Over-expression of Adamts1 in mice alters bone mineral density

ADAMTS1, a secreted multifunctional metalloproteinase with disintegrin and thrombospondin motifs, is an early response gene of parathyroid hormone (PTH) in osteoblasts. Mice engineered to lack Adamts1 are smaller compared to wild-type (WT) mice and ADAMTS1 metalloproteinase activity has been shown to increase osteoblastic growth in collagen gels. However, there are no reports investigating the consequence of Adamts1 over-expression on bone tissue in vivo. Here, we analyze bones of female and male transgenic (TG) mice over-expressing mouse Adamts1 using peripheral quantitative computed tomography to evaluate its effect on bone shape and mineral density. Western blotting of protein extracts and immunohistochemistry of bone sections reveal increased presence of Adamts1 protein in TG bones compared to WT bones. Phenotypic analyses of femur show that female TG mice have reduced metaphyseal total density, trabecular bone mineral density and trabecular mineral content. In contrast, male TG mice which were without changes in the metaphysis showed increased total density and cortical density at the mid-diaphysis cortical site. Female TG mice showed no significant changes at the cortical site compared to WT mice. Furthermore, diaphyseal endosteal compartment was only affected in male TG mice. Along these lines, Adamts1 increased blood levels of PTH only in females whereas it reduced osteocalcin levels only in males. These results reveal that Adamts1 has an impact on bone mineral density and thus further confirm Adamts1 as a potent regulator of bone remodeling.     

Distal femoral bone mineral density after total knee arthroplasty: a comparison with general bone mineral density

The bone mineral density (BMD) of the distal femur may decrease after cemented total knee arthroplasty (TKA) as a result of the stress shielding effect of the femoral component. The purpose of the study was to determine the changes in BMD of the distal femur compared with those of the femoral necks and the lumbar spine after cemented TKA. BMD of two regions of interest in the distal femur, both femoral necks and the lumbar spine was measured with dual-energy X-ray absorptiometry in 10 patients (age range 41–80 years, mean 62 years) with 12 TKAs preoperatively and during follow-up for 1 year after surgery. The hip and spine measurements were performed for comparison to assess if general changes in BMD occurred after TKA. The median decrease in BMD in the region behind the anterior flange of the femoral component was 22% (95% CI: 12%–33%), while the average decrease in the region just above the femoral component was 8% (95% CI: 2%–13%). The difference in change of BMD between both regions before and 1 year after TKA was significant (p = 0.03).We found less than 1% difference in BMD of both femoral necks and the lumbar spine on average between the preoperative and 1 year follow-up measurements (not significant). A significant periprosthetic distal femoral bone resorption occurred after TKA. BMD of the femoral necks and lumbar spine did not differ 1 year after TKA. Received: 21 March 2000     

股骨干骺段骨密度对股骨质量评价作用的研究

目的 探讨股骨干骺段骨密度对股骨质量评价作用。方法 ３０侧股骨标本行骨密度与Ｓｉｎｇｈ指数测定,并行生物力学测试。结果 股骨干骺段骨密度与其他骨密度指标及Ｘｉｎｇｈ指数、假体的稳定性高度相关。结论 股骨干骺段骨密度是评价股骨质量的良好指标。     

Bilateral measurement of femoral bone mineral density.

Both femora were measured on 61 normal adults using dual X-ray absorptiometry (DXA). In a subset of 31 subjects, each femur was scanned once using the conventional leg-positioning device supplied with the densitometer, and once using a new positioning device and software that allowed both legs to be measured simultaneously. In another subgroup (n = 30), subjects were measured three times using the new dual-femur approach to better assess precision error. The data were analyzed for differences owing to the different positioning devices and for differences between right and left sides. The correlation between results with the old and new positioners was high (r > 0.99, standard error of the estimate [SEE] = 0.01-0.02 g/cm(2)). There was no significant difference in the average bone mineral density (BMD) values between the old and new positioner. The precision errors for each femur alone with the dual-femur approach were similar to those reported for the single-femur scans (1 to 2%), but the precision errors for the combined femora were reduced by 30% as expected. The correlation between right and left sides was high (r = 0.94-0.96), and the SEE in predicting one side from the other was moderate for total, trochanteric, and femoral neck BMD (0.05, 0. 05, and 0.06 g/cm(2), respectively). These SEE equate to about 0.5 standard deviation in terms of T-score. Differences in many individual cases between the right and left sides were significantly greater than the precision error. The new dual-femur software and leg positioner allows rapid measurement and analysis of both femora, thereby eliminating the uncertainty between sides.     

