Peak bone mineral density at the hip is linked to chromosomes 14q and 15q

A major determinant of osteoporotic hip fracture is peak hip BMD which is a highly heritable trait. Caucasian American women have lower BMD and higher hip fracture rates than African American women. This study examines linkage of hip BMD in 570 Caucasian sister pairs and 204 African American sister pairs. It compares the results with our published study in a smaller overlapping sample of Caucasian sisters. Hip BMD was measured at neck, trochanter, Wards, shaft, and total hip. Principal component analysis provided a novel BMD phenotype comprising neck and trochanter, common sites of fracture, and Wards, site of lowest BMD. A 9 cM genome scan was performed for these phenotypes. Significant linkage was found at chromosomes 14q and 15q. At 14q, the 774 African American and Caucasian sister pairs together yielded the highest LOD score for trochanter (3.5) and at 15q the highest LOD score for femoral neck (4.3). This linkage study in Caucasian and African American healthy premenopausal sisters demonstrates that chromosomes 14q and 15q harbor genes that affect peak bone mass at the hip in women. Principal component had comparable LOD scores with those of the component phenotypes suggesting pleiotropic effects of these genes on hip phenotypes.     

Assessment of linkage and association of 13 genetic loci with bone mineral density

Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERα] and beta [ERβ], calcium-sensing receptor, vitamin D receptor, collagen type 1α1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor β1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of −1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERα and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERβ and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERβ and BMD at spine and hip; between D14S1026 of ERβ and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERα was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERα, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERα, ERβ and LRP5 are important candidate genes determining BMD variation, especially in females.     

Age,gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study

A genome-wide scan was performed in participants from the Framingham Osteoporosis Study (1557 members of 330 mostly Caucasian pedigrees), with 401 microsatellite markers spaced on average at 10 cM. Bone mineral density (BMD) was measured at the femoral neck, trochanter, Ward's area, and lumbar spine with DXA. Our recent study (J Bone Mines Res 17 (2002), 1718) reported a number of regions with suggestive linkage to possible quantitative trait loci (QTL). The current study estimates the heterogeneity of linkage in these regions in subsamples of our pedigrees, stratified on the known biological contributors to bone mass of sex, age, and body mass index (BMI). The pedigree sample was stratified into three sets of subgroups by sex [males (age range 35- 96 years), females (29-91 years)], by age [60 or younger (29-60 years) and older than 60 (61-96 years)], and by BMI [stratified into low or high BMI, by median cut-off 27.7 in males (BMI range 17-53) and 25.8 in females (14-54)]. Heritability estimates of BMD (adjusted for age, anthropometry, nutrition, physical activity, and, in females, estrogen use) in subsamples ranged from 0.47 to 0.69. Two-point and multipoint variance component linkage analyses of BMD (using SOLAR) in subsamples supported findings of previously reported suggestive linkage results in the total sample on 8q24.13 and 14q31 (LODs>2.0). However, heterogeneity of linkage was observed on 6p21.2 and 21qter, where findings in the total sample were not supported by subsamples. On the other hand, subsample-specific maxima were found, on 4q34.1 (males), 9q22-9q31 (younger), 16p13.2 (high BMI), and 17p13.3 (older), which were not reflected by the total sample results. In conclusion, heterogeneity of QTL effects was revealed in pedigree members stratified by sex, age, and BMI; in some instances new loci were identified in subgroups. These findings may suggest that effects of genes on the determination of BMD differ between men and women, younger and older, and lean and obese adults. Evaluation of family members stratified in homogeneous groups may be warranted in genetic studies of bone mass.     

