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.     

Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women

Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two‐stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 × 10^?6) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p < 10^?5), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230‐kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 × 10^?7) accounted for >2.5% of the variation in spinal BMD in these women. The 230‐kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230‐kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women.     

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     

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     

Longitudinal Trends in Use of Bone Mass Measurement Among Older Americans, 1999–2005

Bone mass measurement (BMM) is useful to identify persons with low bone mass who are at increased risk for fracture. Given the increased emphasis that is being placed on preventive services such as screening for osteoporosis, we evaluated trends in BMM among Medicare beneficiaries. We studied a 5% sample of Medicare beneficiaries ≥65 yr of age in 1999–2005. We identified claims for BMM tests performed in both facility and nonfacility settings, evaluated temporal trends in use of these tests, and described the proportion of tests attributable to each specialty of physicians submitting claims. We also assessed patterns of serial testing among individuals who were tested more than once. Claims data from all years were pooled to describe the proportion of persons in the population ever tested. From 1999 to 2005, use of central DXA increased by ～50%, and use of peripheral DXA declined. The greatest increases in central DXA occurred among internists, family practitioners, and gynecologists. In 1999, the proportion of 65‐yr‐old women tested was 8.4%; this increased to 12.9% in 2005. Corresponding proportions for men were 0.6% and 1.7%, respectively. Between 40% and 73% of persons receiving central DXA were retested, most at ～2‐yr intervals. Aggregating data across all years for whites and blacks, 30.0% of women and 4.4% of men underwent central DXA at least once. We conclude that, although use of DXA steadily increased from 1999 to 2005, only ～30% of women and 4% of men at least 65 yr old had a central DXA study. Given the importance of central DXA to assess the risk of osteoporotic fractures, strategies to increase central DXA use to test at‐risk persons are warranted.     

唑来膦酸连续2年治疗绝经后女性骨质疏松临床观察

目的：观察唑来膦酸连续2年治疗绝经后女性骨质疏松的疗效、急性发热反应情况及其相关因素分析。方法回顾性分析我科2010年7月至2013年7月连续2年静脉使用唑来膦酸5mg滴注治疗绝经后女性骨质疏松患者共46人。年龄60～74岁,平均年龄（66．87±6．77）岁。观察每次急性期发热出现比例及每例患者前后2次药物输注后发热出现情况。比较治疗第1年、第2年骨质疏松差异及甲状旁腺激素、血清钙差异。结果46例患者中第1次输注唑来膦酸共观察到20人发热,占43．4％,次年输注唑来膦酸仅1例出现发热,发热组治疗前甲状旁腺激素水平显著高于无发热组（ P＜0．05）。第2次输注前甲状旁腺激素、血清钙较第1年输注前均无显著差异（ P＞0．05）,第2次输注前骨密度监测腰椎及全髋T值较第1次有所改善（P＜0．05）。结论绝经后女性骨质疏松患者连续静脉用唑来膦酸治疗对骨密度有改善,首次治疗出现急性期发热反应并不少见,但均为一过性,次年均可耐受。治疗前PTH水平可能与发热反应相关。     

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.     

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.     

High Prevalence of Osteoporosis and Morphometric Vertebral Fractures in Indian Males Aged 60 Years and Above: Should Age for Screening Be Lowered?

Current guidelines recommend bone mineral density (BMD) measurement in asymptomatic men above age 70 years and vertebral fracture (VF) assessment above 80 years with T-score <?1.0 with risk factors. We studied the prevalence of osteoporosis and morphometric VF in asymptomatic males aged 60 years and above in North India. Free-living community-dwelling men (n?=?241, age: mean?±?standard deviation 68.0?±?6.2 years) underwent a detailed history, physical examination, biochemical evaluation, and BMD measurements at 3 sites: lumbar spine, total hip (TH), and femoral neck (FN). Morphometric VF were assessed by instant vertebral assessment using Genant et al's semiquantitative method. We observed osteoporosis, osteopenia, and normal BMD in 19%, 56%, and 25% of subjects, respectively. The decade wise prevalence of osteoporosis in the age groups 60–70 years, 71–80 years, and >80 years was 16.9%, 17%, and 50%, respectively. Mean serum 25OHD levels were 17.2?±?10.3?ng/mL. Vitamin D deficiency (<20?ng/mL) and secondary hyperparathyroidism (plasma intact parathyroid hormone >65?ng/mL) were present in 68.8% and 45.4%, respectively. VF were present in 29.6% subjects (grade I: 58%, grade II: 32.4%, and grade III: 8.8%). Age and iPTH had significant negative correlation with BMD at FN and TH. Serum 25OHD had no correlation with BMD at any site. The prevalence of VF was positively associated with age (p?=?0.018) and negatively associated with BMD at FN (p?=?0.002) and TH (p?=?0.013). Osteoporosis and VF are common in asymptomatic Indian males aged 60 years and above. Screening for osteoporosis and instant vertebral assessment may be recommended earlier than currently existing guidelines.     