Relationship of femoral neck areal bone mineral density to volumetric bone mineral density, bone size, and femoral strength in men and women

Summary

Using combined dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography, we demonstrate that men matched with women for femoral neck (FN) areal bone mineral density (aBMD) have lower volumetric BMD (vBMD), higher bone cross-sectional area, and relatively similar values for finite element (FE)-derived bone strength.

Introduction

aBMD by DXA is widely used to identify patients at risk for osteoporotic fractures. aBMD is influenced by bone size (i.e., matched for vBMD, larger bones have higher aBMD), and increasing evidence indicates that absolute aBMD predicts a similar risk of fracture in men and women. Thus, we sought to define the relationships between FN aBMD (assessed by DXA) and vBMD, bone size, and FE-derived femoral strength obtained from quantitative computed tomography scans in men versus women.

Methods

We studied men and women aged 40 to 90?years and not on osteoporosis medications.

Results

In 114 men and 114 women matched for FN aBMD, FN total cross-sectional area was 38% higher (P?P?Conclusions In this cohort of young and old men and women from Rochester, MN, USA who are matched by FN aBMD, because of the offsetting effects of bone size and vBMD, femoral strength and the load-to-strength ratio tended to be relatively similar across the sexes.     

定量CT对股骨头松质骨骨密度的测量

目的探讨利用定量CT(quantitative computed tomography,QCT)中"3D Spine Exam Analysis"软件分析模块测量股骨头松质骨的骨密度的可重复性,以及患者双侧股骨头松质骨骨密度的差异性。方法回顾性研究330名(女性239人,男性91人)受试者的股骨头松质骨骨密度,对其中因各种原因仅可获得一侧髋关节图像的受试者149人进行可重复性研究;对其余的受试者181人进行双侧股骨头松质骨骨密度的差异性研究。利用QCT Pro软件中"3D Spine Exam Analysis"软件分析模块将股骨头划分为上、中、下3个层面:靠近股骨颈上部皮质、经股骨颈中心、靠近股骨颈下部皮质,并对各个层面进行测量。结果2名不同操作者测量同一股骨头的相同层面松质骨骨密度值的差异无统计学意义(P_上=0. 148 0. 05,P_中=0. 05,P_下=0. 0970. 05)。同一患者双侧股骨头相对应层面的松质骨骨密度之间具有良好相关性。在上层,两侧股骨头的松质骨骨密度之间的差异无统计学意义(P_上=0. 4450. 05);而在中层与下层,两侧股骨头的松质骨骨密度之间的差异有统计学意义(P_中=0. 0000. 05,P_下=0. 0000. 05)。结论利用QCT中"3D Spine Exam Analysis"软件分析模块进行股骨头松质骨的骨密度测量具有较好的可重复性。患者双侧股骨头不同层面松质骨的骨密度具有良好的相关性,并且左侧股骨头的中层与下层的松质骨骨密度显著大于右侧。     

The role of Dkk1 in bone mass regulation: Correlating serum Dkk1 expression with bone mineral density

