a risk factor linked to osteoporosis (OP). This chapter discusses the role of different factors involved in OP and in particular the role of oxidative stress (OS) in this disease. Moreover, our aim is extended to show the role of antioxidants in the prevention of OP. In general, many factors such as vitamin D, parathyroid hormones, genetic mutations in coding genes of vitamin D receptor and nitric oxide synthase, as well as environmental pollution with cadmium and/or polychlorinated biphenyls are involved in the development of OP. Mutations or polymorphism of nitric oxide (NO) synthase genes increase susceptibility of many subjects to OP through changes in both bone mass gain and regulation of signal factors involved in bone turnover. Moreover, NO itself changes bone remodeling signals and bone loss since administration of nitroglycerin and nitrates (NO donors) decreases bone resorption and increases both bone mineral density and bone formation through inhibition of the osteoclastic cells activities. OS is generated as a result of excessive production of free radicals (FR) and reactive oxygen species (ROS), which provoke oxidative damage to different biomolecules. Oxidative stress has been linked with aging and many other chronic degenerative diseases including OP. This damage can be counteracted by antioxidant systems which could be enzymatic or nonenzymatic. Administration of antioxidant vitamins has a remarkable influence in decreasing levels of OS and show a beneficial effect on bone quality in various experimental models. Bone healing was accelerated in patients with long-bone fractures after administration of multivitamins (Vitamin A, C, E) and selenium compared to those who did not receive any supplements through decreasing OS and free radical levels. Moreover, vitamin K, C, or B deficiencies are modifiable risk factors for OP. Therefore, improving antioxidant vitamins status could help in the treatment and prevention of OP especially in elderly people.

Vitamin D Receptor Gene Polymorphisms and Bone

Article

Jan 2005
CIRCULATION

Y. Fang

Genetic epidemiology of osteoporosis across four microsatellite markers near the VDR gene

Article

Jul 2013

The large amount of positive genetic association data in a number of bone diseases suggests functional consequences of Vitamin D receptor (VDR) gene polymorphism. In the present study, four microsatellite markers viz., D12S1633, D12S1635, D12S347, and D12S96, that lie in the vicinity of the VDR gene on chromosome 12 were selected to assess the allele distribution pattern and diversity among three groups of individuals - normal, osteopenia and osteoporosis. Genetic association study was performed using allele frequency data. Total genomic DNA was isolated from the whole blood of 226 individuals, after recording their bone mineral density (BMD) using Dual X-ray absorptiometry (DXA). All DNA samples were subjected to multiplex Polymerase Chain Reaction (PCR) - genotyping. Allele frequencies and genetic diversity parameters like - number of alleles, average variance and average heterozygosity across all the four markers among three groups were computed. Effect of population stratification was excluded by investigating population structure. A trend of decreasing genetic diversity across four loci from normal to pre- and post-disease condition has been observed. Lesser recombination rate (θ) indicates linkage between studied microsatellite markers and VDR gene. Statistically significant linkage disequilibrium was detected for the allele - 22 of locus D12S96 with osteoporosis. A positive association of allele - 22 suggests susceptibility to disease whereas predominance of allele - 27 among non - diseased group implicates its association with normal bone health.

Polimorfismos del gen del receptor de vitamina D y riesgo de fractura de cadera en la mujer adulta mayor de la Región del Bío Bío

Article

Full-text available

Apr 2008
REV MED CHILE

Background: Osteoporotic hip fractures are devastating events in older women. There is a genetic modulation of bone phenotypic parameters including bone density (BMD) and bone fragility fractures. Vitamin D receptor (VDR) gene polymorphisms explain a small part of the genetic influence on BMD, whereas their effect on fractures remains uncertain. Aim: To examine the contributions of VDR genotypes to the susceptibility to hip fracture in elderly Chilean women. Patients and methods: We recruited 126 women (67 with fractures and 59 without) from Bio-Bio Region, Chile, aged 65 to 94 years. Genotyping for Bsm-l, Apa-1, Taq-1 and Fok-1 VDR polymorphisms was performed using polymerase chain reaction methods. All hip fractures were confirmed by X-ray. Results: The alíele frequencies were 0.49 for B, 0.57 for A, 0.60 for T and 0.65 for F in the Bsm-l, Apa-1, Taq-1 and Fok-1 polymorphisms respectively. The prevalence of these VDR gene polymorphisms in women with fractures were 16% BB, 69% Bb, 15% bb for Bsm-l; 30% AA, 46% Aa, 14% aa for Apa-1; 17% TT, 34 Tt, 8% tt for Taq-1 and 43%FF, 41% Ff, 16% ff for Fok-1. All VDR genotype frequencies did not differ from Hardy- Weinberg expectations. Alíele or genotype frequencies did not differ between women with or without fractures. These results did not change when analysis was adjusted by age weight, height or gynecologic history. Conclusions: The genotype frequencies of the VDR polymorphisms are in accordance with the frequencies of other Hispanic and Caucasian populations. Our results suggest that VDR polymorphisms are not associated with the risk of hip fracture in older women of this Region of Southern Chile

Association of VDR BsmI gene polymorphism, bone turnover markers and bone mineral density in severe postmenopausal osteoporosis

Article

Full-text available

Jan 2013

Abstract Currently there is no clear answer whether specific vitamin D receptor gene genotype is associated with lower bone mineral density and higher fracture risk. The aim of this study was to analyze the associations of vitamin D receptor gene BsmI polymorphisms with bone turnover markers and bone mineral density in postmenopausal women with severe osteoporosis. Patients and methods. Vitamin D, parathyroid hormone (PTH), bone turnover markers were measured by electrochemical luminescence immunoassay, polymorphism of VDR gene (BsmI) was determined using polymerase chain reaction (PCR) analysis. Bone mineral density was measured by the dual-energy X-ray absorptiometry (iDXA, GE Lunar). Differences between groups were determined using ANOVA test. Subgroup corelation analysis was also conducted. Results. In total, 73 postmenopausal women were included in this study - 28 patients with severe postmenopausal osteoporosis and 45 control persons. It was not found the significant difference of VDR BsmI genotypes between patients and controls. There were no statistically significant correlations between lumbar spine and total hip BMD and biochemical bone markers in bb or Bb genotypes either in women with severe osteoporosis or in control women. In patients with severe postmenopausal osteoporosis, the lumbar spine BMD was significantly higher in the BB genotype bearers as compared to the bb and Bb genotype bearers. In patients with severe osteoporosis bearing VDR BsmI bb genotype, the vitamin D concentration was negatively related to PTH and positively related to femoral neck BMD; PINP was positively related to s- CTX-I. Conclusions. The findings of this study suggest that VDR BsmI gene polymorphism has weak non-significant association with BMD level and severe postmenopausal osteoporosis and needs to be further analyzed. In patients with severe postmenopausal osteoporosis, the lumbar spine BMD was significantly higher in the BB genotype bearers as compared to the bb and Bb genotype bearers

Vitamin D and osteoporosis

Chapter

Jan 2024

Peter R Ebeling

The Impact of Genetic Variation Within the Vitamin D Pathway Upon Skeletal Muscle Function: A Systematic Review

Article

Full-text available

Feb 2023
J STEROID BIOCHEM

Studies in vitro have demonstrated a key molecular role for 1,25-dihydroxyvitamin D (1,25D) in skeletal muscle function, with vitamin D-deficiency (low serum 25-hydroxyvitamin D, 25D) being associated with muscle pain and weakness. Despite this, an understanding of the overall role of vitamin D in muscle health (particularly the impact of vitamin D-related genetic variants) has yet to be fully resolved, relative to more well-studied targets such as the skeleton. Thus, we aimed to review existing studies that have investigated relationships between skeletal muscle function and single nucleotide polymorphisms (SNPs) within vitamin D-related genes. A systematic review of papers published between January 2000 and June 2022 on PubMed, EMBASE and Web of Science pertaining to association between functionally relevant vitamin D receptor genetic variants and variants within genes of the vitamin D pathway and skeletal muscle function/outcomes was performed. 21 articles were included in the review for final analysis, of which 20 only studied genetic variation of the VDR gene. Of the included articles, 81% solely included participants aged ≥50 years and of the 9 studies that did not only include White individuals, only 2 included Black participants. Within the vitamin D system, the VDR gene is the primary gene of which associations between polymorphisms and muscle function have been investigated. VDR polymorphisms have been significantly associated with muscle phenotypes in two or more studies. Of note A1012G was significantly associated with higher handgrip strength, but the results for other SNPs were notably variable between studies. While the lack of definitive evidence and study heterogeneity makes it difficult to draw conclusions, the findings of this review highlight a need for improvements with regards to the use of more diverse study populations, i.e., inclusion of Black individuals and other people of colour, and expanding research scope beyond the VDR gene.

Vitamin D receptor gene polymorphisms and spinal muscular atrophy

Article

Aug 2022

Vitamin D receptor gene polymorphisms have been intensively studied in relation with many diseases, including neurodegenerative disorders. We investigated the relationship between VDR polymorphisms and spinal muscular atrophy type I, a common lower motor neuron disease. Forty clinically and molecular diagnosed patients and 54 healthy subjects were analyzed PCR-RFLP method. We found an association trend (p=0.01) for the BsmI polymorphism taken individually and a significant association for two of four-locus inferred haplotypes (fBAt and fbaT). Also, baT, Bat and bAT were the most frequent estimated haplotypes in our control group, which is in accordance with previous published reports for Caucasian populations. We concluded that future studies performed in order to identify possible modifier genes for spinal muscular atrophy disease should take into consideration the involvement of vitamin D receptor gene polymorphisms

Title: Vitamin D Receptor Bsm I Polymorphism and Osteoporosis Risk in postmenopausal women: A Meta-Analysis from 42 Studies

Preprint

Full-text available

Sep 2020

Objective: This study aimed to quantitatively summarize the evidence for VDR BsmI gene polymorphism and osteoporosis risk in postmenopausal women. Materials and Methods: The PubMed, EMBASE, Weipu, CNKI, and Wanfang database were searched for eligible studies. Case-control studies containing available genotype frequencies of B/b were chosen, and Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. Results: 4485 osteoporosis and 5490 controls were identified in our meta-analysis. In the stratified analysis, a significant association was observed between VDR BsmI gene polymorphism and osteoporosis susceptibility in Caucasians (additive model: OR=0.809, 95% CI 0.678~0.965, p=0.019, recessive model: OR=0.736, 95% CI 0.568~0.955, p=0.021, and co-dominant model: bb vs. BB OR=0.701, 95% CI 0.511~0.962 p= 0.028), and we failed to find any significant relationship in Asians. Conclusion: The present meta-analysis suggests that VDR BsmI genotype is associated with increased risk of postmenopausal osteoporosis in Caucasians but not in Asians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between VDR BsmI polymorphism and osteoporosis in postmenopausal women.

Vitamin D receptor Bsm I polymorphism and osteoporosis risk in postmenopausal women: a meta-analysis from 42 studies

Article

Full-text available

Dec 2020
GENES NUTR

Objective This study aimed to quantitatively summarize the evidence for VDR BsmI gene polymorphism and osteoporosis risk in postmenopausal women. Materials and methods The PubMed, EMBASE, Weipu, CNKI, and Wanfang databases were searched for eligible studies. Case-control studies containing available genotype frequencies of B/b were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. Results 4485 osteoporosis and 5490 controls were identified in our meta-analysis. In the stratified analysis, a significant association was observed between VDR BsmI gene polymorphism and osteoporosis susceptibility in Caucasians (additive model: OR = 0.809, 95% CI 0.678~0.965, p = 0.019; recessive model: OR = 0.736, 95% CI 0.568~0.955, p = 0.021; and co-dominant model: bb vs. BB OR = 0.701, 95% CI 0.511~0.962 p = 0.028), and we failed to find any significant relationship in Asians. Conclusion The present meta-analysis suggests that VDR BsmI genotype is associated with increased risk of postmenopausal osteoporosis in Caucasians but not in Asians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between VDR BsmI polymorphism and osteoporosis in postmenopausal women.

