Comparison of whole genome linkage scans in premenopausal and postmenopausal women: no bone-loss-specific QTLs were implicated

Summary  This study was conducted to investigate if there exist bone-loss-specific quantitative trait loci (QTLs) for females. Genome-wide linkage scans were conducted in total, premenopausal, and postmenopausal women, respectively. No QTLs exclusively were found in postmenopausal women, suggesting that no bone-loss-specific QTL was implicated independent of BMD in our sample. Introduction  Bone mineral density (BMD) in elderly women is determined jointly by peak bone mass achieved before menopause and by subsequent bone loss upon and after menopause. Peak bone mass is under strong genetic control, but whether bone loss has genetic determination independent of peak BMD is unknown. Materials and methods  To investigate if there exist bone-loss-specific quantitative trait loci (QTLs) for females, we conducted genome-wide linkage scans in 2,582 Caucasian females from 451 pedigrees including 1,486 premenopausal and 1,096 postmenopausal women. Linkage analyses were performed in the total sample and premenopausal and postmenopausal women subgroups, respectively, and the results were compared. Results  No linkage evidence was found exclusively in postmenopausal women. Linkage signals identified are largely consistent in the total, premenopausal, and postmenopausal samples. For example, for spine BMD, for the total sample, a significant linkage was obtained on 15q13 (LOD = 3.67), and LOD scores of 1.52 and 2.49 were achieved on 15q13 in premenopausal and postmenopausal women, respectively. Conclusions  We did not find any QTLs exclusively in postmenopausal women; hence, no specific QTL for bone loss was implicated independent of BMD in our female sample.     

Bivariate Whole Genome Linkage Analyses for Total Body Lean Mass and BMD

A genome‐wide bivariate analysis was conducted for TBLM and BMD at the spine and hip in a large white sample. We found some QTLs shared by TBLM and BMD in the entire sample and the sex‐specific subgroups, and QTLs with potential pleiotropy were disclosed. Introduction: Previous studies suggested that total body lean mass (TBLM) and BMD are highly genetically correlated. However, the specific shared genetic factors between TBLM and BMD are unknown. Materials and Methods: To identify the specific quantitative trait loci (QTLs) shared by TBLM and BMD at the spine (L₁–L₄) and total hip, we performed bivariate whole genome linkage analysis (WGLA) in a large sample involving 4498 white subjects of European origin. Results: Multipoint bivariate linkage analyses for 22 autosomes showed evidence of significant linkage with an LOD score of 4.86 at chromosome region 15q13 for TBLM and spine BMD in women, and suggestive linkage findings (LOD > 2.2) at 7p22 for TBLM and spine BMD for the entire sample, at 7q32 for TBLM and BMD at both spine and hip in women, and at 7q21 and 13p11 for TBLM and BMD at both spine and hip in men. Two‐point linkage analyses for chromosome X also showed significant linkage signals at several regions such as Xq25. Complete pleiotropy (a single locus influencing both traits) was suggested at 7q32 and 13q11 for TBLM and BMD. Additionally, complete co‐incident linkage (separate tightly clustered loci each influencing a single trait) was detected at 7p22 for TBLM and spine BMD. Conclusions: We identified several genomic regions shared by TBLM and BMD in whites. Further studies may focus on fine mapping and identification of the specific QTLs in these candidate genomic regions.     

IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal women

To find out which of the following parameters—serum levels of insulin-like growth factor 1 (IGF-1), osteoprotegerin (OPG), leptin, osteocalcin (OC), and urinary excretion of N-terminal telopeptide of type I collagen (NTx), can be used as an early marker for osteopenia/osteoporosis in women diagnosed by dual-energy X-ray absorptiometry (DXA), 282 premenopausal and 222 postmenopausal women aged 20–75 years were investigated by the measurement of bone mineral densities (BMDs) at lumbar spine (LS) and femoral neck (FN) by DXA, together with serum concentrations of IGF-1, OPG, leptin, OC, and urinary NTx. The characteristics of the earliest marker(s) were tested with the receiver operating characteristic (ROC) analysis. The area under the curve (AUC), sensitivity, and specificity parameters were determined. It was revealed that serum levels of IGF-1 and leptin changed the earliest, with both markers significantly decreasing (P < 0.0001) or increasing (P = 0.020), respectively, at age 30. However, in ROC analysis, IGF-1 was the only early parameter that had the capacity to differentiate the low bone mass/osteoporosis women from the normal ones (P < 0.0001). If the serum level of IGF-1 at 1.5 SD below its peak was adopted as a cutoff point, it could identify women with low bone mass/osteoporosis with a sensitivity of 73% and specificity of 67%. In the premenopausal women subgroup analysis, the low bone mass women (30/282, 10.6%) were older (38.2 ± 1.7 vs. 34.5 ± 0.5 years; P = 0.026), with lower serum levels of IGF-1 (215.1 ± 22.4 vs. 278.8 ± 9.4 ng/ml; P = 0.02) and less lean mass (33.1 ± 0.6 vs. 34.8 ± 0.2 kg; P = 0.010) than the normal ones. After controlling for age, the serum level of IGF-1 had a weak, but still significant, positive correlation with lean mass (r = 0.17, P < 0.001). In conclusion, measurement of serum IGF-1 in young women may help in the early identification of those at risk for developing low bone mass and osteoporosis.     

A whole genome linkage scan for QTLs underlying peak bone mineral density

Summary We conducted a whole genome linkage scan for quantitative trait loci (QTLs) underlying peak bone mineral density (PBMD). Our efforts identified several potential genomic regions for PBMD and highlighted the importance of epistatic interaction and sex-specific analyses in identifying genetic regions underlying PBMD variation. Introduction Peak bone mineral density (PBMD) is an important clinical risk predictor of osteoporosis and explains a large part of bone mineral density (BMD) variation. Methods To detect susceptive quantitative trait loci (QTLs) for PBMD variation including consideration of epistatic and sex-specific effects, we conducted a whole genome linkage scan (WGLS) for PBMD using 2,200 Caucasians from 207 pedigrees, aged 20–50 years. All the individuals were genotyped with 410 microsatellite markers. In addition to WGLS in the total combined sample of males and females, we conducted epistatic interaction analyses, and sex-specific subgroup linkage analyses. Results We identified several potential genomic regions that met the criteria for suggestive linkage. The most impressing region is 12p12 for hip PBMD (LOD = 2.79) in the total sample. Epistatic interaction analyses found a significant epistatic interaction between 12p12 and 22q13 (p = 0.0021) for hip PBMD. Additionally, we detected suggestive linkage evidence at 15q26 (LOD = 2.93), 2p13 (LOD = 2.64), and Xq27 (LOD = 2.64). Sex-specific analyses suggested the presence of sex-specific QTLs for PBMD variation. Conclusions Our efforts identified several potential regions for PBMD and highlighted the importance of epistatic interaction and sex-specific analyses in identifying genetic regions underlying PBMD variation. Feng Zhang and Peng Xiao contributed equally to this article     

Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3

BACKGROUND: Prostate cancer (CaP) is a common disorder with multiple genetic and environmental factors contributing to the disease. CaP susceptibility loci can be identified through genome-wide scans of high-risk families. METHODS: Allele sharing at 405 markers, distributed across the genome, among 50 families with hereditary prostate cancer, ascertained throughout Sweden, was evaluated through linkage analyses. Genotype data were analyzed utilizing multipoint parametric and non-parametric methods. RESULTS: Two regions provided suggestive evidence for linkage: 19p13.3 (marker D19S209, LOD = 2.91, P = 0.0001) and 5q11.2 (marker D5S407, LOD = 2.24, P = 0.0007). Additional regions with moderate evidence for linkage in the complete set of families, or stratified subsets, were observed on chromosome 1, 4, 6, 7, 8, and X. CONCLUSIONS: Our results provide strong confirmatory evidence of linkage at 19q13.3 and 5q11.2. The lack of confirmation of linkage at several loci identified in other genome-wide scans emphasizes the need to combine linkage data between research groups.     

IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome‐wide association study

Bone mineral density (BMD) measured at the femoral neck (FN) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. The specific genes influencing FN BMD remain largely unknown. To identify such genes, we first performed a genome‐wide association (GWA) analysis for FN BMD in a discovery sample consisting of 983 unrelated white subjects. We then tested the top significant single‐nucleotide polymorphisms (SNPs; 175 SNPs with p < 5 × 10^?4) for replication in a family‐based sample of 2557 white subjects. Combing results from these two samples, we found that two genes, parathyroid hormone (PTH) and interleukin 21 receptor (IL21R), achieved consistent association results in both the discovery and replication samples. The PTH gene SNPs, rs9630182, rs2036417, and rs7125774, achieved p values of 1.10 × 10^?4, 3.24 × 10^?4, and 3.06 × 10^?4, respectively, in the discovery sample; p values of 6.50 × 10^?4, 5.08 × 10^?3, and 5.68 × 10^?3, respectively, in the replication sample; and combined p values of 3.98 × 10^?7, 9.52 × 10^?6, and 1.05 × 10^?5, respectively, in the total sample. The IL21R gene SNPs, rs8057551, rs8061992, and rs7199138, achieved p values of 1.51 × 10^?4, 1.53 × 10^?4, and 3.88 × 10^?4, respectively, in the discovery sample; p values of 2.36 × 10^?3, 6.74 × 10^?3, and 6.41 × 10^?3, respectively, in the replication sample; and combined p values of 2.31 × 10^?6, 8.62 × 10^?6, and 1.41 × 10^?5, respectively, in the total sample. The effect size of each SNP was approximately 0.11 SD estimated in the discovery sample. PTH and IL21R both have potential biologic functions important to bone metabolism. Overall, our findings provide some new clues to the understanding of the genetic architecture of osteoporosis. © 2010 American Society for Bone and Mineral Research     

成人阻塞性睡眠呼吸暂停低通气综合征与骨密度降低及骨质疏松相关性的Meta分析

目的探讨阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)与骨密度降低及骨质疏松之间的相关性。方法从PubMed、EMBASE、Web of Science、the Cochrane Library、中国生物医学文献数据库(CBM)、中国知网(CNKI)、万方数据库(Wanfang data)和维普数据库(VIP)检索OSAHS与骨密度及骨质疏松相关性的研究。采用纽卡斯尔-渥太华量表(the Newcastle-Ottawa scale,NOS)对纳入研究进行质量评价。所有数据的合并、亚组分析采用Review manager 5.3软件,敏感性分析和发表偏倚检测采用Stata 15.1软件。结果检索到1091篇文献,1074篇文献被排除,17篇全文文献里的17项研究所包含的113460位研究对象的数据被提取。OSAHS组与对照组相比,骨质疏松症的发生率高(OR=1.74,95%CI:1.43~2.13,P<0.00001);性别、年龄的亚组分析显示,男性(OR=1.90,95%CI:1.33~2.72,P=0.0004)、女性(OR=2.56,95%CI:1.96~3.34,P<0.00001)、大于65岁老年人(OR=2.62,95%CI:1.86~3.71,P<0.00001)、40~65岁中年人(OR=1.73,95%CI:1.31~2.28,P=0.0001)骨质疏松症的发生率均高。OSAHS组与对照组相比,腰椎骨密度显著降低(MD=-0.12,95%CI:-0.18~-0.06,P=0.0001)。性别的亚组分析显示,男性腰椎骨密度显著降低(一般人群:MD=-0.08,95%CI:-0.15~-0.01,P=0.02;无伴随疾病人群:MD=-0.12,95%CI:-0.19~-0.05,P=0.0008);女性腰椎骨密度略低(MD=-0.08,95%CI:-0.21~0.06,P=0.27),但差异无统计学意义。OSAHS组与对照组相比,股骨颈骨密度显著降低(MD=-0.12,95%CI:-0.19~-0.05,P=0.0007)。男性亚组股骨颈骨密度显著降低(一般人群:MD=-0.09,95%CI:-0.17~-0.02,P=0.02,无伴随疾病人群:MD=-0.11,95%CI:-0.19~-0.03,P=0.006);女性亚组股骨颈骨密度略低(MD=-0.10,95%CI:-0.33~0.12,P=0.37),但差异无统计学意义。各项分析纳入的研究无明显发表偏倚。结论OSAHS组与对照组相比,骨质疏松症的发生率高,腰椎骨密度、股骨颈骨密度均有所降低。     

