Kisspeptin regulation of human decidual stromal cells motility via FAK-Src intracellular tyrosine kinases.

STUDY QUESTION: Can of Clinical Genetics, Maastricht University Medical Centre, Maastricht kisspeptin and its analogues regulate the motility of human decidual stromal cells and what intracellular signaling pathways are involved? SUMMARY ANSWER: Kisspeptin analogue-mediated cell motility in human decidual stromal cells via the focal adhesion kinase (FAK)-steroid receptor coactivator (Src) pathway suggesting that kisspeptin may modulate embryo implantation and decidual programming in human pregnancy. WHAT IS KNOWN ALREADY: The extravillous trophoblast invades the maternal decidua during embryo implantation and placentation. The motile behavior and invasive potential of decidual stromal cells regulate embryo implantation and programming of human pregnancy. STUDY DESIGN, SIZE, DURATION: Human decidual stromal cells were isolated from healthy women undergoing elective termination of a normal pregnancy at 6- to 12-week gestation, after informed consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: Kisspeptin analogues were synthetic peptides. Cell motility was estimated by an invasion and migration assay. Immunoblot analysis was performed to investigate the expression of kisspeptin receptor and the effects of kisspeptin analogues on the phosphorylation of FAK and Src. Small interfering RNAs (siRNAs) were used to knock down the expression of kisspeptin receptor, FAK, Src, matrix metallo-proteinases (MMPs) 2 and 9, and extracellular signal-regulated protein kinase (ERK) 1/2. MAIN RESULTS AND THE ROLE OF CHANCE: The kisspeptin receptor was expressed in human decidual stromal cells. Kisspeptin agonist decreased, but antagonist increased, cell motility. Kisspeptin agonist decreased the phosphorylation of FAK and Src tyrosine kinases, whereas antagonist increased it. These effects on phosphorylation were abolished by kisspeptin receptor siRNA. The activation of cell motility by kisspeptin analogues was suppressed by siRNA knockdown of endogenous FAK (decreased 66%), Src (decreased 60%), kisspeptin receptor (decreased 26%), MMP-2 (decreased 36%), MMP-9 (decreased 23%), and ERK 1/2 inhibitor (decreased 27%). LIMITATIONS, REASONS FOR CAUTION: Human decidual stromal cells were obtained from women having terminations after 6-12 weeks of pregnancy and differences in timing could affect their properties. WIDER IMPLICATIONS OF THE FINDINGS: Kisspeptin acting within the endometrium has a potential modulatory role on embryo implantation and decidual programming of human pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grant NSC-104-2314-B-182A-146-MY2 (to H.-M.W.) from the Ministry of Science and Technology, Taiwan, and grants CMRPG3E0401 and CMRPG3E0402 (to H.-M.W.). This work was also supported by grants from the Canadian Institutes of Health Research to P.C.K.L. P.C.K.L. is the recipient of a Child & Family Research Institute Distinguished Investigator Award. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Elderly males with or without existing osteoporotic vertebral fracture have much lower future vertebral fracture risk than elderly females: the MrOS (Hong Kong) year-4 follow-up spine radiograph study.

MrOS (Hong Kong)'s year-4 follow-up shows, for subjects at baseline without vertebral deformity (VD) and endplate or/and cortex fracture (ECF), the VD progression/new VD rate during follow-up in males was half of our paired MsOS (Hong Kong) study's results. For those with VD or ECF, the VD progression/new VD was less than one sixth of females' rate. INTRODUCTION: This study documents MrOS (Hong Kong)'s year-4 follow-up, and the results are compared with the MsOS (Hong Kong) study. Of elderly females with Genant's grade-0, -1, -2, and -3 VD, at year-4 follow-up, 4.6%, 8%, 10.6%, and 28.9% had at least one VD progression or incident VD, respectively. METHODS: Spine radiographs of 1500 Chinese males with baseline (mean age 71.7 years, range 65-91 years) and year-4 follow-up were evaluated according to Genant's VD criteria and ECF (non-existent, ECF0; or existent, ECF1). Grade-2 VDs were divided into mild (VD2m, 25-34% height loss) and severe (VD2s, 34-40% height loss) subgroups. Study subjects were graded into eight categories: VD0/ECF0, VD1/ECF0, VD2m/ECF0, VD0/ECF1, VD1/ECF1, VD2m/ECF1, VD2s/ECF1, and VD3/ECF1. With an existing VD, a further height loss of ≥ 15% was a VD progression. A new VD incident was a change from grade-0 to grade-2/3, or to grade-1 with ≥ 10% height loss. RESULTS: Of subjects with Genant's grade-0, 2.05% (25/1219) developed at least one VD progression or/and new VD, while of subjects with Genant's grade-1, -2, and -3 VD, only 2% (3/149), 3.1% (3/96), and 2.8% (1/36) developed at least one VD progression/new VD, respectively. Among the three ECF0 groups, there was a significant difference in new ECF incidence, with VD0/ECF0 being the lowest and VD2m/ECF0 being the highest. CONCLUSION: VD progression/new VD is much less common in elderly men than in elderly women. Vertebrae with VD had a higher risk of developing ECF.