Genome-wide association meta-analyses identified 1q43 and 2q32.2 for hip Ward's triangle areal bone mineral density

Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p = 1.20 × 10^− 8, FHS p = 0.05 for trochanter BMD; rs9287237, discovery p = 3.55 × 10^− 7, FHS p = 9.20 × 10^− 3 for trochanter BMD, GEFOS p = 0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p = 7.48 × 10^− 7, FHS p = 0.10 for inter-trochanter BMD, GEFOS p = 0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p = 3.09 × 10^− 6, FHS p = 8.50 × 10^− 3, GEFOS p = 1.23 × 10^− 24 for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p = 1.64 × 10^− 6, GEFOS p = 1.69 × 10^− 3 for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p = 8.79 × 10^− 7, GEFOS p = 2.61 × 10^− 7 for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.     

Quantitative trait loci for BMD identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish Family Osteoporosis Study.

Using autosome-wide linkage analysis in 964 Amish, strong evidence was found for the presence of genes affecting hip and spine BMD in men on chromosomes 7q31 and 21q22 (LOD = 4.15 and 3.36, respectively). INTRODUCTION: BMD is highly heritable, with genetic factors accounting for 60-88% of variation. The goal of this study was to localize genes contributing to BMD variation. MATERIALS AND METHODS: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. The Amish are a genetically closed population with a homogeneous lifestyle. BMD was measured at the spine, hip, and radius using DXA in 964 participants (mean age, 50.2 +/- 16.3 [SD] years; range, 18-99 years) from large multigenerational families. Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis were performed. RESULTS: In the overall study population, no strong evidence for linkage was detected to any chromosomal region (peak LOD: 2.11 for radius BMD on chromosome 3q26). In a subgroup analysis of men (n = 371), strong evidence was detected for a quantitative trait locus (QTL) influencing BMD variation on chromosome 7q31 at the total hip (LOD = 4.15) and femoral neck (LOD = 3.09) and for a second QTL influencing spine BMD at 21q22 (LOD = 3.36). Suggestive evidence of linkage was found in men for a QTL at 12q24 affecting total hip BMD (LOD = 2.60) and at 18p11 for femoral neck (LOD = 2.07), and in women (n = 593) at 1p36 for femoral neck BMD (LOD = 2.02) and at 1q21 for spine BMD (LOD = 2.11). In age subgroup analyses, suggestive evidence for linkage was found for those <50 years of age (n = 521) on chromosomes 11q22 and 14q23 (LODs = 2.11 and 2.16, respectively) and for those >50 years of age (n = 443) on 3p25.2 (LOD = 2.32). CONCLUSIONS: These results strongly suggest the presence of genes affecting hip and spine BMD in men on chromosomes 7q31 and 21q22. Modest evidence was found for genes affecting BMD in women on chromosomes 1p36 and 1q21 and in men at 12q24, replicating results from other populations.     

中老年女性腰椎、髋部、前臂骨密度和骨质疏松检出率的对比分析

目的 探讨中老年女性在应用双能X线骨密度仪检测不同部位骨密度时应关注检测的部位。 方法 选取2012年9月至2014年4月在我院行双能骨密度检测的中老年女性,比较腰椎、髋部、前臂桡骨下1/3的骨密度（BMD）和T值。结果 中老年女性腰椎、髋部、前臂桡骨下1/3 3个部位的BMD和T评分比较,P<0.001有显著差异。随着年龄逐渐增大,腰椎、髋部和前臂BMD逐渐降低,但70岁以后腰椎BMD趋于平稳。腰椎T评分在40岁和50岁年龄段下降幅度较快,60岁以后下降有所减缓,70岁以后趋于平稳。髋部T评分在各年龄段呈匀速下降。前臂T评分随着年龄的增大下降幅度明显大于腰椎和髋部。骨质疏松检出率也随年增加而增加,重度骨质疏松检出率也以前臂为最高。结论 应用双能X线骨密度仪检测腰椎、髋部、前臂3个部位,经比较发现老年女性前臂骨密度和T评分明显低于腰椎和髋部,提示对老年女性骨质疏松诊断应同时检测前臂骨密度,以免出现骨质疏松的漏诊。     