The Wnt/β‐catenin pathway is a major signaling cascade in bone biology, playing a key role in regulating bone development and remodeling, with aberrations in signaling resulting in disturbances in bone mass. The objectives of our study were to correlate serum Dkk1 expression with bone mineral density (BMD) and assess the potential role of Dkk1 as a serological marker of bone mass. Serum was collected from a cohort of patients (n = 36), 18 patients with a reduced BMD and 18 control patients. Serum Dkk1 expression as quantified by ELISA was correlated with lumbar and femoral t‐ and z‐scores. Serum Dkk1 concentration in the osteoporosis group was significantly higher than control group (941 ± 116 vs. 558 ± 47 pg/ml, p < 0.01). Serum Dkk1 expression was highly correlated with bone mass variables with inverse associations found between serum Dkk1 expression and lumbar t‐score (r = ?0.34, p = 0.00433), lumbar z‐score (r = ?0.22, p = 0.1907), femur t‐score (r = ?0.42, p = 0.0101), and femur z‐score (r = ?0.43, p = 0.0089). Our data further emphasizes the pivotal role played by Wnt/β‐catenin signaling in bone mass regulation. Dkk1, a powerful antagonist of canonical Wnt signaling, may have a role to play as a serological marker for disorders of bone mass, warranting further evaluation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:414–418, 2011     

Genetic regulation of bone mass: from bone density to bone strength

Osteoporosis is a common disease characterized in adults by diminished bone density. Bone is an organ that evolves and grows throughout life, and establishing optimal bone density in childhood and adolescence serves to buffer bone loss later in life. Bone density, a measurable entity, is the clinical substitute for bone strength, or the ability to defend against fracture. Chronic diseases may adversely affect optimal peak bone density. Bone density is under genetic control, as revealed by three lines of investigations. These include (1) the finding of quantitative trait loci for bone density, (2) the finding that specific mutations in genes that are important in the development of osteoblast or osteoclast lineages alter bone density, and (3) the linkeage of known polymorphisms for genes involved in mineral homeostasis to bone density and/or fracture. Future therapeutics for improving peak bone density or delaying bone loss later in life may take advantage of the genetic nature of bone density development.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Endogenous sex steroids and bone mineral density in healthy men

OBJECTIVE: To evaluate the role of endogenous sex steroids on bone mineral density (BMD) in healthy Turkish men. METHODS: Serum total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate and estradiol levels were assayed in 174 healthy men of 240 volunteers, aged 22-76 years. Dual-energy X-ray absorptiometry was used to measure the BMD (g/cm(2)) of lumbar spine, femoral neck and non-dominant proximal and distal radius-ulna sites. Linear regressions were conducted using each BMD site as the dependent variable and each sex steroid as the independent variable. Four models were run for each bone site and sex steroid; crude, age-adjusted, adjusted for age and body mass index (BMI), and adjusted for age, BMI and cigarette-smoking. RESULTS: The mean age and BMI of men enrolled in the study were 47.7 +/- 13.7 years and 26.9 +/- 3.6 kg/m(2). Log of FT was significantly associated with the BMD of distal forearm in all models analyzing the crude and adjusted effects. Dehydroepiandrosterone sulfate effect on BMD of proximal forearm came closer to the level of statistical significance when adjusted with age, BMI and cigarette-smoking. Estradiol and TT levels were not found to be associated with BMD of any sites measured. CONCLUSION: Among the endogenous sex steroids in men, predominantly FT seems to be one of the determinants of BMD. Therefore a decrease in serum levels of testosterone in aging male or secondary causes may negatively affect BMD.     

姜黄素对APP/PS1转基因鼠骨微结构及骨密度的影响

目的应用Micro-CT定量研究用姜黄素治疗前后APP/PS1转基因鼠胫骨近端的骨微结构及骨密度的变化。方法 3月龄雌性小鼠(n=6/组)分为以下3组:野生型小鼠(对照组),APP/PS1转基因鼠(模型组)和APP/PS1转基因鼠+姜黄素(用药组)。对照组和模型组自由摄食和饮水;用药组,姜黄素按600mg·kg-1加入正常小鼠饲料,3组小鼠喂养至12月龄时处死,取其胫骨,应用Micro-CT进行扫描分析。结果 APP/PS1转基因组小鼠胫骨近端骨微结构、骨密度参数明显小于野生型小鼠(P0.05);APP/PS1转基因小鼠用药后胫骨近端骨微结构、骨密度参数明显大于用药前(P0.05),接近于野生型小鼠(P0.05)。结论姜黄素有助于提高APP/PS1转基因组小鼠的骨小梁数目、骨小梁厚度,骨密度,对APP/PS1转基因组小鼠骨微结构的改善有一定的治疗作用。     