Vitamin D receptor (VDR) gene FokI, BsmI, ApaI, and TaqI polymorphisms and osteoporosis risk: a meta-analysis

Article

Full-text available

Dec 2020

Background Osteoporosis is a disease of the bones in which the density of the bones decreases. The prevalence of this disease greatly varies in different populations of the world. Numerous studies have been investigated VDR gene polymorphisms as osteoporosis risk in different ethnic groups. In present meta-analysis, the aim is to find out the role of VDR gene polymorphisms ( Fok I, Bsm I, Apa I, and Taq I) in osteoporosis risk. Methods Suitable case-control studies for present meta-analysis were retrieved from four electronic databases. Open Meta-Analyst program was used for statistical analyses. Results Studies investigated Bsm I (65 studies; 6880 cases/8049 controls), Apa I (31 studies; 3763 cases/3934 controls), Fok I (18 studies; 1895 cases/1722 controls), and Taq I (26 studies; 2458 cases/2895 controls) polymorphisms that were included in the present meta-analysis. A significant association was found between the dominant model of Fok I (OR ff + Ffvs.FF = 1.19, 95% CI = 1.04–1.36, p = 0.01, I ² = 39.36%) in the overall analysis and recessive model of the Caucasian population of Taq I polymorphism (OR TT + Ttvs.tt = 1.35, 95% CI = 1.11–1.63, p = 0.002, I ² = 50.07%) with osteoporosis. On the other hand, no such effect is found in any other genetic models and in any other gene polymorphisms of the overall analyses or sub-group analyses. Conclusion In conclusion, the authors found that the dominant model of Fok I in the overall analysis and recessive model of Taq I in the Caucasian population are significantly associated with the development of osteoporosis.

Vitamin D receptor (VDR) gene FokI, BsmI, ApaI and TaqI polymorphisms and osteoporosis risk: a meta-analysis

Preprint

Full-text available

Oct 2019

Osteoporosis is a bone disease characterized by low bone density. The prevalence of osteoporosis varies between different populations and ethnic groups. Numerous studies have investigated the relationship between VDR gene polymorphisms and osteoporosis across ethnic populations. Present meta-analysis aims to comprehensively evaluate the influence of common FokI, BsmI, ApaI and TaqI VDR gene polymorphisms and osteoporosis. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible studies and all statistical calculations were performed by Open Meta-Analyst software. Studies investigated BsmI (65 studies; 6,880 case/ 8,049 control), ApaI (31 studies; 3,763 case/ 3,934 control), FokI (18 studies; 1,895 case/ 1,722 control), and TaqI (26 studies; 2,458 case/ 2,895 control) polymorphisms were included in the present meta-analysis. Results of meta-analysis revealed significant association between dominant model of FokI (ORff+Ff vs. FF= 1.19, 95% CI= 1.04-1.36, p= 0.01, I2= 39.36%) in overall analysis and recessive model of Caucasian population of TaqI polymorphism (ORTT+Tt vs. tt= 1.35, 95% CI= 1.11-1.63, p= 0.002, I2= 50.07%). While no such effect is found in any other genetic model in any other gene polymorphisms of the overall analyses or sub-group analyses. In conclusion, we found the FokI polymorphism is associated with osteoporosis in overall analysis, also the TaqI polymorphism is a risk factor for the Caucasian population.

Association of vitamin D receptor gene polymorphism with a bone mineral density level in postmenopausal women

Article

Full-text available

Jul 2019

The analysis of association of polymorphic variants of the vitamin D receptor gene ( VDR ) with bone mineral density (BMD) values in menopausal women was performed. The study included 66 patients with postmenopausal osteoporosis (PMO group) and 170 postmenopausal women with normal BMD values (CON group). The statistically significant diﬀerence between the analyzed groups in the genotypes and the alleles frequency distribution for the VDR ApaI gene variant was revealed: for the carriers of C/C genotype, the risk of osteoporosis was higher compared to individuals with A/A genotype (OR = 2.7 [95 % CI: 1.5–4.7], p = 0.002). Allele A was overrepresented in the CON group and associated with the reduced risk of disease (OR = 0.6 [95 % CI: 0.4–0.8], p = 0.001). Statistically significant diﬀerences were found between the studied groups when analyzing VDR BsmI gene variant distribution. For the individuals with the unfavorable VDR BsmI G/G-genotype, the risk of PMO was significantly higher when compared to the carriers of the A/A-genotype (OR = 2.1 [95 % CI: 1.0–4.4], p = 0.02). For the bearers of A-allele, the risk of osteoporosis was significantly lower (OR = 0.6 [95 % CI: 0.4–0.9], p = 0.007). Among the carriers of the VDR ApaI C/C-genotype, the average BMD level was by 13.7 % lower compared to the carriers of the VDR ApaI A/A-genotype (0.767 and 0.872 g/cm ² , respectively, p = 0.04); among individuals with the TaqI C/C-genotype, the BMD level was by 13.8 % lower compared to TaqI T/T-genotype bearers (0.803 and 0.914 g/cm2, respectively, p = 0.03). VDR gene polymorphism may play an important role in the susceptibility to osteoporosis and is significantly associated with the BMD level in postmenopausal women.

Osteobiology of Aging

Chapter

Mar 2018

The goals of this chapter will be to give a brief overview of bone biology, describe the molecular mechanisms of bone remodeling and pathologic uncoupling, and provide a general survey of the multiple pathways leading to aging bone and osteoporosis.

성인 남녀의 VDR FokI 유전자다형성과 근력 및 골강도와의 관련성 Association between the VDR FokI Polymorphism, Muscle Strength and Bone Strength in Male and Female Adults

Article

Full-text available

Aug 2017

1]. 골의 건강과 밀접한 관련이 있는 비타민 D는 칼슘과 인 산염의 항상성 조절 역할을 하는 것으로 잘 알려져 있으며, 비타민 D 수용체(vitamin D receptor, VDR)와 복합체를 형성하여 그 효과를 중 재 할 수 있다. 특히, 칼슘과 인산염 모두 골 대사에 관여하기 때문에 초기 유전학 연구의 대부분은 VDR 유전자다형성과 골밀도(BMD) 사 이의 관련성에 초점을 두었고, 유전적 결정요인으로 간주되어 연구가 진행되어 오고 있다[2]. 그럼에도 불구하고 VDR 유전자다형성과 골밀 도의 관련성이 유전자형마다 다르고 관련성도 연구 결과마다 차이가 있어 명확한 결론을 내리지 못하고 있다[3-7]. VDR 유전자는 12q 염색체에 위치하며, 엑손 8과 9 사이의 인트론에 존재하는 BsmI 유전자다형성을 포함하여 엑손 2에 존재하는 FokI 유 전자다형성(restrition length polymorphism) 등의 다양한 대립형질 변 PURPOSE: The purpose of this study was to investigate the relationship between the VDR Fok I gene polymorphism and basic physical fitness including bone strength (calcaneus) in male and female adults. METHODS: FokI VDR polymorphisms were genotyped in 191 men (36.7±12.3 years) and 218 women (33.5±12.1 years). Basic physical fitness (50 m run, handgrip strength, back strength, push-up, sit-up) and body weight were measured and analyzed using ANOVA. RESULTS: No association was found between the VDR FokI genotypes and bone strength (calcaneus) including body mass in men and women. However, the handgrip strength (HGS) was 5.2-6.7% higher in women with the FF and Ff FokI genotype than in women with the ff genotype (p<.05, p<.05, respectively). CONCLUSIONS: Female VDR FokI FF homozygotes and Ff heterozygotes showed higher HGS than ff homozygotes. On the other hand, there was no statistically significant difference in both handgrip and back strengths for male, but both VDR FokI FF and Ff genotypes showed higher tendency than ff genotype. Therefore, the VDR FokI gene polymorphism is considered to be a useful candidate gene especially reflecting female muscle strength.

Dalle evidenze alla pratica clinica: emorragia del tratto digestivo superiore, pancreatite acuta, sepsi ed osteoporosi. Il contributo dei giovani internisti FADOI

Article

Full-text available

Nov 2016

p class="titolo"> Gestione del paziente con sanguinamento dal tratto digestivo superiore di origine non varicosa: dall’evidenza alla pratica clinica M. Zippi, C. Marzano, M. Frualdo, L. Mucci, M. Zanon, C. Cassieri, P. Gnerre, P. Crispino La gestione del paziente con pancreatitie acuta: dalle evidenze alla pratica clinica Gruppo Giovani: C. Cenci, T. Restuccia, P. Gnerre, I. Chiti, L. Betti Gruppo Ecografia: M. Micati, C. Tana La gestione del paziente settico: dall’evidenza in letteratura alla pratica clinica R. Gerloni, L. Mucci, C. Casati, A. Crociani, O. Para, E. Benetti, P. Gnerre, A. Bovero, E. Romagnoli, N. Tarquinio, C. Canale, D. Brancato, L. Massarelli, S. Piras Management del paziente con osteoporosi: dall’evidenza alla pratica clinica I. Ambrosino, A. Riccardo, P. Gnerre, L. Castelnovo, R. Muscariello, M. Vacante </p

Vitamin D receptor gene BsmI polymorphism and bone phenotypes in the region of Central Moravia

Article

Jan 2012

In recent years, results of studies in exposed families or association projects have supported the significant role of heredity in the etiology of osteoporosis. In the description of clinical manifestations of osteoporosis, various surrogate bone phenotypes have been used, including bone mineral density of the lumbar spine and femur, hip geometry, microarchitecture, bone turnover markers and skeletal fractures. The relationship between BsmI polymorphism of the vitamin D receptor gene and bone phenotypes has been analyzed to track one of possible link between heredity and clinical manifestations of osteoporosis. This was another aim of the present study.

Genetic and environmental factors in human osteoporosis

Article

Mar 2013

Osteoporosis is a reduction in skeletal mass associated with bone micro-architectural deterioration. Often, it is most considered a bone disorder of postmenopausal women. However, younger women can also be affected. There are a lot of genetic and non-genetic risk factors, contributing to the development of osteoporosis. The aim of this study is to determinate the prevalence of known polymorphisms, associated to osteoporosis in different healthy postmenopausal women from Sub Saharan to Mediterranean areas. Moreover a control group of Mediterranean women with documented osteoporosis was also included in this study. From the analysis of these results and comparing the life habits of these women, it has been possible to identify some characteristics which influence the appearance of this debilitating disease (bone fracture in all districts) with devastating health and economic consequences. The statistical analysis of allele frequencies showed that the Vitamin D receptor (VDR B) polymorphism was significantly lower in healthy African women with respect to healthy Mediterranean (P < 0.001) and osteoporotic Mediterranean (P< 0.01) women. The estrogens receptor (ER X) allele frequency was significantly lower in both healthy African and healthy Mediterranean than in osteoporotic Mediterranean women (P< 0.001). In contrast, the estrogens receptor (ER P) allele frequency was significantly lower only in healthy when compared to osteoporotic Mediterranean women (P <0.01). The calcitonin receptor (CTR T) in healthy African and Mediterranean women was significantly lower than in Mediterranean osteoporotic women (P < 0.001). The collagen type 1 (Colia 1) polymorphism did not show statistical significant differences among the three studied groups. In conclusion, the multivariate analysis, once the social characteristics have been taken into account, demonstrated that both physical activity and healthy diet, associated with a outside work and bone densitometry monitoring are the best prognostic factors for this severe diseases.