Osteoporotic vertebral deformity with endplate/cortex fracture is associated with higher further vertebral fracture risk: the Ms. OS (Hong Kong) study results.

Compared with vertebrae without deformity, vertebrae with mild/moderate deformity have a higher risk of endplate or/and cortex fracture (ecf). Compared with subjects without ecf, subjects with ecf are at a higher risk of short-term (4-year period) deformity progression and new incident deformity. INTRODUCTION: The progression and incidence of osteoporotic vertebral deformity/fracture (VD/VF) in elderly Chinese females remain not well documented. METHODS: Spine radiographs of 1533 Chinese females with baseline and year-4 follow-up (mean age 75.7 years) were evaluated according to Genant's VD criteria and endplate/cortex fracture (non-existent: ecf0 or existent: ecf1). Grade-2 VDs were divided into mild (vd2m, 25-34% height loss) and severe (vd2s, 34-40% height loss) subgroups. According to their VD/VF, subjects were graded into seven categories: vd0/ecf0, vd1/ecf0, vd2m/ecf0, vd1/ecf1, vd2m/ecf1, vd2s/ecf1, and vd3/ecf1. With an existing VD, a further height loss of ≥ 15% was a VD progression. A new incident VD was a change from grade-0 to grade-2/3 or to grade-1 with ≥ 10% height loss. RESULTS: Of subjects with Genant's grades 0, - 1, - 2, and - 3 VD, at follow-up, 4.6%, 8%, 10.6%, and 28.9% had at least one VD progression or new incident VD respectively. Among the three ecf0 groups, there was no difference in VD progression or new VD; while there was a significant difference in new ecf incidence, with vd0/ecf0 being lowest and vd2m/ecf0 being highest. Vd1/ecf0 and vd2m/ecf0 vertebrae had a higher risk of turning to ecf1 than vd0/ecf0 vertebrae. If vd1/ecf0 and vd2m/ecf0 subjects were combined together (range 20-34% height loss) to compare with vd1/ecf1 and vd2m/ecf1 subjects, the latter had significantly higher VD progression and new VD rates. CONCLUSION: Vertebrae with grade-1/2 VDs had a higher risk of developing ECF. Subjects with pre-existing ECFs had a higher risk of worsening or new vertebral deformities.

Density, structure, and strength of the distal radius in patients with psoriatic arthritis: the role of inflammation and cardiovascular risk factors.

UNLABELLED: We investigated the densitometric and microstructural features of the distal radius in psoriatic arthritis (PsA) patients using high-resolution peripheral quantitative computed tomography. PsA patients have unique bone microstructural deficits, manifested as lower cortical bone density and higher cortical porosity, which are associated with a propensity to bone fragility. INTRODUCTION: The aim of this study was to investigate the densitometric, geometric, microstructural, and biomechanical features of the distal radius in psoriatic arthritis (PsA) patients. METHODS: This study cohort consisted of 53 PsA patients (24 males and 29 females), with an average age of 53.1 years and 53 gender- and age-matched controls. Areal bone mineral density (aBMD) of the hip, lumbar spine, and ultradistal radius was measured by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed at the distal radius to obtain measures of volumetric BMD (vBMD), microstructure, and derived biomechanical indices. RESULTS: There were no significant between-group differences in aBMD at the femoral neck, total hip, and ultradistal radius, while aBMD at the lumbar spine was significantly higher in patients. The only indices indicating compromised bone quality in PsA patients were related to cortical bone quality. Cortical vBMD were -3.8% significantly lower, while cortical pore volume, porosity index, and pore diameter were 108, 79.5, and 8.6%, respectively, significantly higher in patients. Cortical stress was marginally lower (-1.3%, p = 0.077) in patients with stress significantly more unevenly distributed (4.9%, p = 0.035). Endocortical perimeter and cortical pore volume were significantly higher in patients with vertebral fracture. Deficits in cortical bone quality were associated with indices of disease activity/severity and were more prominent in patients with type 2 diabetes mellitus or hypertension. CONCLUSIONS: There is an intertwined relationship between chronic inflammation, cardiovascular risk factors, and bone loss in PsA. PsA patients seem to have unique bone microstructural deficits which are associated with a propensity to bone fragility.