老年男性性激素与骨密度测定

目的　为了解老年男性的骨密度和性激素水平,以探讨性激素在老年男性骨质疏松症发病机理中的作用。方法　６３ 例老年男性分为骨质疏松组与非骨质疏松组,测定骨密度（ＢＭＤ）、血清睾酮（Ｔ）、雌二醇（Ｅ２）、黄体生成素（ＬＨ）、促卵泡刺激素（ＦＳＨ）水平,并与３７ 例青年男性对照。结果　老年男性之ＢＭ Ｄ、Ｔ、Ｅ２ 明显低于青年对照组,而ＬＨ、ＦＳＨ 增高明显。老年男性骨质疏松症的发病率为３９．６８％ 。骨质疏松组与非骨质疏松组比较,Ｔ、Ｅ２ 明显降低,ＬＨ、ＦＳＨ 明显增高,尤以Ｔ 降低明显。结论　由于增龄性激素不足引致骨丢失,雄激素降低可能是老年男性骨质疏松症的主要原因。     

Total lymphocyte count and femoral bone mineral density in postmenopausal women

In vitro studies showed that several cytokines produced by the immune system can play a relevant role in modulating bone turnover, thus affecting the health of bone tissue. Our aim was to evaluate the association between total lymphocyte count (TLC) and femoral bone mineral density (BMD) in a sample of postmenopausal women. We studied 114 out of 124 consecutive, caucasian, home-dwelling, apparently healthy postmenopausal women referred for osteodensitometry by general practitioners. Femoral BMD was measured by dual-energy X-ray absorptiometry at five sites. A significant positive correlation (p 0.001) was observed between TLC and BMD (T score) measured the five sites: total proximal femur (r = 0.45), trochanter (r = 0.43), intertrochanteric region (r = 0.38), femoral neck (r = 0.49), and Wards triangle (r = 0.42). With a linear multiple regression model, TLC adjusted for age, weight, height, body mass index, and erythrocyte sedimentation rate showed a significant association with femoral BMD assessed at each of the five sites. The R² values ranged from 0.33 with BMD measured at Wards triangle to 0.51 with BMD measured at the trochanter. The significance of the association between TLC and BMD ranged from P 0.001 with BMD measured at the femoral neck to P 0.05 with BMD measured at the intertrochanteric area. The results were similar when BMD was expressed as either a Z score (in the 110 of the 114 women aged 84 years or younger) or as absolute values. Our data show a positive association between TLC and femoral BMD in a sample of apparently healthy, postmenopausal women, supporting the view of a close connection between the immune system and bone tissue.     

Distal femoral bone mineral density decreases following patellofemoral arthroplasty: 1-year follow-up study of 14 patients

Background  

The bone mineral density (BMD) of the distal femur decreases by 16-36% within one year after total knee arthroplasty (TKA) because of the femoral component's stress-shielding effect. The aim of this prospective study was to determine the quantitative change from the baseline BMD in the distal femur 1 year after patellofemoral arthroplasty using dual-energy X-ray absorptiometry (DXA).     

年龄对股骨颈骨密度和皮质厚度的影响

目的观察年龄对股骨颈骨密度和皮质厚度的影响,及与股骨颈骨折的关系。方法对73例50岁以上因髋关节疾病住院病人行股骨近段CT扫描和DXA髋部骨密度测定,分为50～65岁组、66～80岁组和>80岁组,以股骨颈骨密度为标准判断骨质疏松程度,以皮质比率作为评估皮质厚度的标准。结果股骨颈骨密度:50～65岁组为0.710±0.139、66～80岁组为0.613±0.104和>80岁组为0.572±0.061。66～80岁组和>80岁组与50～65岁组有非常显著性差异,66～80岁组与>80岁组差异无统计学意义。T20长径皮质比率:50～65岁组与66～80岁组差异无统计学意义,而66～80岁组与>80岁组有非常显著性差异。股骨颈宽径皮质比率:50～65岁组与>80岁组有非常显著性差异。结论股骨颈骨密度和皮质厚度随年龄增高而降低,提示股骨颈皮质厚度变薄是高龄髋部骨折风险高的原因之一。     