Vitamin D and Osteoporosis

Article

May 2011

The major effects of vitamin D on the skeleton are recognized in deficiency states as the failure of normal mineralization of bone. The presence of the vitamin D receptor (VDR) in bone cells suggests direct effects on bone. These receptors are expressed in osteoblasts and in immature cells of the osteoclast precursor lineage. It was proposed some time ago that the effect of the active vitamin D metabolites on osteoclasts was indirect via osteoblasts. Treatment with the combination of calcium and vitamin D prevents bone loss and results in small increases in bone mineral density (BMD) at most sites. For long-term maintenance of BMD up to five years, the combination of calcium and vitamin D appears to be better than calcium alone. These skeletal benefits of calcium and vitamin D may be maintained at some, but not all, skeletal sites after withdrawal. However, there are no data to suggest that vitamin D alone is effective in maintaining or in increasing BMD. The addition of vitamin D to calcium is also likely to reduce the risk of falling, particularly in winter, in patients with a history of falling and vitamin D insufficiency. This may result in a reduction of falls-related fractures.

Single gene mutations and variations affecting bone turnover and strength: a selective 2006 update

Article

Dec 2006
Int Bone Miner Soc Virt J

Serge Ferrari

Osteoporosis is a bone fragility disorder with a strong genetic predisposition. Thus far, most gene variations associated with bone density, turnover and/or fractures have been identified through a candidate gene approach, which presupposes prior knowledge of the gene's function in bone biology and/or of the skeletal phenotype caused by single mutations in the gene. Here we review recent advances in the genetic defects leading to alterations in bone matrix composition; osteoblast function, including mineralization; osteoclast activity; and endocrine regulation of bone turnover and phosphate metabolism, and further summarize the genetic association studies relating common variations (polymorphisms) in these genes to BMD and fracture risk in the general population.

La influencia de algunos factores de riesgo dietéticos y genéticos y su probable asociación con la osteoporosis en una población habanera. Monografía 1er Congreso Iberoamericano de Antropología. ANTHROPOS 2007, Págs.1407-1426.ISBN 959-282-043-0

Conference Paper

Full-text available

Jan 2007

Carmen Margarita Santos-Hernández

Santos-Hernandez, C. La influencia de algunos factores de riesgo dietéticos y genéticos y su probable asociación con la osteoporosis en una población habanera. Monografía 1er Congreso Iberoamericano de Antropología. ANTHROPOS 2007, Págs.1407-1426.ISBN 959-282-043-0. (en formato digital) 1er Congreso Iberoamericano de Antropología. https://doi.org/10.1525/an.2007.48.6.37.1. ISBN 959-282-043-0; First published: 24 December 2008 https://doi.org/10.1525/an.2007.48.6.37.1 Introducción: Al componente genético se le reconoce fuerte responsabilidad en el riesgo de fragilidad ósea. Material y métodos: Se consideraron para el estudio genético 121 sujetos sanos de ambos sexos menores de 40 años de edad, según origen étnico. Se realiza análisis comparativo de densidad ósea (gm/cm2) y declinación (%), según edades, origen étnico y cocientes relativos según estatura del día de medición. mediante densitometría de haz de rayos x de doble haz de fotones por un equipo DEXA Lunar a diversos sitios anatómicos: vértebras lumbares (antero-posterior), cuello de fémur, triángulo de Ward, trocánter y cuerpo total. Se determina el genotipo de los alelos del receptor de vitamina D (VDR) realizado en 100 ng de DNA por amplificación de la región que contiene el polimorfismo asociado al gen de la vitamina D, mediante reacción en cadena de polimerasa. Se aplicó análisis de regresión lineal multivariada, como variables independientes, consumo de calcio en pubertad y en semana previa a la encuesta (mg por día), tiempo de sedentarismo (horas sentado), estatura en centímetros, edad, peso corporal (kg) y masa magra (kg). Los análisis estadísticos fueron realizados por el sistema SPSS/PC versión 13.0. Resultados y discusión: La mayor frecuencia de polimorfismo del gen del receptor de la vitamina D fue observada en identificados con la clasificación ancestral de europoide (67%) y en una menor proporción en los mestizos (33%). Los cambios según el escore t de vertebras lumbares en las mujeres tuvieron diferencias no significativas. Conclusiones: Se encuentra aparente carácter protector del mestizaje en el origen étnico en las evaluaciones de la asociación del polimorfismo y la masa ósea. Palabras claves: densidad ósea, escore t, polimorfismo, genes, vitamina D. Santos-Hernandez, C. The influence of some dietary and genetic risk factors and their probable association with osteoporosis in a Havana population. Monograph 1st Iberoamerican Congress of Anthropology. ANTHROPOS 2007, Pp. 1407-1426. ISBN 959-282-043-0. 1st Iberoamerican Congress of Anthropology. https://doi.org/10.1525/an.2007.48.6.37.1. ISBN 959-282-043-0; First published: 24 December 2008 https://doi.org/10.1525/an.2007.48.6.37.1 Introduction: The genetic component is recognized as a major contributor to the risk of bone fragility. Material and methods: 121 healthy subjects of both sexes under 40 years of age were considered for the genetic analysis., according to ethnic origin . Comparative analysis of bone density (gm/cm2) and decline (%), according to age, ethnic origin and relative ratios according to height on the day of measurement, by means of double photon beam x-ray densitometry using a Lunar DEXA equipment at various anatomical sites: lumbar vertebrae (anteroposterior), lumbar vertebrae (anteroposterior), lumbar vertebrae (anteroposterior) femoral neck, Ward's triangle, trochanter and total body. The genotype of the vitamin D receptor (VDR) alleles performed on 100 ng of DNA by amplification of the region that containing the polymorphism associated with the vitamin D gene, by polymerase chain reaction (PCR). D gene. Multivariate linear regression analysis was applied, as independent variables, calcium intake at puberty and in the week prior to the before the survey (mg per day), sedentary time (hours sitting), height in centimetres, age, body weight (kg) and body weight (kg), age, body weight (kg) and lean mass (kg). Statistical analyses were performed SPSS/PC version 13.0. Results and discussion: The highest frequency of polymorphism of the vitamin D gene polymorphism was observed in those identified with the Europoid ancestral classification (67%) and in a lower proportion in mestizos "mulattos" (33%). The changes according to lumbar vertebral score in women with non-significant differences. Conclusions: Apparent protective character of mixed race in ethnicity is found inthe evaluations of the association between polymorphism and bone mass. Multivariate linear regression analysis multivariate linear regression analysis was applied, as independent variables, calcium intake at puberty and in the week prior to the before the survey (mg per day), sedentary time (hours sitting), height in centimetres, age, body weight (kg) and body weight (kg), age, body weight (kg) and lean mass (kg). Statistical analyses were performed SPSS/PC version 13.0. Results and discussion: The highest frequency of polymorphism of the vitamin D gene polymorphism was observed in those identified with the Europoid ancestral classification (67%) and in a lower in a lower proportion in mestizos , known as "mulattos" (33%). The changes according to lumbar vertebral score lumbar vertebrae in women had non-significant differences. Conclusions: Apparent protective character of mixed race in ethnicity is found in the evaluations of the association between polymorphism and bone mass. Keywords: bone density, t-score, polymorphism, genes, vitamin D.

Vitamin D receptor gene and risk of fracture in postmenopausal women: A meta-analysis

Article

Oct 2013
CLIMACTERIC

Objective: Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and fracture risk, but evidence remains conflicting. The aim of this study was to evaluate the genetic effect of the BsmI, TaqI, ApaI and FokI polymorphisms in the VDR gene on fracture risk in postmenopausal women. Methods: Relevant studies were identified from the following electronic databases: PubMed, Embase, and Web of Science before September 2013. Statistical analysis was performed by using the software STATA 12.0. A total 1975 fracture cases and 4565 controls in 14 studies with a total of 16 eligible comparisons were identified for data analysis. Results: No evidence of relationship between the VDR BsmI, TaqI, ApaI or FokI polymorphisms and fracture risk was observed with any genetic model in postmenopausal women (BsmI: b vs. B: odds ratio (OR) 1.07, 95% confidence interval (CI) 0.90-1.29; TaqI: T vs. t: OR 0.89, 95% CI 0.68-1.15; ApaI: A vs. a: OR 0.91, 95% CI 0.76-1.08; FokI: F vs. f: OR 1.20, 95% CI 0.76-1.90). Conclusion: This meta-analysis suggests that ApaI, BsmI, TaqI and FokI polymorphisms may be not associated with the risk of fracture in postmenopausal women. Further studies in a larger sample population are required to confirm this finding.

TaqI Polymorphism of the Vitamin-D Receptor Gene and Quality of Life in Postmenopausal Turkish Women

Article

Full-text available

Feb 2008

Aim: We aimed to assess vitamin-D receptor (VDR) gene polymorphism in postmenopausal osteoporotic Turkish women as well as the impact of this on diagnosis, treatment and quality of life. Materials and Methods: Seventy postmenopausal osteoporotic women and 71 postmenopausal healthy women constituted the disease and control groups, respectively. Genomic DNA was extracted from blood of all participants and analyzed for the TaqI gene polymorphism of the VDR gene. The osteoporotic group was taking calcitonin, alendronate, calcitriol and elementary calcium, while the control group was taking only vitamin D and calcium. Quality of life of patients was measured by Nottingham Health Profile (NHP). Bone mineral density (BMD) was measured using DEXA method. Results: Genotype distribution of disease and control subjects, respectively, were as follows: TT (28.6%; 42.3%), Tt (62.8%; 40.8%), and tt (8.6%; 16.9%). Tt genotype was significantly higher in the study group (P < 0.005). There were no significant differences between the distribution of TT and tt genotypes between groups. However, BMD scores were significantly higher in the subjects with active T allele. There were also significant differences in before and after treatment NHP scores (p:0.001). Conclusions: Frequency of Tt variant was found higher in the disease group. The NHP score was significantly lower after treatment. Presence of T allele leads to higher BMD values than observed with t allele. The genetic variations with respect to polymorphism of the VDR gene may be important in determining the diagnosis, treatment outcome and quality of life in osteoporosis.

Evaluation and management of osteoporosis and fragility fractures in the elderly

Article

Dec 2009

Osteoporosis is characterized by low bone mass and microarchitectural deterioration that leads to increased bone fragility and fracture. The medical, psychosocial and economic burden that fragility fractures have on individuals and society is staggering. As the geriatric segment of the population continues to expand, so to will the magnitude of this epidemic. There are multiple mechanisms influencing bone quality and bone loss with age. Fragility fracture is a composite of multiple intrinsic and extrinsic factors related to the individual and their environment. Fall prevention remains the cornerstone of management in this problem. The FRAX® fracture risk assessment program, which estimates the 10-year probability of a major osteoporotic fracture, is an exciting new tool in assessing risk. Novel therapeutics, including zoledronic acid, strontium and teriparatide, are now available to complement proven osteoporosis treatments and more effectively decrease fracture risk in vulnerable individuals. Agents in Phase III trials, including denosumab and lasofoxifene, will probably increase the armamentarium of tools clinicians can use to combat the growing problem of osteoporosis and its complications.