髋部定量CT骨密度与髋螺钉置入位置分析

目的对髋部不同空间位置骨松质作定量CT骨密度测定,从骨密度的角度来分析内固定手术治疗老年股骨粗隆间骨折时髋螺钉的合理安放位置。方法选择年龄大于60岁的老年妇女共66例行双侧髋部CT扫描,其中股骨粗隆间骨折35例（骨折组）,无骨折的正常老年妇女31例（对照组）。测定从髋螺钉入口到股骨头的CT值。同时对股骨头内密度较高的压力骨小梁（PCT）及其内、外、前、后侧5个区域的骨松质作定量CT骨密度测定。结果骨折组从髋螺钉人口内侧到股骨头下区域的CT值为负值。骨折组PCT及其内、外、前、后侧的定量CT骨密度分别为（229．71±55．58）、（64．58±25．31）、（39．50±22．56）、（79．85±24．89）、（79．08±19．99）mg／cm^3,而对照组分别为（296．36±40．48）、（85．31±26．99）、（69．49±20．88）、（99．96±27．62）、（98．57±29．38）mg/cm^3。两组PCT的骨密度均明显高于其周围4个区域,差异有统计学意义（P〈0．01）。两组间比较,骨折组5个区域骨密度均明显低于对照组,差异有统计学意义（P〈0．01）。结论从骨密度角度来讲,自髋螺钉人口到股骨头下这一区域的组织密度低于软组织密度,对置入的髋螺钉无锚定力量。PCT是髋部密度最高的骨松质,对髋螺钉锚定起主要作用。在股骨头的外上、前方和后方3个区域内,骨松质的密度远低于压力骨小梁,为髋螺钉发生切割的危险区。老年人存在严重的骨小梁退变,因此正确放置髋螺钉尤其重要。     

Quantitative trait loci for bone density in mice: the genes determining total skeletal density and femur density show little overlap in F2 mice

Bone mineral density variation is a highly heritable trait and is the best predictor of skeletal fragility. Total skeletal density was determined by PIXIMUS, and femur density was determined by pQCT. The data were analyzed for quantitative trait loci (QTL) to determine if bone density at a specific skeletal site (femur) would identify new gene loci or the same gene loci as total body (PIXIMUS). In order to show concordance and differences in QTL for total body bone density versus femur bone density, we performed a genome-wide scan from 633 (MRL x SJL) F2 mice. The bone mineral density (BMD) data from pQCT were used to identify nine QTL on chromosomes 1, 3, 4, 9, 12, 17, and 18, while nine QTL on chromosomes 1, 2, 4, 9, 11, 14, and 15 were identified by PIXIMUSdata, accounting for 32.5% and 30.4% variation in F2 mice, respectively. QTL on chromosomes 1, 2, 3, 9, 11, 12, 14, 15, 17, and 18 are unique to our study, as they have never been described before. Chromosome 1 (D1Mit33 and D1Mit362) had similar QTL between pQCT and PIXIMUS. Several QTL were identified for both femur and total body BMD but only two QTL were common for both of these phenotypes. This suggests that genes regulating bone density differ depending on the skeletal site analyzed.     

Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study.

A genome-wide scan was performed in a randomly ascertained set of 330 extended families from the population-based Framingham Study to identify chromosomal regions possibly linked to bone mineral density (BMD). A set of 401 microsatellite markers was typed at a 10-centimorgan (cM) average density throughout the genome. BMD was measured at the femoral neck, trochanter, Ward's area, and lumbar spine in 1557 participants of both Framingham cohorts. BMDs were adjusted for age, body mass index (BMI), height, alcohol, caffeine, calcium and vitamin D intakes, smoking, physical activity, and estrogen use in women within each sex and cohort. Strong heritabilities (values between 0.543 and 0.633) were found for the adjusted BMD at all sites. Two-point and multipoint quantitative linkage analyses were performed for each BMD site using the maximum likelihood variance components method. By two-point screening, loci of suggestive linkage were identified on chromosomes 6 and 21, with the maximum log10 of the odds ratio (LOD) scores of 2.34 for the trochanter at D21S1446 and 2.93 for the femoral neck at D6S2427. Lumbar spine BMD had maxima at D6S2427 (LOD = 1.88) and at D12S395 (LOD = 2.08). Multipoint linkage analysis revealed suggestive linkage of trochanteric BMD at a broad (approximately 20 cM) interval on chromosome 21q, with the peak linkage close to D21S1446 (LOD = 3.14). LOD scores were 2.13 at 8q24 with Ward's BMD and 1.92 at 14q21.3 with lumbar spine BMD. This largest genome screen to date for genes underlying normal variation in BMD, adjusted for a large number of covariates, will help to identify new positional candidate genes, otherwise unrecognized.     