老年股骨上段标本几何参数及骨密度与生物力学性能的相关性分析

目的 探讨股骨颈部几何因素及骨密度对髋部骨折的影响,通过生物力学试验研究髋部生物力学性能与二者的关系.方法 随机选取16例甲醛浸泡国人成年男性尸体股骨上段标本,测量其几何参数(包括股骨颈长、股骨颈直径、股骨头直径及颈干角)和骨密度,再通过生物力学试验,比较各因素对股骨颈生物力学特性的影响.结果 转子间骨密度、股骨颈骨密度及股骨头直径与股骨的生物力学特性有明显的相性(r=0.792,r2=0.628,P0.001;r=0.749,r2=0.560,P=0.001;r=0.706,r2=0.499,P=0.002);逐步线性回归分析结果显示转子间骨密度、股骨头直径和股骨颈直径相结合是预测髋部骨折的最好方法(r2=0.844,P＜0.001).结论 骨密度值结合股骨近端几何参数能提高对骨质疏松性髋部骨折的预测.     

Lower femoral neck bone mineral density in prepubertal former preterm girls.

The purpose of this case-control study was to determine bone mineral content and areal bone mineral density at various skeletal sites in former preterm girls, aged 7-9 years, and to compare these data with age-matched term controls. Subjects included 25 white, prepubertal, former preterm girls (gestational age 30.8 +/- 0.3 weeks, birthweight 1461 +/- 56 g [mean +/- SEM]). Controls included 50 healthy, white, prepubertal girls born at term and matched for age (two controls per case). Measurements included anthropometric variables, calcium intake according to a food-frequency questionnaire, bone mineral content (BMC; grams), and areal bone mineral density (aBMD; grams per square centimeter), using dual-energy X-ray absorptiometry (DXA) at six skeletal sites. Thirteen preterm girls and 13 age-matched term controls were reassessed 1 year after the first DXA measurement. The former preterm girls were similar to controls in terms of age and height, but were lighter (24.6 +/- 0.6 vs. 27.0 +/- 0.6 kg, p = 0.02). They also reported a higher median calcium intake (1058 vs. 759 mg/day, p = 0.004). aBMD was lower in former preterms compared with controls at the level of the radial metaphysis (0.283 +/- 0.006 vs. 0.298 +/- 0.004, p = 0.04), femoral neck (0.593 +/- 0.011 vs. 0.638 +/- 0.010, p = 0.007), and total hip (0.596 +/- 0.012 vs. 0.640 +/- 0.010, p = 0.007), but was similar between the two groups at the radial diaphysis (0.437 +/- 0.004 vs. 0.436 +/- 0.004) and femoral diaphysis (1.026 +/- 0.015 vs. 1.030 +/- 0.011). Femoral neck aBMD remained lower compared with controls in the subgroup of preterm girls reassessed after 1 year (0.608 +/- 0.017 vs. 0.672 +/- 0.020, p = 0.02). In random effects models for longitudinal data, taking into account the effects of age, weight, and height on aBMD (dependent variable), femoral neck aBMD remained lower in former preterms (p < 0.001). Prepubertal former preterm girls showed growth recovery, but had lower aBMD at the hip and radial metaphysis than age-matched term controls, despite spontaneously higher calcium intake. Preterm girls had similar aBMD results compared with controls at sites with predominantly cortical bone (radial and femoral diaphysis), which are known to be more sensitive to calcium intake.     