Ebullition of biogenic gas bubbles from samples of near-surface peat

Article

There is evidence that peat soils are not water-saturated below the water table (e.g. Rosenberry et al. 2003; Baird and Waldron, 2003), owing to accumulations of biogenic gas bubbles, consisting of poorly-soluble gases such as CH4. It has been shown that gas bubbles can block pores and reduce rates of water flow in peat soils (Baird and Waldron, 2003). It has also been shown that, beyond certain levels, biogenic gas bubble accumulations become unstable, giving rise to large but episodic ebullition events, and that ebullition may be an important mechanism of CH4 transfer between peat soils and the atmosphere (e.g. Romanowicz et al., 1995; Rosenberry et al., 2003). However, the studies that have been done on ebullition have looked at relatively deep peat where the bubbles were apparently held below a confining layer of low hydraulic conductivity. Very little is known about the degree to which gas bubbles accumulate in near-surface peat (i.e. the upper 40 cm) and whether they accumulate to such an extent that ebullition and transfer of carbon gases to the atmosphere occur. To address this lack of knowledge we conducted experiments on eight `undisturbed' samples of near-surface (depths of c. 8 cm to 30 cm) peat taken from two lowland raised bogs, one in SW Scotland and one in W Wales. The samples were c. 10 l in volume and were incubated at 12 deg. C with the water table maintained above the sample surface. Water was allowed to flow through the samples periodically for the measurement of hydraulic conductivity (not reported here). Gas traps were fitted to the tops of the samples and the volume of gas in these was measured c. every 2-3 days. Finally, the samples were fitted with TDR probes and gas permeation samplers to measure gas volume and to take gas samples for the measurement of gas content (CH4 and CO2) using a GC. Ebullition was recorded in every sample but only after a build up of biogenic gas bubbles had occurred. We found that ebullition was not episodic and that it appeared to match gas production. The amount of ebullition varied substantially between samples. In two samples from the Scottish bog consisting respectively of Sphagnum papillosum and S. magellanicum litter, over 400 ml of gas per sample was lost over a 90-day period. At the other extreme, virtually no ebullition occurred from one of the Welsh peat samples, with only 14.5 ml being lost in 125 days. Provisional calculations based on CH4 concentrations in our gas permeation samplers suggest that CH4 efflux from the peatland surface via ebullition is potentially as important as that via diffusional transfer. We consider how transportable our data are to field conditions.

Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures

Article

Full-text available

Aug 2000

Vitamin D is essential for normal bone metabolism. Polymorphisms in exon 2, intron 8 and exon 9 of the vitamin D receptor (VDR) gene have previously been found to be associated with bone mass and bone turnover. We examined the effect of these polymorphisms, separately and in combination, on bone mineral density (BMD), bone turnover, and the prevalence of osteoporotic fractures in 192 osteoporotic patients and 207 normal controls. The four polymorphisms were determined by RFLP using Fok I (T2-C), Bsm I (intron 8), Apa I (intron 8) and Taq I (T1055-C) after PCR. We did not find any association between the Fok I polymorphism and bone mass, bone turnover or prevalence of osteoporotic fractures. We found that BB + Bb-genotypes were more frequent in patients with osteoporotic fractures (chi2 = 3.50, P = 0. 06). Furthermore, BMD of the intertrochanteric region (P < 0.0001, ANOVA) as well as the total hip (P < 0.01, ANOVA) were higher in individuals with the bb-genotype. The Apa I and the Taq I polymorphisms were not distributed differently among osteoporotic patients and normal controls. Apa I was not associated with differences in BMD. BMD of the intertrochanteric region was higher in individuals with the TT-genotype compared with individuals with the Tt- or tt-genotypes (P < 0.01, ANOVA), while no differences could be demonstrated in BMD of the lumbar spine, femoral neck, trochanter or Wards triangle. Combining the genotypes generally reflected the differences caused by the Bsm I polymorphism. We have found that the B-allele of the Bsm I polymorphism in the 3' untranslated region of the VDR was associated with low BMD at the hip, and tended to be associated with osteoporotic fractures. The translation initiation polymorphism in the VDR does not affect BMD and is not associated with osteoporotic fractures in men or women.

Genetic determinants of bone mass in adults: A twin study

Article

Full-text available

Oct 1987

The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.

Prediction of bone density from Vitamin D receptor

Article

Full-text available

Feb 1994

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Vitamin D receptor polymorphisms as a determinant of bone mass and PTH secretion: From facts to controversies

Article

Full-text available

Jun 1999

A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality

Article

Full-text available

May 2001

Osteoporosis is a common disease with a strong genetic component. We previously described a polymorphic Sp1 binding site in the COL1A1 gene that has been associated with osteoporosis in several populations. Here we explore the molecular mechanisms underlying this association. A meta-analysis showed significant associations between COL1A1 "s" alleles and bone mineral density (BMD), body mass index (BMI), and osteoporotic fractures. The association with fracture was stronger than expected on the basis of the observed differences in BMD and BMI, suggesting an additional effect on bone strength. Gel shift assays showed increased binding affinity of the "s" allele for Sp1 protein, and primary RNA transcripts derived from the "s" allele were approximately three times more abundant than "S" allele--derived transcripts in "Ss" heterozygotes. Collagen produced from osteoblasts cultured from "Ss" heterozygotes had an increased ratio of alpha 1(I) protein relative to alpha 2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2. Finally, the yield strength of bone derived from "Ss" individuals was reduced when compared with bone derived from "SS" subjects. We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality.

Identification and Fracture Outcomes of Undiagnosed Low Bone Mineral Density in Postmenopausal WomenResults From the National Osteoporosis Risk Assessment

Article

Full-text available

Dec 2001

Large segments of the population at risk for osteoporosis and fracture have not been evaluated, and the usefulness of peripheral measurements for short-term prediction of fracture risk is uncertain. To describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up. The National Osteoporosis Risk Assessment, a longitudinal observational study initiated September 1997 to March 1999, with approximately 12 months of subsequent follow-up. A total of 200 160 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis, derived from 4236 primary care practices in 34 states. Baseline BMD T scores, obtained from peripheral bone densitometry performed at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire responses; and clinical fracture rates at 12-month follow-up. Using World Health Organization criteria, 39.6% had osteopenia (T score of -1 to -2.49) and 7.2% had osteoporosis (T score </=-2.5). Age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use were associated with significantly increased likelihood of osteoporosis; higher body mass index, African American heritage, estrogen or diuretic use, exercise, and alcohol consumption significantly decreased the likelihood. Among the 163 979 participants with follow-up information, osteoporosis was associated with a fracture rate approximately 4 times that of normal BMD (rate ratio, 4.03; 95% confidence interval [CI], 3.59-4.53) and osteopenia was associated with a 1.8-fold higher rate (95% CI, 1.49-2.18). Almost half of this population had previously undetected low BMD, including 7% with osteoporosis. Peripheral BMD results were highly predictive of fracture risk. Given the economic and social costs of osteoporotic fractures, strategies to identify and manage osteoporosis in the primary care setting need to be established and implemented.

Vitamin D and Muscle Function

Article

Full-text available

Apr 2002

The aim of this review is to summarize current knowledge on the relation between vitamin D and muscle function. Molecular mechanisms of vitamin D action on muscle tissue have been known for many years and include genomic and non-genomic effects. Genomic effects are initiated by binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) to its nuclear receptor, which results in changes in gene transcription of messenger RNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a membrane-bound vitamin D receptor (VDR). Genetic variations in the VDR and the importance of VDR polymorphisms in the development of osteoporosis are still a matter of controversy and debate. Most recently, VDR polymorphisms have been described to affect muscle function. The skin has an enormous capacity for vitamin D production and supplies the body with 80-100% of its requirements of vitamin D. Age, latitude, time of day, season of the year and pigmentation can dramatically affect the production of vitamin D in the skin. Hypovitaminosis D is a common feature in elderly people living in northern latitudes and skin coverage has been established as an important factor leading to vitamin D deficiency. A serum 25-hydroxyvitamin D level below 50 nmol/l has been associated with increased body sway and a level below 30 nmol/l with decreased muscle strength. Changes in gait, difficulties in rising from a chair, inability to ascend stairs and diffuse muscle pain are the main clinical symptoms in osteomalacic myopathy. Calcium and vitamin D supplements together might improve neuromuscular function in elderly persons who are deficient in calcium and vitamin D. Thus 800 IU of cholecalciferol in combination with mg of elemental calcium reduces hip fractures and other non-vertebral fractures and should generally be recommended in individuals who are deficient in calcium and vitamin D. Given the strong interdependency of vitamin D deficiency, low serum calcium and high levels of parathyroid hormone, however, it is difficult to identify exact mechanisms of action.

Fracture incidence and association with bone mineral density in elderly men and women: The Rotterdam Study

Article

Full-text available

Feb 2004
BONE

The incidence of all non-vertebral fractures, as well as the relation to bone mineral density (BMD), was quantified in 7806 men and women from the Rotterdam Study, a prospective, population-based cohort study of men and women aged 55 years and older. In addition, the sensitivity of using a T-score at or below -2.5 for identifying subjects at risk for fractures was assessed. At baseline, between 1990 and 1993, femoral neck BMD was measured by dual energy X-ray absorptiometry (DXA). Subsequently, gender-specific T-scores were calculated using the NHANES reference population. During a mean follow-up of 6.8 years, information on incident non-vertebral fractures was gathered. In general, hip, wrist and upper humerus fractures are the most frequent fractures in both men and women. Femoral neck BMD appears to be an equally important risk factor in both genders, and is especially related to hip fractures. For all non-vertebral fractures, the age-adjusted hazard ratio (95% confidence interval) per standard deviation decrease in femoral neck BMD was 1.5 (1.4-1.6) for women and 1.4 (1.2-1.6) for men. For hip fractures, the hazard ratios were 2.1 (1.7-2.5) for women and 2.3 (1.6-3.3) for men. Only 44% of all non-vertebral fractures occurred in women with a T-score below -2.5; in men, this percentage was even lower (21%). Thus, there is a clear need for the development of more sensitive risk assessment tools, using not only BMD, but also other clinical predictors of fractures.

Genetics and biology of Vitamin D receptor polymorphisms

Article

Full-text available

Oct 2004
GENE

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.

VITAMIN-D RECEPTOR ALLELES AND PREDICTION OF BONE-MINERAL DENSITY

Article

Aug 1993

Corrigendum to “Fracture incidence and association with bone mineral density in elderly men and women: The Rotterdam Study” [Bone 34 (2004) 195–202]

Article

Apr 2006
BONE

The standard deviation (SD), derived from the NHANES reference population and used to calculate T scores, was incorrect for women. The SD used was 0.12 g/cm 2 and should have been 0.14 g/cm 2. The cutoff values for osteoporosis and osteopenia for women should therefore have been 0.69 and 0.90 g/cm 2 , respectively, instead of 0.73 g/cm 2 and 0.91 g/cm 2. However, the case made in the article is even stronger when the correct SD is used. Fewer women than described fell into the osteoporotic category and more women into the normal BMD group. The age-adjusted prevalence of osteoporosis in the Rotterdam Study was only 19.1% (it was previously published as 29.1%). Furthermore, 34% (instead of 44%) of all non-vertebral fractures occurred in women with a T score below − 2.5. That means that the T score is an even less sensitive assessment tool for predicting fractures in women. The results in men remain unchanged because the correct SD was used.

Endogenous Hormones and the Risk of Hip and Vertebral Fractures Among Older Women

Article

Feb 1999

Interaction Between the Vitamin D Receptor Gene and Collagen Type Iα1 Gene in Susceptibility for Fracture

Article

Feb 2001
J BONE MINER RES

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Iα1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The “baT ” VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0–3.3) for heterozygous carriers and 2.6 (95%CI, 1.4–5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 “reference” group (genotype GG) while in the COLIA1 “risk” group (genotypes GT and TT) the risk of fracture was 2.1 (95%CI, 1.0–4.4) for heterozygous and 4.4 (95%CI, 2.0–9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.