血清瘦素与绝经后2型糖尿病女性患者骨密度的相关性研究

目的探索血清瘦素与绝经后2型糖尿病患者骨密度的相关性。方法共纳入98名2型糖尿病女性进行分析,通过双能X线骨密度仪对受试者髋部BMD进行检查,并测定T评分,按照骨密度检测结果分为骨质疏松症组(PMOPW)以及非骨质疏松组(PMW)。对照组按照BMI与骨质疏松症受试者匹配。通过酶联免疫吸附法(ELISA)测定检测血清瘦素水平。结果两组血清瘦素和BMD值差异均有统计学意义(瘦素,(18.23±8.56) ng/m L vs (22.44±9.56) ng/m L,P0.05)和(BMD,(-0.74±0.13) vs(-3.127±0.55),P0.05)。在PMOPW中,血清瘦素和BMD与体重、BMI、腰围、臀围显著相关。多元线性逐步回归分析显示PMW和PMOPW的体重和BMI是BMD的独立预测因子。未发现血清瘦素水平是两组BMD的预测因子。结论体重和BMI对2型糖尿病患者BMD影响显著,但是未发现血清瘦素与PMW和PMOPW的BMD有关。     

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.     

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.     

Leukocyte Telomere Length Is Not Associated With BMD,Osteoporosis, or Fracture in Older Adults: Results From the Health,Aging and Body Composition Study

Short leukocyte telomere length (TL), low BMD, and osteoporosis have been associated with increased inflammation. Previous reports suggest an association between TL, BMD, and osteoporosis in women. We sought to verify these associations and to determine whether TL is related to fracture in a cohort of older men and women. Participants included 2750 community‐dwelling older persons from the longitudinal Health, Aging, and Body Composition Study (Health ABC) in who average leukocyte TL was measured at baseline using qPCR. We used unconditional logistic regression to determine the association of TL with prevalent fracture, Cox proportional hazards regression for the association with 7‐yr incident fracture, and mixed linear models for the association with BMD, change in BMD, and the number of incident fractures. TL was negatively correlated with age, weight, fasting insulin, and fasting glucose in men and women, and additionally, with C‐reactive protein and IL‐6 in men. TL was not associated with BMD; change in BMD over 1, 3, or 5 yr; osteoporosis; baseline fracture; or 7‐yr incident fracture, before or after adjustment for age, race, smoking, and health characteristics. TL is not associated with BMD, osteoporosis, or fracture in older men or women in this sample.     

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.     

High‐Density Association Study of 383 Candidate Genes for Volumetric BMD at the Femoral Neck and Lumbar Spine Among Older Men

Genetics is a well‐established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community‐dwelling white men ≥65 yr of age in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (p < 0.01) were validated by genotyping an additional 1156 white men from MrOS. This analysis identified 8 SNPs in 6 genes (APC, DMP1, FGFR2, FLT1, HOXA, and PTN) that were associated with femoral neck vBMD and 13 SNPs in 7 genes (APC, BMPR1B, FOXC2, HOXA, IGFBP2, NFATC1, and SOST) that were associated with lumbar spine vBMD in both genotyping samples (p < 0.05). Although most associations were specific to one skeletal site, SNPs in the APC and HOXA gene regions were associated with both femoral neck and lumbar spine BMD. This analysis identifies several novel and robust genetic associations for volumetric BMD, and these findings in combination with other data suggest the presence of genetic loci for volumetric BMD that are at least to some extent skeletal‐site specific.