骨质疏松的影像学与骨密度诊断专家共识

随着我国进入老龄化社会,骨质疏松症已经成为严重威胁老年人健康的常见疾病之一。骨质疏松表现为骨量减少、易发生骨折。影像学检查包括X线平片、CT、MRI、核医学检查和骨密度测量,在骨质疏松症的防治中发挥重要作用。由于骨质疏松症防治涉及多学科和多专业合作,但目前缺乏统一的共识,影响着学科发展和规范临床服务。为此,由来自放射、骨科、内分泌、影像技术和核医学专业专家组成的共识专家组,在充分复习国际指南、共识、文献以及国内最新研究成果的基础上,结合我国医疗实际情况,针对骨质疏松的影像学和骨密度测量技术、诊断标准和鉴别诊断形成共识,为临床医务工作者在骨质疏松的影像学与骨密度临床应用方面提供科学、具体的指导,促进我国骨质疏松症的影像学与骨密度诊断规范化发展。     

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.     

男性骨质疏松与冠心病相关性的Meta分析

目的运用Meta分析探究男性骨质疏松与冠心病之间的关系。方法检索中外文献数据库,包括Pubmed、Cochrane、Embase、CNKI、万方数据库、维普中文科技期刊全文数据库(VIP)和中国生物医学文献数据库(CBM)等,检索时间自建库至2020年6月,通过纳入、排除标准筛选合适的文献,根据Newcastle-Ottawa Scale (NOS)量表评价文献质量,应用Review Manager5.3软件进行数据分析。结果最终纳入11篇文献,共涉及1 962例患者,包括骨质疏松组603例,非骨质疏松组(骨量减少和骨量正常) 1 359例。Meta分析结果发现,男性骨质疏松组冠心病的发病率显著高于非骨质疏松组(OR=1.43,95%CI 1.14～1.79,P0.05);根据患者不同年龄段进行亚组分析,中年男性骨质疏松组冠心病的发病率与非骨质疏松组相比无统计学意义(OR=0.92,95%CI 0.23～3.69,P 0.05),但老年男性骨质疏松组冠心病的发病率显著增高(OR=1.86,95%CI1.12～3.08,P0.05);根据患者不同骨量减少程度进行亚组分析,中、老男性骨量减少组冠心病的发病率与骨量正常组相比均无统计学意义(中年男性OR=1.25,95%CI 0.66～2.36,P0.05;老年男性OR=1.11,95%CI 0.35～3.53,P0.05)。结论老年男性骨质疏松与冠心病的发病率密切相关,中年男性骨质疏松与冠心病的发病率无明显相关性,且中、老年男性骨量减少与冠心病的发病率无明显相关性。     

Adipose tissue and volumetric bone mineral density of older Afro‐Caribbean men

Although low body weight is a risk factor for osteoporosis‐related fractures, conflicting data exist for the association between adiposity and bone mineral density (BMD). Studies examining these relationships have measured body fat and BMD with dual‐energy X‐ray absorptiometry (DXA), which cannot distinguish subcutaneous adipose tissue area (SAT) from total adiposity or trabecular from cortical bone. To investigate the relationship between adiposity and BMD further, we analyzed body composition and adipose tissue distribution by quantitative computed tomography (QCT) in 1829 Afro‐Caribbean men aged 40 years and older from a population‐based sample. Cortical volumetric BMD, muscle cross‐sectional area, total adipose tissue area (TAT), and percentage SAT were measured at the proximal tibia. Trabecular volumetric BMD was measured at the distal tibia. We used analysis of covariance to test for associations between quartile of the adipose tissue measures and BMD, adjusting for anthropometric, health, and lifestyle factors. Higher TAT was associated with lower cortical BMD in both unadjusted and adjusted models (p < .001). Men with a higher percentage SAT had greater cortical BMD (p < .001). Similar associations were seen between percent SAT and trabecular BMD at the distal tibia. These results indicate that total adiposity is a potentially important correlate of bone mass in older men and that different fat depots may have opposing associations with bone mass. Additional research is needed to better understand the mechanisms underlying the relationship between body fat distribution and bone mass. © 2010 American Society for Bone and Mineral Research.     

Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men

In contrast to conventional dual‐energy X‐ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single‐nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment. © 2010 American Society for Bone and Mineral Research     

An assessment of bone scans for monitoring osseous metastases in patients being treated for prostate carcinoma

The National Prostatic Cancer Project held a workshop in March 1980 to examine procedures used to evaluate bone metastases. Variations in techniques used by each of 9 treatment centers, as well as the National Cancer Institute, were compared. One center in particular had developed procedures for quantitating bone scans in addition to the customary qualitative evaluation. Changes in bone scan assessments were also related to changing levels of isoenzymes of acid and alkaline phosphatase. Most consistently correlated with disease changes were prostatic acid phosphatase, as determined by counter-immunoelectrophoresis, and the isoenzyme of bone alkaline phosphatase. Gamma cameras were recommended over rectilnear scanners as were multiple spot films to concentrate on problem areas. Bone scans must be performed prior to therapy and for best assessment no sooner than 3 months to avoid the flair phenomenon. Consistency of both machine settings and patient position are paramount, as are quality of equipment and review of past scans and X-ray films where appropriate to obtain the best assessment of disease status.     

A genome scan for all-cause end-stage renal disease in African Americans.

BACKGROUND: In an attempt to map the genes predisposing to the common, complex aetiologies of end-stage renal disease (ESRD), we performed a genome-wide scan in 1023 individuals with chronic kidney disease (946 dialysis dependent and 77 with advanced chronic renal failure) from 483 African American families. METHODS: The study sample comprised 563 ESRD-affected sibling pairs, with nephropathy attributed to diabetes mellitus, chronic glomerular disease or hypertension. Multipoint non-parametric linkage (NPL) analysis methods were employed. RESULTS: NPL regression provided modest evidence of linkage to 13q33.3 near D13S796 [log of the odds (LOD) = 1.72], 9q34.3 near D9S1826 (LOD = 1.22), 4p15.32 near D4S2639 (LOD = 1.11) and 1q25.1 near D1S1589 (LOD = 1.01). Adjusting for the evidence of linkage at the other loci using NPL regression analysis provided evidence for linkage to 4p15.32, 9q34.3 and 13q33.3. NPL regression interaction and ordered subset analysis (OSA) suggested that the evidence for linkage to ESRD significantly increased with higher body mass index (BMI) at 13q33.3 (LOD = 4.94 in 61% of families with the highest BMI). Additionally, OSA suggested that linkage significantly improved in the 13% of families with earliest age at ESRD onset (LOD = 3.05 at 2q32.1) and in the 16% of families with latest age at ESRD onset (LOD = 2.47 at 10q26.3). CONCLUSIONS: Multipoint single-locus linkage analysis provided modest evidence of linkage to all-cause ESRD in African Americans on 13q33.3, and NPL regression and OSA suggested that evidence for linkage in this region markedly increased in obese families. This region, as well as 9q34.3, 4p15.32 and 1q25.1, should receive priority in the search for loci contributing to ESRD susceptibility in African Americans.     