Genetic determinants of bone mass in adult women: A reevaluation of the Twin Model and the potential importance of gene interaction on heritability estimates

Article

Jun 2009

We estimated genetic effects on bone density in pre- and postmenopausal twins and critically considered the assumptions of the twin model. Bone mass in the radius, lumbar spine, and hip, anthropometric measurements, usual calcium and caffeine intake, tobacco and alcohol use, number of pregnancies and live births, menstrual history, usual physical activity, and medical history were measured in a volunteer sample of 171 twin pairs [124 monozygotic (MZ) and 47 dizygotic (DZ)], aged 25-80, free of diseases known to affect bone mass or mineral metabolism. At all skeletal sites, MZ intraclass correlations exceeded DZ correlations for both pre- and postmenopausal women, yielding highly significant estimates of heritability for bone mass. Adjustments for height, age, and environmental characteristics did not reduce the heritability estimates. However, many of these estimates were unrealistically high, suggesting some violation(s) of the assumptions of the twin model. Thus, the familial resemblance in bone mass is due primarily to genetic effects at all skeletal sites and at all ages, although the importance of genetic effects is diminished with aging, as evidenced by increasing within-MZ pair variability in older women. Because of failures in the assumptions of the twin model, however, particularly the greater MZ environmental similarity and the probability of gene interaction, heritability estimates are probably too high and require cautious interpretation.

Genetic Factors in Bone Turnover*

Article

May 1991

Genetic factors are major determinants of adult bone density, however, it is unknown how these effects may be mediated. Since bone mineral density is the net result of bone formation and bone resorption we studied biochemical indices of bone formation (serum osteocalcin) and resorption [fasting urinary calcium:creatinine (Ca/Crt) and hydroxyproline:creatinine (OH/Crt)] in adult female twins; 39 monozygotic (MZ) and 31 dizygotic (DZ) twin pairs (age, mean +/- SEM, MZ: 51.1 +/- 1.5 yrs; DZ: 46.5 +/- 1.5 yrs, P = NS). Of these subjects, 18 MZ twin pairs and 10 DZ twin pairs were postmenopausal. The MZ twin pair correlations (rMZ) for each index of bone turnover exceeded that between DZ pairs (rDZ), but this difference was only significant for osteocalcin (rMZ = 0.81, rDZ = 0.21, P less than 0.001). Similarly, in the postmenopausal group examined alone, the rMZ (r = 0.84) for serum osteocalcin was significantly greater than rDZ (r = -0.003, P less than 0.03). These osteocalcin data imply that 80% of the variance in serum osteocalcin could be explained by genetic factors. Although genetic effects on fasting urinary hydroxyproline:creatine and calcium:creatinine were not demonstrable, these indices may be less precise and specific. The data indicate that circulating osteocalcin, and therefore bone formation, is strongly genetically determined. These studies suggest at least one of the mechanisms of the genetic effect on bone mass relates to the regulation of bone turnover.

Heritability of bone mass: A longitudinal study in aging male twins

Article

Apr 1989

Midshaft radial bone mass was first measured from 1970 through 1972 by photon absorptiometry in 42 pairs of monozygotic (MZ) and 38 pairs of dizygotic (DZ) male Caucasian twins (age 44-55 years). The MZ intraclass correlation (rMZ) of .70 was significantly larger (P less than .05) than the DZ correlation (rDZ) of .45, providing evidence for genetic influences (Smith et al. 1973). Radial bone mass measurements repeated 16 years later (1986-87) on 25 of the MZ pairs and on 21 of the DZ pairs revealed an rMZ of .61 and an rDZ of .44, but the difference was not significant (P greater than .05). The twins had an average radial mass loss of 0.49%/year between the two examinations. The rMZ (.52) and rDZ (.49) values for the 16-year loss in radial mass were both significantly different from zero, but their similar size indicated that the correlations were due to nongenetic factors. In a search for the source of genetic influences on adult radial mass, heritability was estimated by the formula 2(rMZ - rDZ) for radial width and was found to be .66 and .76 (P less than .05) for examinations 1 and 2, respectively. An index of radial density (mass/width) was calculated, and the differences between rMZ and rDZ were not significant at either examination. The intraclass correlations (rMZ = .35; rDZ = .43) were both significant for the loss of bone density between examinations but provided no evidence for genetic influences, results similar to the findings for the loss of mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic determinants of bone mineral content at the spine and radius: A twin study

Article

Feb 1987
BONE

The possible role of genetic and/or environmental factors in determining bone mass has been investigated in 30 pairs of twins (16 monozygotic and 14 dizygotic) divided in two age groups (below and above 25 years of age). Bone mineral content was evaluated by single- and dual photon absorptiometry at the distol third of the radius for peripheral cortical bone and in the lumbar spine for the axial bone. The "within pair" variance has been used as an index of genetic influence. A significant (p less than 0.01) genetic determinant was found for the bone mass of the radius in adults and for the spinal bone mass in the age group younger than 25 years. The heritability index h2 was 0.75 for cortical BMC and 0.88 for axial BMC. Such a genetic determinant could not conclusively be demonstrated in adult twins for the spine and in youngsters for the cortical bone, suggesting that environmental factors may play a more dominant role in growth of cortical bone during adolescence and diminution of axial bone during adult life.

Vitamin D receptor alleles and rates of bone loss: Influences of years since menopause and calcium intake

Article

Jun 2009

A genetic marker for the 1,25-dihydroxyvitamin D receptor (VDR) is reported to account for much of the heritable component of bone density. It is not known whether VDR genotype influences bone accretion or loss, or how it is related to calcium metabolism. The VDR genotype was determined in 229 healthy postmenopausal women who previously participated in a calcium trial. VDR alleles were designated according to presence (b) or absence (B) of the BsmI restriction enzyme cutting site. There were 83 bb, 102 Bb, and 44 BB individuals. Two-thirds of the women took 500 mg of calcium supplement (mean calcium intake = 892 mg/day) and one-third a placebo (mean = 376 mg/day). Bone mineral density (BMD) at the femoral neck, spine, and radius were measured by dual- and single-photon absorptiometry at baseline and after 1 and 2 years. Among women more than 10 years postmenopausal, those with the BB genotype had the lowest femoral neck BMD. Rates of bone loss over 2 years were greater in the BB group at all sites (e.g., at the femoral neck, bb, 0.45 +/- 0.43; Bb, -0.01 +/- 0.40; BB, -0.99 +/- 0.50%/year; BB vs. bb, p = 0.01), and this trend was found both in women < 10 years since menopause (e.g., at the radius, bb, 0.43 +/- 0.47; Bb, -0.37 +/- 0.42; BB, -1.20 +/- 0.59% per year; BB vs. bb, p = 0.02) and those > or = 10 years (radius, bb, -0.71 +/- 0.41; Bb, 0.08 +/- 0.39; BB, -1.41 +/- 0.49% per year; BB vs. Bb, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of a high prevalence of the BB Vitamin D receptor genotype in severely osteoporotic women

Article

Aug 1995

Studies of twins strongly suggest that more than 50% of the peak spinal bone density is determined by genetics. It was reported recently that this genetic effect is primarily determined by vitamin D receptor (VDR) alleles; specifically, a VDR genotype termed BB has been highly associated with low peak bone density. Homozygotes for the second VDR allele, bb, are associated with high peak bone density. If peak bone density is an important determinant of osteoporosis and if the VDR genotype is an important determinant of peak bone density, then patients with severe osteoporosis should have a high prevalence of the BB VDR genotype compared with that of control subjects. To test this hypothesis, we used Southern blot analysis to determine the VDR genotype of 41 Caucasian patients (72 +/- 14 yr) with severe osteoporosis (27 women with spinal bone densities below 50 mg/cm3 as determined by quantitative computed tomography; 14 women with spinal bone densities below 0.75 g/cm2 as determined by dual energy x-ray absorptiometry) and 23 Caucasian control subjects (68 +/- 7 yr) without osteoporosis (quantitative computed tomography values at or above the fracture threshold of 100 mg/cm3). Only 6 of the 41 individuals in the group with severe osteoporosis had the BB genotype, whereas 16 had the bb genotype. In the control group comprising 23 individuals, 7 had the BB genotype and only 6 had the bb genotype. We conclude that the BB VDR genotype is not a good predictor of risk for developing severe osteoporosis in our population.

Genetic influences on bone density: Physiological correlates of vitamin D receptor gene alleles in premenopausal women

Article

Oct 1995

Common vitamin D receptor (VDR) gene alleles have recently been shown to contribute to the genetic variability in bone mass and bone turnover, however, the physiological mechanisms involved are unknown. To examine this, the response to 7 days of 2 micrograms oral 1,25-dihydroxyvitamin D[1,25-(OH)2D] (calcitriol) stimulation was assessed in 21 premenopausal women, homozygous for one or other of the common VDR alleles (bb, n = 11; BB, n = 10). Indices of bone turnover and calcium homeostasis were measured during 2 weeks. Baseline osteocalcin, 1,25-(OH)2D, type I collagen carboxyterminal telopeptide, and inorganic phosphate levels were significantly higher and spinal bone mineral density was significantly lower in the BB allelic group. After calcitriol administration, similar levels of 1,25-(OH)2D were attained throughout the study in both genotypic groups. The increase in serum osteocalcin levels in the BB group was significantly less than that in the bb group (11% vs. 32%, P = 0.01). The genotype-related baseline difference in osteocalcin levels was not apparent at the similar serum 1,25-(OH)2D levels. By contrast, the baseline differences in phosphate and type I collagen carboxyterminal telopeptide persisted throughout the study. Serum ionized calcium levels did not differ between genotypes, nor did it move out of normal range values. However, parathyroid hormone was less suppressed in the low bone density group (38% vs. 11%, P = 0.01). These data indicate that the VDR alleles are associated with differences in the vitamin D endocrine system and may have important implications in relation to the pathophysiology of osteoporosis.

Genetic influences on Type I collagen synthesis and degradation: Further evidence for genetic regulation of bone turnover

Article

Jul 1994

Circulating osteocalcin, a marker of bone formation, is under strong genetic influence, and this effect is related to the genetic influence on bone density. To examine genetic influences on bone turnover further, other markers of bone formation (serum carboxyterminal propeptide of type I procollagen, PICP), bone resorption (serum pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, ICTP), and nonosseous connective tissue synthesis (serum aminoterminal propeptide of type III procollagen, PIIINP) were studied in 82 female twin pairs: 42 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs (mean age, MZ; 48.4 yr; DZ; 45.6 yr). The intraclass correlation coefficients of MZ twin pairs, rMZ, for serum PICP (0.78) and serum ICTP (0.68) were significantly greater than the corresponding rDZ (0.31 and 0.36, respectively), but a genetic effect on serum PIIINP was not demonstrable. Within DZ twin pair differences in serum PICP predicted differences in lumbar spine bone density (r = -0.37); higher serum PICP levels indicating the twin with the lower lumbar spine bone density. Also within pair differences in serum ICTP and PICP predicted differences in bone density at the lumbar spine independent of serum osteocalcin. These data indicate that both synthesis and degradation of type I collagen are genetically determined and that this phenomenon is related to the genetic regulation of bone density.

Vertebral assessment using a semiquantitativ technique

Article

Sep 2009

The assessment of vertebral fracture by conventional radiography has been refined and improved using either semiquantitative or quantitative criteria. The inter- and intraobserver variability was determined for a semiquantitative visual approach that we routinely use in clinical studies for assessing prevalent and incident vertebral fractures. In addition, the semiquantitative approach was compared with a quantitative morphometric approach. The incidence and prevalence of vertebral fractures were determined in 57 postmenopausal women (age 65-75 years) by three independent observers. The radiographic basis for fracture definitions and the source of interobserver agreement for the semiquantitative technique. We conclude that the semiquantitative approach can be applied reliably in vertebral fracture assessment when performed using well-defined criteria.