Cortical thinning and progressive cortical porosity in female patients with systemic lupus erythematosus on long-term glucocorticoids: a 2-year case-control study.

UNLABELLED: In this study, we characterized longitudinal changes of volumetric bone mineral density and cortical and trabecular microstructure at the distal radius using HR-pQCT in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. Cortical thinning and increased cortical porosity are the major features of longitudinal microstructural deterioration in SLE patients. INTRODUCTION: The study aims to characterize longitudinal changes of volumetric bone mineral density (vBMD) and bone microstructure at distal radius in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. METHODS: This 2-year case-control study consisted of 166 premenopausal subjects (75 SLE patients and 91 controls) and 79 postmenopausal subjects (44 SLE patients and 35 controls). We obtained areal BMD (aBMD) by dual-energy X-ray absorptiometry at multiple skeletal sites and indices of vBMD and microstructure at distal radius by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, 12 and 24 months. RESULTS: In either premenopausal or postmenopausal subjects, changes in aBMD did not differ between patients and controls except that decrease in aBMD at total hip at 24 months in premenopausal patients was significantly higher. In premenopausal subjects, decrease in cortical area (-0.51 vs. -0.06 %, p = 0.039) and thickness (-0.63 vs. 0.02 %, p = 0.031) and increase in cortical porosity (21.7 vs. 7.16 %, p = 0.030) over study period were significantly larger in patients after adjustment of age and body mass index. Decreased in trabecular vBMD was significantly less (-0.63 vs. -2.32 %, p = 0.001) with trabecular microstructure better maintained in patients. In postmenopausal subjects, decrease in cortical vBMD (-2.66 vs. -1.56 %, p = 0.039) and increase in cortical porosity (41.6 vs. 16.3 %, p = 0.021) were significantly higher in patients, and there was no group-wise difference in change of trabecular microstructure. CONCLUSION: Longitudinal microstructural deterioration in SLE is characterized by cortical thinning and increased cortical porosity. Cortical bone is an important source of bone loss in SLE patients on glucocorticoids.

The functional muscle-bone unit in subjects of varying BMD.

SUMMARY: This study used the "functional muscle-bone unit" concept to investigate muscle-bone interaction of the lumbar spine in subjects of varying bone mineral density. It was found that unit bone mass corresponded to a relatively more muscle mass in subjects with reduced bone mineral density, indicating a relatively higher mechanical load from muscles exerted on trabecular bone. INTRODUCTION: Bone is an architecturally adaptive tissue which responds to mechanical loading. This study is proposed to use "functional muscle-bone unit" to reflect this muscle-bone interaction at spine in subjects with different bone mineral density. METHODS: The study was carried out in young normal subjects (21 females; age, 29 ± 3) and elderly subjects (155 females; age, 73 ± 3.9) with varying bone mineral density. Cross-sectional area of paravertebral muscle groups was measured in MR images to indicate the muscle mass, while the bone mineral content by dual X-ray absorptiometry was used to represent the bone mass. The functional muscle-bone unit was calculated as the ratio between the bone mass to muscle mass. RESULTS: It showed that with aging, the muscle mass decreased with the bone mass losing. However, more pronounced reduction was found in bone mass than in muscle mass in the subjects with lower bone mineral density. CONCLUSIONS: Muscle-bone interaction was changed in elderly, especially in those with osteoporosis. Unit bone mass corresponded to a higher muscle mass in subjects with reduced bone mineral density than those normal subjects. This may be contributory to the occurrence of nontraumatic vertebral fractures in elderly subjects with reduced bone mineral density.

Effects of 18-month low-magnitude high-frequency vibration on fall rate and fracture risks in 710 community elderly--a cluster-randomized controlled trial.

UNLABELLED: This study is a prospective cluster-randomized controlled clinical trial involving 710 elderly subjects to investigate the long-term effects of low-magnitude high-frequency vibration (LMHFV) on fall and fracture rates, muscle performance, and bone quality. The results confirmed that LMHFV is effective in reducing fall incidence and enhancing muscle performance in the elderly. INTRODUCTION: Falls are direct causes of fragility fracture in the elderly. LMHFV has been shown to improve muscle function and bone quality. This study is to investigate the efficacy of LMHFV in preventing fall and fractures among the elderly in the community. METHODS: A cluster-randomized controlled trial was conducted with 710 postmenopausal females over 60 years. A total of 364 participants received daily 20 min LMHFV (35 Hz, 0.3 g), 5 days/week for 18 months; 346 participants served as control. Fall or fracture rate was taken as the primary outcome. Also, quadriceps muscle strength, balancing abilities, bone mineral density (BMD), and quality of life (QoL) assessments were done at 0, 9, and 18 months. RESULTS: With an average of 66.0% compliance in the vibration group, 18.6% of 334 vibration group subjects reported fall or fracture incidences compared with 28.7% of 327 in the control (adjusted HR = 0.56, p = 0.001). The fracture rate of vibration and control groups were 1.1 and 2.3 % respectively (p = 0.171). Significant improvements were found in reaction time, movement velocity, and maximum excursion of balancing ability assessment, and also the quadriceps muscle strength (p < 0.001). No significant differences were found in the overall change of BMD. Minimal adverse effects were documented. CONCLUSION: LMHFV is effective in fall prevention with improved muscle strength and balancing ability in the elderly. We recommend its use in the community as an effective fall prevention program and to decrease related injuries.