Estimates of the Proportion of Older White Women Who Would Be Recommended for Pharmacologic Treatment by the New U.S. National Osteoporosis Foundation Guidelines

The new U.S. National Osteoporosis Foundation Clinician's Guide to Prevention and Treatment of Osteoporosis includes criteria for recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck (FN), or spine BMD T‐scores ≤?2.5 and presence of low bone mass at the FN or spine plus a 10‐yr risk of hip fracture ≥3% or of major osteoporotic fracture ≥20%. The proportion of women who would be recommended for treatment by these guidelines is not known. We applied the NOF criteria for treatment to women participating in the Study of Osteoporotic Fractures (SOF). To determine how the SOF population differs from the general U.S. population of white women ≥65 yr of age, we compared women in SOF with women who participated in the National Health and Nutrition Examination Survey (NHANES) III on criteria included in the NOF treatment guidelines that were common to both cohorts. Compared with NHANES III, women in SOF had higher FN BMD and were younger. Application of NOF guidelines to SOF data estimated that at least 72% of U.S. white women ≥65 yr of age and 93% of those ≥75 yr of age would be recommended for drug treatment. Application of the new NOF Guidelines would result in recommending a very large proportion of white women in the United States for pharmacologic treatment of osteoporosis.     

Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent.

Mutations of SQSTM1 are an important cause of PDB, but other genes remain to be discovered. A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations. INTRODUCTION: Paget's disease of bone (PDB) has a strong genetic component, and several susceptibility loci have been identified by genome-wide linkage scans. We previously identified three susceptibility loci for PDB using this approach on chromosomes 5q35, 2q36, and 10p13 in 62 families of mainly British descent, but subsequently, mutations in the SQSTM1 gene were found to be the cause of PDB in 23 families from this cohort. Here we reanalyzed the results of our genome-wide search in families from this cohort who did not have SQSTM1 mutations. MATERIALS AND METHODS: The study population consisted of 210 individuals from 39 families of predominantly British descent with autosomal dominant inheritance of PDB in whom SQSTM1 mutations had been excluded by mutation screening. The average family size was 5.44 +/- 3.98 (SD) individuals (range, 2-24 individuals). Genotyping was performed using standard techniques with 382 microsatellite markers spaced at an average distance of 9.06 cM throughout the autosomes. Multipoint linkage analysis was performed using the GENEHUNTER program under models of homogeneity and heterogeneity. RESULTS: Multipoint parametric linkage analysis under a model of homogeneity and nonparametric linkage analysis under a model of heterogeneity both showed strong evidence of linkage to a single locus on chromosome 10p13 (LOD score, +4.08) close to the marker D10S1653 at 41.43cM. No evidence of linkage was detected at the chromosome 2q36 locus previously identified in this population, and linkage to other candidate loci previously implicated in the pathogenesis of PDB was excluded. CONCLUSIONS: We conclude that there is an important susceptibility gene for PDB on chromosome 10p13 in families of British descent and find no evidence to support the existence of a susceptibility locus on chromosome 2q36 or other previously identified candidate loci for PDB in this population. The gene that lies within the 10p13 locus seems to account for the development of PDB in the vast majority of families of British descent who do not carry SQSTM1 mutations.     

Genetically based influences on the site-specific regulation of trabecular and cortical bone morphology.

The degree of site-specificity by which genes influence bone quantity and architecture was investigated in the femur of three strains of mice. Morphological indices were highly dependent on both genetic makeup as well as anatomical location showing that the assessment of bone structure from a single site cannot be extrapolated to other sites even within a single bone. INTRODUCTION: The identification of genes responsible for establishing peak BMD will yield critical information on the regulation of bone quantity and quality. Whereas such knowledge may eventually uncover novel molecular drug targets or enable the identification of individuals at risk of osteoporosis, the site-specificity by which putative genotypes cause low or high bone mass (and effective bone morphology) is essentially unknown. MATERIALS AND METHODS: microCT was used to determine morphological and microarchitectural features of the femora harvested from three genetically distinct strains of 4-month-old female mice, each with distinct skeletal mass (low: C57BL/6J [B6], medium: BALB/cByJ [BALB], high: C3H/HeJ [C3H]). Two trabecular regions (distal epiphysis and metaphysis) were considered in addition to four cortical regions within the metaphysis and diaphysis. RESULTS AND CONCLUSIONS: Comparing morphological properties of the different trabecular and cortical femoral regions between the three strains of mice, it was apparent that high or low values of specific parameters of bone morphology could not be consistently attributed to the same genetic strain. Trabecular metaphyseal bone volume, for instance, was 385% larger in C3H mice than in B6 mice, yet the two strains displayed similar bone volume fractions in the epiphysis. Similarly, BALB mice had 48% more trabecular bone than C3H mice in the epiphysis, but there were no strain-specific differences in cortical bone area at the diaphysis. These data suggest that the genetic control of bone mass and morphology, even within a given bone, is highly site-specific and that a comprehensive search for genes that are indicative of bone quantity and quality may also have to occur on a very site-specific basis.     