Changes in axial bone density with age: A Twin Study

Article

Dec 2009

Bone mineral density in adult life, which is an important determinant of fracture risk, is determined by peak adult bone density, achieved in early adulthood and subsequent rates of change during adult life. Cross-sectional twin and family studies indicate that the majority of population variation in bone density may be explained by genetic factors. Although there is evidence for a genetic effect on peak bone mass, it is unknown whether there is a genetic effect on rates of changes in bone density with age. Changes in lumbar spine and femoral neck bone density determined by dual-photon absorptiometry (Lunar DP3) were examined in a cohort of monozygotic (MZ, n = 21, 3 male and 18 female pairs, median age, range, 46; 24-75 years) and dizygotic twins (DZ, n = 19; 43, 25-65 years). The median follow-up was 3 years (range 1.1-5.5 years), with each subject having at least two and up to four bone density assessments. In these twins, genetic factors determine variation in rates of change (% change/year) in lumbar spine bone density, rMZ = 0.93 and rDZ = 0.51, p < 0.02 (one tailed), and Ward's triangle, rMZ = 0.60, rDZ = 0.11, p < 0.05 (one tailed). Model-fitting analysis was also consistent with a genetic effect on rates of change in bone density at the trochanteric site, although such an effect was not shown at the femoral neck. These data demonstrate, for the first time, the possible existence of genetic determinants of rates of change in bone mineral density in adults.

Genetic influence on bone turnover in postmenopausal twins

Article

Feb 1996

Postmenopausal bone mass is determined by both peak bone mass and subsequent bone loss. Previous studies have shown that peak bone mass is under genetic influence mediated partly by factors affecting bone formation. The rate of bone loss increases markedly after the menopause, but is highly variable from subject to subject. The aims of this study were to determine whether postmenopausal bone turnover was under genetic control, which should be linked to the genetic influence on the rate of postmenopausal bone loss. A classical twin study was performed that compared the intraclass correlations in monozygotic (MZ) twins with those in dizygotic (DZ) twins, with any difference assumed to be due to genetic factors. Markers of bone formation and resorption were measured in 240 untreated postmenopausal twins, aged 45-69 yr, on the average 12.3 yr (SD, 6.0) postmenopause, including 61 MZ pairs and 59 DZ pairs. The intraclass correlation coefficient of MZ twin pairs, rMZ (95% confidence interval), for 2 specific markers of bone formation, serum osteocalcin and bone-specific alkaline phosphatase, were higher than the corresponding rDZ [0.67 (range, 0.59-0.75) vs. 0.48 (range, 0.35-0.61; P = 0.06) for osteocalcin and 0.53 (range, 0.41-0.65) vs. 0.21 (range, 0.01-0.41; P = 0.02) for bone-specific alkaline phosphatase]. For serum propeptide of type I collagen, a type I collagen synthesis marker that exhibits only a slight increase after menopause, a high proportion of its variance was explained by genetic factors [rMZ = 0.82 (0.77-0.87), rDZ = 0.33 (0.16-0.50); P < 0.001]. The correlations for bone resorption measured by three distinct urinary markers, total deoxypyridinoline and two cross-linked type I collagen peptides (CrossLaps and NTX), that increase markedly after menopause were higher in MZ than in DZ pairs, but the difference reached significance only for NTX (P = 0.03). For urinary free dexoypyridinoline, a marker reflecting bone collagen degradation that increases moderately after menopause, the proportion of the variance explained by genetic factors was highly significant (P = 0.002). In conclusion, our data indicate that a proportion of the variance in postmenopausal levels of both bone formation and resorption markers are explained by genetic factors, but this contribution was clearly significant only for markers that do not change markedly at the menopause. These data suggest that the contribution of genetic factors to overall postmenopausal bone turnover and possibly bone loss is likely to be small.

Vitamin D receptor polymorphism, bone mineral density, and osteoporotic vertebral fracture: Studies in a UK population

Article

Apr 1996
BONE

Bone mineral density is under strong genetic control and polymorphisms of the vitamin D receptor (VDR) have been suggested to account for some of the genetic variation in bone mass. However, the relationship between VDR polymorphisms and bone density is controversial and has not been confirmed by all workers. Since there is little information on the association between VDR genotype and bone mass in the UK, we studied VDR genotype, bone mineral density, and osteoporotic fracture in a cohort or pre- and postmenopausal women from the Northeast of Scotland. We found a highly significant "inverse" association between the VDR genotype and bone mineral density at the hip such that individuals of "bb" genotype had a femoral neck bone density of 0.79 standard deviation lower than individuals of BB genotype (p < 0.02). This contrasts with most previous studies in which the "bb" genotype has been associated with high bone density. A similar, but nonsignificant trend was seen for lumbar spine BMD. To study the clinical significance of this observation, we examined the distribution of VDR genotypes in a subgroup of patients with severe osteoporosis who had vertebral compression fractures (n = 44) as compared with with age-and gender-matched controls (n = 44). Despite the differences in BMD between genotypes, there was no significant excess of any specific VDR genotype in osteoporotic fracture patients, indicating that VDR genotyping may be of limited practical value in identifying patients at risk of vertebral fracture. This study confirms that there is a significant association between VDR genotype and bone mass in our population. The "inverse" relationship between VDR genotype noted in this, as compared with previous studies, would be consistent with a model whereby VDR polymorphisms are not the cause of reduced BMD, but rather, are in linkage disequilibrium with a disease-causing locus nearby.

Vitamin D receptor gene polymorphisms are not related to bone turnover, rate of bone loss, and bone mass in postmenopausal women: The OFELY Study

Article

Jun 2009

Vitamin D receptor (VDR) gene polymorphisms have been reported to account for most of the well established genetic influence on bone mineral density (BMD). However, discordant studies have been published and it is still not clear whether VDR genotypes influence bone mass accretion and/or postmenopausal bone loss. In this study, we analyzed VDR gene polymorphisms, i.e., that of BsmI, ApaI, and TaqI restriction enzymes in 268 untreated postmenopausal women 1-26 years postmenopausal. There were 37 BBAA homozygote (absence of BsmI and ApaI restriction sites on both alleles), 55 bbaa homozygote (presence of restriction sites on both alleles), and 176 heterozygotes. At baseline, women between the three genotypes did not differ significantly in age, years since menopause, body mass index (BMI), nor dietary calcium intake. We found no relationship between VDR genotypes and bone turnover assessed by three serum markers of bone formation and three urinary bone resorption markers, nor with BMD measured at the spine, hip, forearm, and whole body by dual-energy X-ray absorptiometry (DXA). Rates of bone loss assessed by repeated DXA measurements over 2 years were highly significant (p = 0.02-0.0001) at all skeletal sites except for the lumbar spine but did not differ between genotypes at any sites either before or after adjustment for potential confounding factors such as years since menopause, BMI, calcium intake, serum 25 hydroxyvitamin D levels, and baseline BMD. When we restricted the analysis to early postmenopausal women, within 10 years of menopause (n = 128), lumbar spine bone loss became significant, but no significant difference between VDR genotypes in the rate of bone loss measured at any site was found. We conclude that VDR genotypes are not predictive of bone turnover, rate of postmenopausal bone loss, and bone mass in either early or late postmenopausal women. In a subgroup of women with a low calcium intake (below 600 mg/day), we also found no significant differences between genotypes in BMD and the rate of bone loss measured at any site, although the sample size (n = 64) may be too small to detect small differences. In conclusion, these data, along with the absence of relationships between VDR gene polymorphisms and peak bone mass that we recently reported, suggest that the determination of VDR genotypes is probably not a useful clinical test for the risk assessment of osteoporosis.

Polymorphisms of the vitamin D receptor gene do not predict quantitative ultrasound of the calcaneus or hip axis length

Article

Feb 1996

Quantitative ultrasound of the calcaneus and hip axis length are independent predictors of hip fracture and have a major genetic component. Polymorphisms of the vitamin D receptor gene (VDR) have been associated with variations in bone density in a number of studies. The aim of this study was to examine the role of VDR on other parameters associated with the risk of fracture. One hundred and eighty-nine pairs of healthy female dizygous twins were genotyped and had calcaneal ultrasound (broadband ultrasound attenuation and velocity of sound) and hip axis length measurements performed. Twin analysis using intraclass correlation coefficients and intrapair differences failed to find an association between the VDR polymorphisms and hip axis length or calcaneal ultrasound. Analysing the twins as a population, irrespective of twinning, also failed to find any association. The search for alternative genes influencing bone fragility should continue as a research priority.

The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: A study of postmenopausal twins

Article

Apr 2009

Population based studies have demonstrated that having a first degree relative with a hip fracture is predictive of future hip fractures. Postmenopausal bone mineral density (BMD), ultrasound of calcaneus and hip axis length are associated with hip fracture, with the association for ultrasound and hip axis length being independent of BMD. The aim of this study was to determine the genetic component of these three important risk factors. We performed a classical twin study using 500 normal female twins, 128 identical and 122 non-identical pairs, aged 50 to 70 years. We measured bone mineral density at multiple sites, hip axis length (distance from the inner rim of the acetabulum to the greater trochanter), broadband ultrasound attenuation and velocity of sound of the calcaneus. Bone density had a strong genetic component at all sites with estimates of heritability ranging from 0.46 to 0.84. Hip axis length and velocity of sound had major genetic components with estimates of 0.62 and 0.61 respectively, which remained virtually unchanged after adjustment for bone mineral density. Broadband ultrasound attenuation had a moderate genetic component with an estimate of 0.53, which was reduced further to 0.45 after adjustment for BMD. In summary, all three bone measurements, which are independently associated with hip fracture, are independently heritable. This study suggests that a combination of different genetic factors acting on the structure, dimensions and density of bone may explain the importance of family history as a risk factor for hip fracture.

Vitamin D Receptor Genotypes and Intestinal Calcium Absorption in Postmenopausal Women

Article

Jan 1998

Several studies have shown that bone mass and bone turnover are genetically determined. This genetic component is thought to be mediated in part by polymorphisms at the vitamin D receptor (VDR) locus, even though the underlying molecular mechanisms are still unknown. To evaluate a possible site of differential action of the VDR gene alleles we examined their correlation with intestinal calcium absorption in 120 Caucasian postmenopausal women (aged 61 +/- 0.6 years). VDR gene polymorphisms for Apa I, Bsm I, and Taq I restriction endonucleases were assessed by Southern blotting analysis. The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%). Although there was some evidence of 13% higher lumbar BMD values in aabbTT genotype with respect to AABBtt genotype, this difference of approximately 0.1 g/cm2 did not reach statistical significance, possibly because of the limited number of observations. On the contrary, no relationship was found between genotypes and femoral neck BMD values. Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotypes (P = 0.0015 ANOVA). No significant differences in intact PTH, alkaline phosphatase, 25OHD3, and 1, 25(OH)2D3 were found among subjects with different VDR genotypes. These results are consistent with a possible role of VDR alleles on intestinal calcium absorption.

Do Dietary Calcium and Age Explain the Controversy Surrounding the Relationship Between Bone Mineral Density and Vitamin D Receptor Gene Polymorphisms?