绝经前女性双生子前臂桡骨骨密度的遗传度分析

目的 探讨绝经前女性前臂桡骨骨密度值的遗传度大小及其在年龄上的变化趋势。方法 根据统一的问卷收集443对5－55岁女性双胞胎的人口学特征及环境资料,利用Nosrland公司生产的周末双能X线吸收骨密度仪（pDEXA）测量前臂桡骨骨密度。将研究对象分成5－,20－,35－三个年龄组,根据经典的双生子模型进行遗传度分析。结果 同卵双生子（MZ)为272对,异卵双生子（DZ）为171对;经t检验,5－及20－年龄组MZ听骨密度对内差值显性小于DZ;方差分析结果表明MX及DZ的对内均方显性低于对间均方,这种趋势在MZ中更为显;另我们发现各年龄组中MZ对内相关系数均大于DZ,MZ的对内相关系数随年龄呈显性降低;MZ与DZ对内相关系数的差异随年龄而降低;根据Falconer公式,前臂桡骨密度遗传度介于0．2－0．6之间,平均遗传度值为0．474,5－年龄组及20－年龄组的遗传度略高于35－年龄组。结论 遗传因素与前臂骨密度值的大小密切相关,并且遗传度随年龄有下降趋势。     

Congenic strains of mice for verification and genetic decomposition of quantitative trait loci for femoral bone mineral density.

Peak femoral volumetric bone mineral density (femoral bone mineral density) in C57BL/6J (B6) 4-month-old female mice is 50% lower than in C3H/HeJ (C3H) and 34% lower than in CAST/EiJ (CAST) females. Genome-wide analyses of (B6 x C3H)F2 and (B6 x CAST)F2 4-month-old female progeny demonstrated that peak femoral bone mineral density is a complex quantitative trait associated with genetic loci (QTL) on numerous chromosomes (Chrs) and with trait heritabilities of 83% (C3H) and 57% (CAST). To test the effect of each QTL on femoral bone mineral density, two sets of loci (six each from C3H and CAST) were selected to make congenic strains by repeated backcrossing of donor mice carrying a given QTL-containing chromosomal region to recipient mice of the B6 progenitor strain. At the N6F1 generation, each B6.C3H and B6.CAST congenic strain (statistically 98% B6-like in genomic composition) was intercrossed to obtain N6F2 progeny for testing the effect of each QTL on femoral bone mineral density. In addition, the femoral bone mineral density QTL region on Chr 1 of C3H was selected for congenic subline development to facilitate fine mapping of this strong femoral bone mineral density locus. In 11 of 12 congenic strains, 6 B6.C3H and 5 B6.CAST, femoral bone mineral density in mice carrying c3h or cast alleles in the QTL regions was significantly different from that of littermates carrying b6 alleles. Differences also were observed in body weight, femoral length, and mid-diaphyseal periosteal circumference among these 11 congenic strains when compared with control littermates; however, these latter three phenotypes were not consistently correlated with femoral bone mineral density. Analyses of eight sublines derived from the B6.C3H-1T congenic region revealed two QTLs: one located between 36.9 and 49.7 centiMorgans (cM) and the other located between 73.2 and 100.0 cM distal to the centromere. In conclusion, these congenic strains provide proof of principle that many QTLs identified in the F2 analyses for femoral bone mineral density exert independent effects when transferred and expressed in a common genetic background. Furthermore, significant differences in femoral bone mineral density among the congenic strains were not consistently accompanied by changes in body weight, femur length, or periosteal circumference. Finally, decomposition of QTL regions by congenic sublines can reveal additional loci for phenotypes assigned to a QTL region and can markedly refine genomic locations of quantitative trait loci, providing the opportunity for candidate gene testing.     