Selective glucocorticoid receptor modulation maintains bone mineral density in mice

Glucocorticoids (GCs) are potent anti‐inflammatory drugs, but their use is limited by their adverse effects on the skeleton. Compound A (CpdA) is a novel GC receptor modulator with the potential for an improved risk/benefit profile. We tested the effects of CpdA on bone in a mouse model of GC‐induced bone loss. Bone loss was induced in FVB/N mice by implanting slow‐release pellets containing either vehicle, prednisolone (PRED) (3.5 mg), or CpdA (3.5 mg). After 4 weeks, mice were killed to examine the effects on the skeleton using quantitative computed tomography, bone histomorphometry, serum markers of bone turnover, and gene expression analysis. To assess the underlying mechanisms, in vitro studies were performed with human bone marrow stromal cells (BMSCs) and murine osteocyte‐like cells (MLO‐Y4 cells). PRED reduced the total and trabecular bone density in the femur by 9% and 24% and in the spine by 11% and 20%, respectively, whereas CpdA did not influence these parameters. Histomorphometry confirmed these results and further showed that the mineral apposition rate was decreased by PRED whereas the number of osteoclasts was increased. Decreased bone formation was paralleled by a decline in serum procollagen type 1 N‐terminal peptide (P1NP), reduced skeletal expression of osteoblast markers, and increased serum levels of the osteoblast inhibitor dickkopf‐1 (DKK‐1). In addition, serum CTX‐1 and the skeletal receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) ratio were increased by PRED. None of these effects were observed with CpdA. Consistent with the in vivo data, CpdA did not increase the RANKL/OPG ratio in MLO‐Y4 cells or the expression of DKK‐1 in bone tissue, BMSCs, and osteocytes. Finally, CpdA also failed to transactivate DKK‐1 expression in bone tissue, BMSCs, and osteocytes. This study underlines the bone‐sparing potential of CpdA and suggests that by preventing increases in the RANKL/OPG ratio or DKK‐1 in osteoblast lineage cells, GC‐induced bone loss may be ameliorated. © 2012 American Society for Bone and Mineral Research.     

Genetic and environmental determinants of bone mineral density in Chinese women

BMD is a complex trait determined by genetic and lifestyle factors. To assess the genetic and environmental determinants of BMD in southern Chinese women, we studied a community-based cohort of 531 pre- and postmenopausal southern Chinese women and assessed the influence of 12 candidate gene loci and lifestyle risk factors on spine and hip BMD. The candidate genes studied include estrogen receptor alpha (ESR1) and beta (ESR2), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Ialpha1 (COLIA1), and LDL receptor-related protein 5 (LRP5). Social, medical, reproductive history, dietary habits and lifestyle factors were determined using a structured questionnaire. Single nucleotide polymorphisms (SNPs) of the COLIA1 and LRP5 gene in Chinese were determined by direct sequencing. Nucleotide (nt) -1363C/G and -1997 G/T of COLIA1, nt 266A/G, 2220C/T and 3989C/T of LRP5 gene were analyzed. Using stepwise multiple linear regression analyses, body weight was the strongest predictor for BMD in premenopausal women (n = 262), which accounted for 15.9% of the variance at the spine, 20% at femoral neck, 17.1% at trochanter, 24.3% at total hip and 10.9% at the Ward's triangle. Other significant predictors were ESR1 Ivs1-397T/C genotype (2.2% at the spine); LRP5 2220C/T genotype (1.3% at the spine, 1.6% at the trochanter); LRP5 266A/G genotype (1.1% at Ward's triangle); age at menarche (1.3% at trochanter) and age (2.0% at Ward's triangle). As for postmenopausal women (n = 269), body weight ( approximately 25% at various sites) and age (approximately 16% at femoral neck, trochanter, total hip and Ward's triangle sites) were the strongest predictors of BMD. Other significant predictors were age at menarche (4.4% at spine, 0.7% at femoral neck, 1.4% at trochanter, and 1.4% at Ward's triangle); weight bearing physical activity (2.1% at trochanter and 1% at total hip); calcium intake (1.1% at femoral neck, 0.9% at trochanter, and 1.7% at total hip) ; height (0.7% at trochanter); and ESR2 1082A/G genotype (0.8% at trochanter). We conclude that BMD at various sites and at different time span of a woman is modified by different genetic and lifestyle factors, suggesting that BMD is highly dependent on gene-environmental interactions.