银杏叶提取物对糖皮质激素诱导的骨质疏松症大鼠骨密度和骨生物力学的影响

目的评估银杏叶提取物(ginkgo biloba extract, Gbe)对糖皮质激素诱导的骨质疏松大鼠血清骨碱性磷酸酶、骨密度、胫骨生物力学的影响。方法经过糖皮质激素诱导骨质疏松后,将大鼠分为五组:骨质疏松组、Gbe-1组、Gbe-2组、阿仑膦酸钠组和对照组。经过4周和8周的治疗,将对照组与骨质疏松组的血清骨碱性磷酸酶、骨密度、胫骨生物力学改变进行比较(Student’s t检验),而骨质疏松组和其他治疗组通过ANOVA检验然后行Tukey/Dunnett’ T3(P0.05)进行分析。结果在骨质疏松组中,骨碱性磷酸酶、骨密度、骨刚度、最大负荷和弹性降低(P0.05)。Gbe-1和Gbe-2组骨碱性磷酸酶值增加。此外,Gbe-1,Gbe-2和阿仑膦酸钠组,骨密度增加(P0.05);与骨质疏松组相比,Gbe-1,Gbe-2和阿仑膦酸钠组显示出骨硬度、最大负荷和弹性值显著增加(P0.05)。结论银杏叶提取物可显著提高糖皮质激素诱导的骨质疏松大鼠的骨碱性磷酸酶、骨刚度、最大负荷和弹性及骨密度。     

A Population‐Based Assessment of Rates of Bone Loss at Multiple Skeletal Sites: Evidence for Substantial Trabecular Bone Loss in Young Adult Women and Men

Using QCT, we made a longitudinal, population‐based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes. Introduction: Although conventional wisdom holds that bone loss begins at menopause in women and later in life in men, this has not been examined longitudinally in population‐based studies using precise technology capable of distinguishing cortical and trabecular bone. Materials and Methods: In an age‐ and sex‐stratified population sample (n = 553), we measured volumetric BMD (vBMD) of trabecular and cortical bone by QCT annually for up to 3 yr at the distal radius (DR) and distal tibia (DT) (n = 552) and trabecular vBMD at baseline and 3 yr at the lumbar spine (LS) (n = 474). Results: Substantial cortical bone loss began in middle life in women but began mainly after age 75 in men. In contrast, substantial trabecular bone loss began in young adult women and men at all three skeletal sites and continued throughout life with acceleration during perimenopause in women. Women experienced 37% and men experienced 42% of their total lifetime trabecular bone loss before age 50 compared with 6% and 15%, respectively, for cortical bone. Median rates of change in trabecular bone (%/yr) were ?0.40, ?0.24, and ?1.61 in young adult women and ?0.38, ?0.40, and ?0.84 in young adult men at the DR, DT, and LS, respectively (all p < 0.001). The early trabecular bone loss did not consistently correlate with putative causal factors, except for a trend with IGF‐related variables at DT in women. However, in postmenopausal women and, to a lesser extent, in older men, higher rates of cortical and trabecular bone loss were associated with lower levels of biologically‐active sex steroids and with higher levels of follicle‐stimulating hormone and bone turnover markers. Conclusions: The late onset of cortical bone loss is temporally associated with sex steroid deficiency. However, the early‐onset, substantial trabecular bone loss in both sexes during sex steroid sufficiency is unexplained and indicates that current paradigms on the pathogenesis of osteoporosis are incomplete.