Genetic and environmental determinants of bone mineral density in Mexican Americans: results from the San Antonio Family Osteoporosis Study

Osteoporosis is a major cause of disability in the United States. Numerous factors contribute to the decline in bone mineral density (BMD) that characterizes this disease, and the importance of heredity is now widely appreciated. We evaluated the joint contributions of genes and environmental factors on variation in BMD in 895 participants of the San Antonio Family Osteoporosis Study (SAFOS). Participants of the SAFOS ranged in age from 18 to 96 years and were members of 34 large families of Mexican American ancestry. BMD was measured at the spine, hip, and forearm by dual-energy X-ray absorptiometry. Information about medical history, lifestyle habits, dietary intake, and physical activity patterns was obtained by questionnaire. Age and body mass index were strongly associated with BMD at nearly every site; these and other measured risk factors accounted in aggregate for up to 46% of the total variation in BMD. In general, the environmental risk factors accounted for proportionately more of the total variation in BMD in men than in women. Genes accounted for 65-80% of the residual variation in spine and hip BMD, and 25-55% of the residual variability in forearm BMD. Although residual heritabilities were generally comparable between men and women across all ages combined, heritabilities at all sites tended to be higher in premenopausal women than in men younger than 50 years of age. Identifying the individual genes involved will shed insights into the processes that govern bone remodeling and may suggest strategies for the prevention of osteoporosis.     

Familial Paget's disease of bone: nonlinkage to the PDB1 and PDB2 loci on chromosomes 6p and 18q in a large pedigree.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. Susceptibility loci for Paget's disease of bone have been mapped to chromosome 6p21.3 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. We have identified a large pedigree of over 250 individuals with 49 informative individuals affected with Paget's disease of bone; 31 of whom are available for genotypic analysis. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Linkage analysis has been performed with markers at PDB1; these data show significant exclusion of linkage with log10 of the odds ratio (LOD) scores < -2 in this region. Linkage analysis of microsatellite markers from the PDB2 region has excluded linkage with this region, with a 30 cM exclusion region (LOD score < -2.0) centered on D18S42. These data confirm the genetic heterogeneity of Paget's disease of bone. Our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree and will be identified using a microsatellite genomewide scan followed by positional cloning.     

Exclusion mapping of chromosomes 1, 4, 6 and 14 with bone mineral density in 79 Caucasian pedigrees

Low bone mineral density (BMD) is a major determinant of osteoporosis and is under strong genetic control. A large number of linkage and association studies for BMD variation have been conducted, with the results being largely inconsistent. Linkage exclusion analysis is a useful tool for gene mapping but has never been used on BMD. In the present study, we conducted a linkage exclusion mapping for BMD variation on chromosomes 1, 4, 6 and 17 in 79 Caucasian pedigrees. For hip BMD variation, several genomic regions were excluded for effect sizes of 10% or greater, including regions of 61-77 cM at 1p35-p34, 167-196 cM at 1q21-q23 and 261-291 cM at 1q42-q44; 85-112 cM at 4q21-q25 and 146-150 cM at 4q31; and 77-85 cM at 6p12-q13. For spine BMD, we were able to exclude the regions of 168-189 cM at 1q21-q23, 92-94 cM at 4q21 and 106-107 cM at 4q24 and 56-103 cM at 17q12-q25, as having effect sizes of 10% or greater. These results suggest that a number of candidate genes located in the excluded regions, such as interleukin 6 receptor (IL6R) gene, type I collagen alpha 1 (COL1A1) gene and bone morphogenetic protein-3 (BMP3) gene are unlikely to have a substantial effect on BMD variation in this Caucasian population. Along with previous studies searching for genes underlying BMD variation, the current study has further delineated the genetic basis of BMD variation and provided valuable information for future genetic studies.     