Article

Apr 1998

Whether vitamin D receptor (VDR) gene polymorphisms are associated with osteoporosis is highly controversial. The relationship between VDR gene polymorphisms and bone mineral density (BMD) might, however, be modified by age-related and/or environmental factors. We studied the potential association between BMD and VDR genotypes in females from prepuberty to premenopause and prospectively investigated the interaction of VDR genotypes with dietary calcium and BMD changes during childhood. Bsm I VDR gene polymorphisms and BMD at the lumbar spine (LS) and femur (neck [FN] and midshaft [FS]) were assessed in 369 healthy Caucasian females, aged 7-56 years (143 prepubertal girls, 54 peri- and postpubertal adolescents, and 172 premenopausal adults). Femoral trochanter (FT) and distal radius BMD (metaphysis and diaphysis) were also measured in 101 of the prepubertal girls who participated in a 1-year, double-blind, randomized study of calcium supplementation (850 mg/day) versus placebo on bone mineral mass accrual. Among all females, 150 (40.7%) had bb, 167 (45.3%) Bb, and 52 (14%) BB VDR genotypes. In prepubertal and adolescent girls altogether, LS BMD (Z scores) was associated with VDR genotypes and was significantly lower in BB than in Bb or bb subjects. Trends for a similar difference were also detected at the FN level as well as on the mean BMD (Z scores) of the three sites measured (LS, FN, and FS). By contrast, no BMD differences were detectable among VDR genotypes in the adults. In 101 prospectively studied prepubertal girls, calcium supplementation significantly increased BMD at most skeletal sites, except LS. After segregation for VDR genotypes (40 bb, 47 Bb, and 14 BB), a significant calcium effect was present in Bb but not bb girls, whereas in BB girls there was a positive but nonsignificant trend for a calcium effect. Moreover, dietary calcium intake was significantly correlated with BMD changes at various independent bone sites in Bb girls but not in bb girls. In contrast, BMD gain in bb girls appeared to be higher than among the other genotypes when the dietary calcium intake was low, i.e., in the absence of calcium supplements. BMD was significantly associated with VDR gene polymorphisms only before puberty, BB girls having significantly lower BMD (Z scores) than the other genotypes. By increasing dietary calcium intake, BMD accrual was increased in Bb and possibly BB prepubertal girls, whereas bb subjects had the highest spontaneous BMD accrual and remained unaffected by calcium supplements. Taking into account complex interactions between VDR gene polymorphisms and environmental factors, including calcium intake, may thus help to understand the discordant relationships between BMD and VDR gene polymorphisms.

Bone Mineral Density and Its Change in White Women: Estrogen and Vitamin D Receptor Genotypes and Their Interaction

Article

Apr 1998

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and maintenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3-year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre- and perimenopausal women who were part of the Michigan Bone Health Study, a population-based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone-related serum protein measurements, and life-style characteristics were also available on each woman. Based on evaluation of women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.05) and total body BMD level, but not their change over the 3-year period examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone-related serum and body composition measurements in the 372 women in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene x gene interaction effect (p < 0.05) for the VDR locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD levels. Women who had the (-/-) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (-/-) PvuII ER and BB VDR genotype had significantly lower BMD levels. This contrast was not explained by differences in serum levels of osteocalcin, parathyroid hormone, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D. These data suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.

Vitamin D Receptor Alleles Do Not Predict Bone Mineral Density or Bone Loss in Danish Perimenopausal Women

Article

Jun 1998
BONE

A BsmI restriction enzyme polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with bone mineral density (BMD) and bone turnover. However, findings in other studies suggest the presence of considerable interaction by race, body size, and environmental factors. Therefore, we VDR BsmI genotyped 200 healthy perimenopausal Danish white women (mean age 50.8 years, mean calcium intake 900 mg/day) in a comprehensive, longitudinal, community-based population study. Bone loss was assessed by dual-energy X-ray absorptiometry (DXA) using cross-calibrated Hologic QDR-1000W and QDR-2000 densitometers, with a mean follow-up period of 4 years (range 1-5 years). Despite a distribution of genotypes similar to that of other white populations (28% bb, 49% Bb, 23% BB), VDR genotypes were not associated with lumbar or femoral baseline BMD, subsequent bone loss rates, or biochemical markers of bone metabolism (bone-specific alkaline phosphatase, urinary hydroxyproline, and serum osteocalcin). Controlling for body size, calcium intake, and serum levels of 25-hydroxyvitamin D3 [25(OH)D3] did not alter this finding. The possible existence of a threshold effect was subsequently investigated by restricting analysis to women with low serum 25(OH)D3 levels or low calcium intake. VDR BsmI genotypes showed no significant impact on bone density or bone loss in healthy Danish early postmenopausal women, even when allowance was made for calcium intake, serum 25(OH)D3, and body size.

Vitamin D Receptor Genotype and the Risk of Bone Fractures in Women

Article

Oct 1998
EPIDEMIOLOGY

Several studies have confirmed an initial report of a relation between bone density and polymorphic forms of the calcitriol (vitamin D) receptor gene, whereas others have failed to find an association. We examined whether variants of the vitamin D receptor gene are associated with the risk of bone fracture, using a nested case-control analysis within the Nurses' Health Study cohort. The study women all were Caucasian and were 43-69 years of age when they provided a blood sample. Cases included the 54 proximal femur (hip) fractures and 163 distal radius (forearm) fractures that occurred subsequent to the blood draw. Cases and controls were genotyped by polymerase chain reaction for the BsmI polymorphism. The BB genotype, previously associated with lower bone density, was associated with a more than twofold increased risk of hip fracture compared with the bb genotype. Risk was greater for women who were older, leaner, or less physically active or who had a lower calcium intake. The heterozygous genotype was not associated with any increased risk of hip fracture, and we observed little association between vitamin D receptor genotype and forearm fracture. This study supports an association between vitamin D receptor genotype and hip fracture. It also implies that modification by other risk factors may have contributed to the conflicting results from previous studies of vitamin D receptor genotype and femoral bone density.

Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women

Article

Sep 1998

In postmenopausal women, the serum concentrations of endogenous sex hormones and vitamin D might influence the risk of hip and vertebral fractures. In a study of a cohort of women 65 years of age or older, we compared the serum hormone concentrations at base line in 133 women who subsequently had hip fractures and 138 women who subsequently had vertebral fractures with those in randomly selected control women from the same cohort. Women who were taking estrogen were excluded. The results were adjusted for age and weight. The women with undetectable serum estradiol concentrations (<5 pg per milliliter [18 pmol per liter]) had a relative risk of 2.5 for subsequent hip fracture (95 percent confidence interval, 1.4 to 4.6) and subsequent vertebral fracture (95 percent confidence interval, 1.4 to 4.2), as compared with the women with detectable serum estradiol concentrations. Serum concentrations of sex hormone-binding globulin that were 1.0 microg per deciliter (34.7 nmol per liter) or higher were associated with a relative risk of 2.0 for hip fracture (95 percent confidence interval, 1.1 to 3.9) and 2.3 for vertebral fracture (95 percent confidence interval, 1.2 to 4.4). Women with both undetectable serum estradiol concentrations and serum sex hormone-binding globulin concentrations of 1 microg per deciliter or more had a relative risk of 6.9 for hip fracture (95 percent confidence interval, 1.5 to 32.0) and 7.9 for vertebral fracture (95 percent confidence interval, 2.2 to 28.0). For those with low serum 1,25-dihydroxyvitamin D concentrations (< or =23 pg per milliliter [55 pmol per liter]), the risk of hip fracture increased by a factor of 2.1 (95 percent confidence interval, 1.2 to 3.5). Postmenopausal women with undetectable serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin have an increased risk of hip and vertebral fracture.

How About Vitamin D Receptor Polymorphisms?

Article

Feb 1998

Vitamin D Receptor Gene Polymorphisms and the Risk of Fractures in Older Women

Article

Nov 1999

The association between vitamin D receptor gene polypmorphisms and bone mineral density is controversial. The relationship between vitamin D receptor genotype and risk of fracture is uncertain. To determine whether vitamin D receptor polymorphisms were associated with the risk of hip, vertebral, and other (nonhip, nonvertebral) fractures in elderly women, we conducted a case-cohort study within a prospective study of 9704 community-dwelling women aged 65 years and older. Vitamin D receptor allele and genotype frequencies in women who experienced first incident hip (n = 181), vertebral (n = 127), and other (n = 223) fractures were compared with those of control women selected randomly from the cohort. Average length of follow-up was 6.5, 3.7, and 5.4 years for women in hip, vertebral, and other fracture analyses, respectively. Vitamin D receptor polymorphisms were determined by polymerase chain reaction amplification of genomic DNA using TaqI and ApaI restriction site endonuclease digestion. All nonvertebral fractures were confirmed by X-ray reports; hip fractures were validated by review of X-ray films. Vertebral fractures were defined by morphometry using lateral spine radiography at baseline and an average of 3.7 years later. Allele or genotype frequencies did not differ between fracture cases and their respective controls. Vitamin D receptor genotype (defined by TaqI, ApaI, or the combination of TaqI and ApaI) was not significantly associated with the risk of hip, vertebral, or other fractures. For example, compared with the referent group of women with TT genotype, those with Tt and tt genotypes had similar age- and weight-adjusted risks of fracture at the hip (hazard ratios 0.9, 95% confidence interval [CI] 0.6-1.3, and 0.8, 95% CI 0.5-1.2, respectively), spine (odds ratios 1.1, 95% CI 0.7-1.8, and 0.7, 95% CI 0.4-1.3, respectively), or other skeletal site (hazard ratios 1.0, 95% CI 0. 7-1.4, and 1.0, 95% CI 0.7-1.5, respectively). These findings were not altered in additional analyses including those adjusted for and stratified by age, ethnic ancestry, calcaneal bone density, dietary calcium intake, use of calcium supplements, use of vitamin D supplements, and oral estrogen use. We conclude that Vitamin D receptor polymorphisms defined by TaqI and ApaI are not associated with the risk of fracture in older women. Our results suggest that determination of these vitamin D receptor polymorphisms is not a clinically useful test for the prediction of fracture risk in elderly women.

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Article

Feb 1999

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p = 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men.

Biochemical Markers of Bone Turnover, Endogenous Hormones and the Risk of Fractures in Postmenopausal Women: The OFELY Study

Article

Aug 2000

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

Polymorphisms of the VDR, ER and COLIA1 Genes and Osteoporotic Hip Fracture in Elderly Postmenopausal Women

Article

Feb 2000

In view of the reported associations between osteoporosis and polymorphisms of the vitamin D receptor (VDR), collagen Ialpha1 (COLIA1) and estrogen receptor (ER) genes, an association study was performed between VDR, COLLIA1, and ER genotypes and bone mineral density, biochemical markers of bone turnover and hip fracture occurrence in Belgian older postmenopausal women. The gene polymorphisms were evaluated by restriction fragment length polymorphism analyses, using the restriction enzymes BsmI (VDR), AccB7I (COLIA1), and PvuII and XbaI (ER), respectively. As expected, bone mineral density and biochemical analyses demonstrated significant differences between hip fracture patients and elderly controls. However, no significant differences in genotype distributions or allele frequencies were observed between the cases (n = 135, age 78 +/- 9 years) and controls (n = 239, age 76 +/- 4 years) for any of the gene polymorphisms. Stratification of both study populations according to VDR, COLIA1 or ER genotype did not reveal any statistically significant difference in bone density or bone turnover between subgroups with different genotypes. In conclusion, despite its limited statistical power the outcome of this study does not support the hypothesis of a major contribution of the VDR, COLIA1 or ER polymorphisms to explain variations in bone mineral density or bone turnover, or to identify elderly women at risk of osteoporotic hip fracture.

Role of genetic factors in the pathophysiology and management of osteoporosis

Article

Feb 2001

Type I Collagen Racemization and Isomerization and the Risk of Fracture in Postmenopausal Women: The OFELY Prospective Study

Article

Jun 2002

The Asp1211 residue of the 1209AHDGGR1214 sequence of the C-terminal cross-linking telopeptide of type I collagen (CTX) can undergo spontaneous post-translational modifications, namely, racemization and isomerization, which result in the formation of four isomers: the native form (alpha-L) and three age-related forms, that is, an isomerized form (beta-L), a racemized form (alpha-D), and an isomerized/racemized (beta-D) form. Previous studies have suggested that changes in the pattern of type I collagen racemization/isomerization, which can be assessed in vivo by measuring the degradation products of the CTX isoforms, may be associated with alterations of bone structure. The aim of this study was to examine prospectively the value of the different urinary CTX isoforms and their related ratio in the prediction of osteoporotic fractures in 408 healthy untreated postmenopausal women aged 50-89 years (mean, 64 years) who were part of the OFELY cohort. During a median 6.8 years follow-up, 16 incident vertebral fractures and 55 peripheral fractures were recorded in 65 women. The baseline levels of the four CTX isoforms in women who subsequently had a fracture were compared with those of the 343 women who did not fracture. At baseline, women with fractures had increased levels of ratios of native alpha-L-CTX to age-related isoforms (beta-L, alpha-D, and beta-D) compared with controls (p < 0.01). In logistic regression analysis after adjustment for age, prevalent fractures, and physical activity, women with levels of alpha-L/beta-L, alpha-L/alpha-D, and alpha-L/beta-D-CTX ratios in the highest quartile had a 1.5- to 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 2.0 (1.2-3.5), 1.8 (1.02-2.7), and 1.5 (0.9-2.7), respectively. Adjustment of alpha-L/beta-L and alpha-L/alpha-D-CTX ratios by the level of bone turnover assessed by serum bone alkaline phosphatase (ALP)- or femoral neck bone mineral density (BMD) decreased slightly the RR, which remained significant for the alpha-L/beta-L-CTX ratio (RR [95%] CI, 1.8 [1.1-3.2] after adjustment for bone ALP, 1.8 [1.03-3.1] after adjustment for BMD, and 1.7 [0.95-2.9] after adjustment for both bone ALP and BMD). Women with both high alpha-L/beta-L-CTX ratio and high bone ALP had a 50% higher risk of fracture than women with either one of these two risk factors. Similarly, women with both increased CTX ratio and low femoral neck BMD (T score < -2.5) had a higher risk of fracture with an RR (95% CI) of 4.5 (2.0-10.1). In conclusion, increased urinary ratio between native and age-related forms of CTX, reflecting decreased degree of type I collagen racemization/isomerization, is associated with increased fracture risk independently of BMD and partly of bone turnover rate. This suggests that alterations of type I collagen isomerization/racemization that can be detected by changes in urinary CTX ratios may be associated with increased skeletal fragility.

Vitamin D receptor-mediated gene regulation mechanisms and current concepts of vitamin D analog selectivity

Article

Aug 2002

Lipophilic hormones of steroidal origin such as the sex hormones and 1,25-dihydroxy vitamin D(3) (1,25[OH](2)D(3)) function by regulating patterns of gene expression in cells. The mediators of such actions are nuclear receptors that recognize these ligands with high affinity and selectivity and function through several mechanisms as gene specific transcription factors. As a result of the mechanistic complexity of nuclear receptor action, recent studies have revealed that both synthetic analogs as well as novel mimetics of a receptor's natural hormonal ligand are capable of modulating functional responses in both cell- and gene-selective manners. These findings have given rise to the term selective receptor modulators, typified by such synthetic estrogen receptor ligands as tamoxifen and raloxifene. A number of vitamin D analogs have been prepared that appear to exhibit tissue-selective activity--most notable through their inability to induce levels of hypercalcemia typical of the activity of the natural hormone 1,25(OH)(2)D(3). Because this debilitating yet normal feature of the natural ligand limits its usefulness in a variety of clinical indications, including its application to prevent bone disease caused by secondary hyperparathyroidism, this feature of many of the new analogs is especially welcome. This article discusses what constitutes a selective receptor modulator and whether the current vitamin D analogs represent such entities.

Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study

Article

Jan 2003
BONE

Several epidemiological studies have identified clinical factors that predict the risk of hip fractures in elderly women independently of the level of bone mineral density (BMD), such as low body weight, history of fractures, and clinical risk factors for falls. Their relevance in predicting all fragility fractures in all postmenopausal women, including younger ones, is unknown. The objective of this study was to identify independent predictors of all osteoporosis-related fractures in healthy postmenopausal women. We prospectively followed for 5.3 +/- 1.1 years a cohort of 672 healthy postmenopausal women (mean age 59.1 +/- 9.8 years). Information on social and professional conditions, demographic data, current and past medical history, fracture history, medication use, alcohol consumption, caffeine consumption, daily calcium intake, cigarette smoking, family history of fracture, and past and recent physical activity was obtained. Anthropometric and total hip bone mineral density measurements were made. Incident falls and fractures were ascertained every year. We observed 81 osteoporotic fractures (annual incidence, 21 per 1000 women/year). The final model consisted of seven independent predictors of incident osteoporotic fractures: age > or = 65 years, odds ratio estimate (OR), 1.90 [95% confidence interval (CI) 1.04-3.46], past falls, OR, 1.76 (CI 1.00-3.09), total hip bone mineral density (BMD) < or = 0.736 g/cm(2), OR, 3.15 (CI 1.75-5.66), left grip strength < or = 0.60 bar, OR, 2.05 (CI 1.15-3.64), maternal history of fracture, OR, 1.77 (CI 1.01-3.09), low physical activity, OR, 2.08 (CI 1.17-3.69), and personal history of fragility fracture, OR, 3.33 (CI 1.75-5.66). In contrast, body weight, weight loss, height loss, smoking, neuromuscular coordination assessed by three tests, and hormone replacement therapy were not independent predictors of all fragility fractures after adjustment for all variables. We found that some--but not all--previously reported clinical risk factors for skeletal fragility predicted all fragility fractures independently of BMD in healthy postmenopausal women, although they differed somewhat from those predicting specifically hip fractures in elderly women. These risk factors appear to reflect quality of bone structure (previous fragility fracture), lifestyle habits (physical activity), muscle function and health status (grip strength), heredity (maternal history of fracture), falls, and aging. Measurements of these variables should be included in the clinical assessment of the risk of osteoporotic fractures in postmenopausal women.

Contribution of clinical risk factors to bone density-based absolute fracture risk assessment in postmenopausal women

Article

Jul 2003

Hip fractures are independently associated with advancing age, specific clinical risk factors (CRFs), and low bone mineral density (BMD). The use of BMD T-scores for quantifying fracture risk ignores the contribution of age and CRFs. We previously developed a mathematical model of absolute hip fracture risk that incorporates patient age, BMD, and the results of eleven specific CRFs. The purpose of this study was to compare the contribution of an approach to fracture risk stratification using the full model (age, CRFs and BMD) with that of a unidimensional BMD-only model. We selected 213 consecutive postmenopausal females (mean age 65.3, range 50-87.9) with CRF data referred for BMD assessment of fracture risk. Absolute hip fracture risk (over the next 5 years and remaining lifetime) was estimated using both the full and BMD-only models. The mean ratio of absolute hip fracture risks (BMD-only/full model) derived for each patient was 0.8 (95% CI, 0.16-4.0) for hip fracture in the next 5 years and 1.1 (CI, 0.1-7.6) for remaining lifetime. The wide confidence intervals indicate a large contribution of age and CRFs to fracture risk stratification. Categorization of women as "high risk" was frequently discordant for the two models. One-half of the women designated "high risk" under the full model were classified as "low risk" based upon BMD alone. In conclusion, we have shown that a multidimensional approach to hip fracture risk stratification is feasible, and greatly modifies risk stratification based on BMD alone.

Characterization of Common Genetic Variants in Cathepsin K and Testing for Association With Bone Mineral Density in a Large Cohort of Perimenopausal Women From Scotland

Article

Jan 2004

BMD values in approximately 3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes. CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population. To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in approximately 3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al. We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (> 1% frequency), and found that three STRs at the immediate 5' end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.

Meta-Analysis of Molecular Association Studies: Vitamin D Receptor Gene Polymorphisms and BMD as a Case Study

Article

Apr 2004

With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved. With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of vitamin D receptor (VDR) gene polymorphisms and BMD/osteoporosis and highlights methodological issues. Studies published from 1994 to 2001 were identified through Medline using PubMed software. The reference lists of the articles retrieved were also reviewed. Where eligible papers had insufficient information, we contacted authors by mail (up to three mailings) for additional information. Any observational study, which tested the association between VDR BsmI genotypes and either BMD or osteoporosis at the femoral neck or spine in adult women, was included in the review. Data were extracted independently by two reviewers (AT and JA) using a standardized data extraction form. The B allele was significantly associated with BMD at the spine; it seemed to follow a recessive model, with the BB genotype having lower BMD than Bb/bb genotypes at baseline, which led to greater bone mineral loss over time. Highlighted methodological lessons included the need to check Hardy-Weinberg equilibrium and the importance of exploring heterogeneity, pooling data in a manner that is sensitive to genetic models, and avoiding multiple comparisons. With the proliferation of molecular association studies, there will be an increased need to quantify the magnitude of the risk associated with genetic polymorphisms. This will likely entail meta-analytic methods, and this meta-analysis highlights some of the methodological issues that will need to be resolved.

Polymorphisms in the Low-Density Lipoprotein Receptor–Related Protein 5 (LRP5) Gene Are Associated with Variation in Vertebral Bone Mass, Vertebral Bone Size, and Stature in Whites

Article

May 2004

Stature, bone size, and bone mass are interrelated traits with high heritability, but the major genes that govern these phenotypes remain unknown. Independent genomewide quantitative-trait locus studies have suggested a locus for bone-mineral density and stature at chromosome 11q12-13, a region harboring the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Mutations in the LRP5 gene were recently implicated in osteoporosis-pseudoglioma and "high-bone-mass" syndromes. To test whether polymorphisms in the LRP5 gene contribute to bone-mass determination in the general population, we studied a cross-sectional cohort of 889 healthy whites of both sexes. Significant associations were found for a missense substitution in exon 9 (c.2047G-->A) with lumbar spine (LS)-bone-mineral content (BMC) (P=.0032), with bone area (P=.0014), and with stature (P=.0062). The associations were observed mainly in adult men, in whom LRP5 polymorphisms accounted for <or=15% of the traits' variances. Results of haplotype analysis of five single-nucleotide polymorphisms in the LRP5 region suggest that additional genetic variation within the locus might also contribute to bone-mass and size determination. To confirm our results, we investigated whether LRP5 haplotypes were associated with 1-year gain in vertebral bone mass and size in 386 prepubertal children. Significant associations were observed for changes in BMC (P=.0348) and bone area (P=.0286) in males but not females, independently supporting our observations of a mostly male-specific effect, as seen in the adults. Together, these results suggest that LRP5 variants significantly contribute to LS-bone-mass and size determination in men by influencing vertebral bone growth during childhood.

Genetic determinants of bone mass

Article

Aug 2004

This review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. Recent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. The combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.

Association of Multiple Nucleotide Variations in the Pituitary Glutaminyl Cyclase Gene ( QPCT ) With Low Radial BMD in Adult Women

Article

Aug 2004

Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene and adjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium, R54W showed a prominent association (p = 0.0003), which was more striking when examined among 309 elder subjects (> or =50 years; p = 0.0001). Contribution for postmenopausal bone loss was suggested. Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis (HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have been proposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene (GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essential modifier of pituitary peptide hormones, including GnRH. Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locus with adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) was analyzed by haplotype estimation and calculation of D' and r2. Multiple regression analysis was applied for evaluating the combined effects of the variations. LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of the QPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD, among which R54W (nt + 160C>T) presented the most prominent association (p = 0.0003). Striking association was observed for these SNPs among the 309 subjects >50 years of age (R54W, p = 0.0001; -1095T>C, p = 0.0002; -1844C>T, p = 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might act in combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are the important factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The data should provide new insight into the etiology of the disease and may suggest a new target to be considered during treatment.

Influence of LRP5 Polymorphisms on Normal Variation in BMD

Article

Nov 2004

Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD. Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 x 10(-5) in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation. These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.

Vitamin D Receptor Gene Polymorphisms Are Associated with the Risk of Fractures in Postmenopausal Women, Independently of Bone Mineral Density

Abstract

No full-text available

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