Effect of subtle positioning flaws on measured bone mineral density of the hip.

Careful hip positioning is necessary for accurate and precise measurement of bone mineral density (BMD) by dualenergy X-ray absorptiometry (DXA). Large, intentional rotational deviations from best hip position reportedly increase measured BMD at the femoral neck. The aim of this study is to determine the effect of unintentional, subtle deviations from best hip position ("flaws") on expected and measured BMD of the hip and its subregions. Two hundred DXA scans (GE/Lunar Prodigy) performed in the dual-femur mode were randomly selected and scrutinized for hip-positioning flaws. Hips were sorted by side (right/left), positioning quality (flawless/flawed), and specific positioning flaw (under/over-rotation and adduction/abduction). Individual hip pairs in which at least one hip was flawlessly positioned were further sorted as flawless/flawless, flawless/vertically flawed, flawless/rotationally flaw, and flawless/dually flawed. Differences and direction of difference in BMD between sorted groups and within individual hip pairs were analyzed by univariate analysis (t-test for equal samples). Two hundred hip pairs (400 individual hip scans) were analyzed. Overall, there was no significant difference in BMD between all right and all left hips or between all flawlessly positioned and all flawed hips. In hip pairs in which one hip was flawlessly positioned and the contralateral hip position was flawed (vertically, rotationally, or both), the measured BMD of the latter hip was not predictably greater than the former. Average absolute intrapair BMD difference between hip subregions was 0.038+/-0.001 g/cm2 and was unaffected by the presence or type of positioning flaw. Net intrapair difference between sorted hip groups and within hip pairs was negligible, indicating that the direction of the variance was equally positive and negative. In the practice of clinical densitometry, subtle positioning flaws do not generate predictable changes in measured BMD at any hip region of interest. The current teaching that rotational deviations from best hip position results in a greater measured BMD needs to be reconsidered when comparing a rotationally flawed hip with a contralateral flawlessly positioned hip.     

Changes in bone mineral density in transient osteoporosis of the hip

Transient osteoporosis of the hip is a disorder characterised by pain, and associated with temporary osteopaenia. Although osteopaenia is the essence of the condition, data do not exist about the local bone density of the femoral neck if no medication is administered. We describe three patients who were treated with limitation of weight-bearing only. Repeated bone mineral density measurements were obtained, and that at the femoral neck was lowest two months after the onset of the condition. The mean reduction in bone mineral density when compared with an age-matched control group was 13% (3% to 24%). Spontaneous recovery was observed in all patients.     

Added value of bone mineral density in hip fracture risk scores.

Hip fractures constitute a major health problem. For effective prevention, high-risk groups need to be identified. The objective here was to develop hip fracture risk scores while assessing the added value of bone mineral density relative to more conventional risk indicators. We prospectively followed during 4 years a cohort of 5208 persons (2193 men) aged 55 years and over from the Rotterdam Study, a population-based cohort study conducted in the Netherlands. Risk scores for hip fracture were constructed using several conventional risk indicators requiring interview and anthropometry only, and bone mineral density. During follow-up, 50 persons (14 men) suffered hip fracture. Hip fracture risk was independently determined by age, gender, height, the use of a walking aid, cigarette smoking, and either bone mineral density or weight. We developed two risk scores, with and without bone mineral density. The observed 4-year risk ranged from 3/3389 (0.1%) to 17/169 (10.1%) for the lowest and highest category of the score including bone mineral density, respectively. For the score without bone mineral density, these risks were 8/3117 (0.3%) and 16/144 (11.1%), respectively. The area under the receiver operating characteristic curve indicating discriminatory power was 0.88 for the risk score including, and 0.83 for the score excluding, bone mineral density (p for difference = 0.04). In conclusion, risk scores with and without bone mineral density measurement can be used for hip fracture risk assessment in elderly persons. While the score with bone mineral density has a modestly better performance, the score requiring interview and anthropometry only may be especially useful in primary care settings.     

Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice.

Significant differences in vertebral (9%) and femoral (50%) adult bone mineral density (BMD) between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice have been subjected to genetic analyses for quantitative trait loci (QTL). Nine hundred eighty-six B6C3F2 females were analyzed to gain insight into the number of genes that regulate peak BMD and their locations. Femurs and lumbar vertebrae were isolated from 4-month-old B6C3F2 females at skeletal maturity and then BMD was determined by peripheral quantitative computed tomography (pQCT). Estimates of BMD heritability were 83% for femurs and 72% for vertebrae. Genomic DNA from F2 progeny was screened for 107 polymerase chain reaction (PCR)-based markers discriminating B6 and C3H alleles on all 19 autosomes. The regression analyses of markers on BMD revealed ten chromosomes (1, 2, 4, 6, 11, 12, 13, 14, 16, and 18) carrying QTLs for femurs and seven chromosomes (1, 4, 7, 9, 11, 14, and 18) carrying QTLs for vertebrae, each with log10 of the odds ratio (LOD) scores of 2.8 or better. The QTLs on chromosomes (Chrs) 2, 6, 12, 13, and 16 were unique to femurs, whereas the QTLs on Chrs 7 and 9 were unique to vertebrae. When the two bone sites had a QTL on the same chromosome, the same marker had the highest, although different, LOD score. A pairwise comparison by analysis of variance (ANOVA) did not reveal significant gene x gene interactions between QTLs for either bone site. BMD variance accounted for by individual QTLs ranged from 1% to 10%. Collectively, the BMD QTLs for femurs accounted for 35.1% and for vertebrae accounted for 23.7 % of the F2 population variances in these bones. When mice were homozygous c3/c3 in the QTL region, 8 of the 10 QTLs increased, while the remaining two QTLs on Chrs 6 and 12 decreased, femoral BMD. Similarly, when mice were homozygous c3/c3 in the QTL region for the vertebrae, five of the seven QTLs increased, while two QTLs on Chrs 7 and 9 decreased, BMD. These findings show the genetic complexity of BMD with multiple genes participating in its regulation. Although 5 of the 12 QTLs are considered to be skeleton-wide loci and commonly affect both femurs and vertebrae, each of the bone sites also exhibited unique QTLs. Thus, the BMD phenotype can be partitioned into its genetic components and the effects of these loci on normal bone biology can be determined. Importantly, the BMD QTLs that we have identified are in regions of the mouse genome that have known human homology, and the QTLs will become useful experimental tools for mechanistic and therapeutic analyses of bone regulatory genes.     

老年性髋部骨折骨密度与骨形态计量学的关系

目的通过老年髋部骨折患者骨密度的测定和骨组织形态计量分析,探讨骨质疏松性骨折骨密度与骨结构的关系。方法选择低、中能量创伤所致髋部骨折需要手术治疗的老年患者30例,分为2组,男性14例,女性16例。以双能X线吸收骨密度仪(DEXA)测量患者健侧股骨近端大转子BMD。手术中用切面积1cm×1cm的环钻于患侧股骨大转子间区松质骨按统一标准定位后,钻取骨柱,进行骨组织形态计量学观察与分析。结果根据BMD测定的结果男性患者能诊断为骨质疏松症的有9例(64.29%),女性患者能诊断为骨质疏松症的有12例(75.00%)。骨组织形态计量学结果提示老年男女骨结构参数差异不明显,无统计学意义。老年男、女性股骨大转子BMD均与%Tb.Ar、Tb.Th、Tb.N、N/F成正相关,与Tb.Sp成负相关(P<0.05)。结论老年人男女两个组的股骨近端转子间区骨组织形态计量参数无明显差异,股骨近端转子间区的BMD与骨结构有一定的相关性,骨形态计量学分析较BMD更可靠、更敏感、更真实地反映骨质疏松的情况。