Race/ethnic differences in associations between bone mineral density and fracture history in older men.

SUMMARY: To determine whether there are race/ethnic differences in bone mineral density (BMD) by fracture history in men aged 65 years and older, we performed cross-sectional analysis in five large independent cohorts. Low BMD was associated with a higher prevalence of fracture in all cohorts, and the magnitude of the BMD differences by fracture status was similar across groups. INTRODUCTION: We aimed to determine whether there are race/ethnic and geographic differences in bone mineral density by fracture history in men aged 65 years and older. METHOD: The datasets included the Osteoporotic Fractures in Men (MrOS) Study (5,342 White, 243 African-American, 190 Asian, and 126 Hispanic), MrOS Hong Kong (1,968 Hong Kong Chinese), Tobago Bone Health Study (641 Afro-Caribbean), Namwon Study (1,834 Korean), and Dong-gu Study (2,057 Korean). The two Korean cohorts were combined. RESULTS: The prevalence of self-reported non-traumatic fracture was US white, 17.1 %; Afro-Caribbean, 5.5 %; US African-American, 15.1 %; US Hispanic, 13.7 %; US Asian, 10.5 %; Hong Kong Chinese, 5.6 %, and Korean, 5.1 %. The mean differences in hip and lumbar spine BMD between subjects with fracture and without fracture were statistically significant in all cohorts except US African American and US Asian men. There was a significant race/ethnic interaction for lumbar spine BMD by fracture status (p for interaction = 0.02), which was driven by the small number of Hispanic men. There was no interaction for femoral neck or total hip BMD. There were no significant race/ethnic differences in the odds ratio of fracture by BMD. CONCLUSIONS: Low BMD was associated with a higher prevalence of fracture in all cohorts and the magnitude of the BMD differences by fracture status was similar across groups suggesting homogeneity in the BMD-fracture relationship among older men.

Incidence of and risk factors for non-vertebral and vertebral fracture in female Chinese patients with systemic lupus erythematosus: a five-year cohort study.

OBJECTIVE: The objective of this paper is to investigate the incidence of both non-vertebral and vertebral fracture in female patients with systemic lupus erythematosus (SLE) and to identify risk factors for incident fracture. METHODS: In a five-year prospective study of 127 female Chinese SLE patients with an average age of 46.9 years (SD: 10.1 years), information on potential risk factors, including demographics, clinical data and bone mineral density (BMD) at lumbar spine and hip by dual-energy X-ray absorptiometry was collected at baseline. At follow-up, participants reported incident non-vertebral fracture during the study period. Semi-quantitative analysis was used to determine incident vertebral fracture on lateral thoracic and lumbar radiographs, defined as any vertebral body graded normal at baseline and at least mildly deformed (20%-25% reduction or more in any vertebral height) at follow-up. RESULTS: Nine incident non-vertebral fractures occurred in eight patients during the study period. Six patients had one or more incident vertebral fractures. The incidence of non-vertebral and vertebral fracture was 1.26 and 0.94 per 100 patient-years, respectively. In multivariate logistic analyses, independent variables associated with incident non-vertebral fracture were duration of glucocorticoid use and prevalent lumbar spine osteoporosis, while risk factors associated with incident vertebral fracture were higher organ damage and prevalent lumbar spine osteoporosis. CONCLUSIONS: The incidence of fracture in SLE patients is lower than the prevalence reported in cross-sectional studies. Lumbar spine BMD appears to have a stronger relationship with incident fracture than hip BMD. This warrants further investigation regarding the optimal site of BMD measurement when predicting fracture risk in SLE patients.

International and ethnic variability of falls in older men.

AIMS: Fallers and especially recurrent fallers are at high risk for injuries. The aim of this study was to evaluate fall epidemiology in older men with special attention to the influence of age, ethnicity and country of residence. METHODS: 10,998 men aged 65 years or above recruited in Hong Kong, the United States (US) and Sweden were evaluated in a cross-sectional retrospective study design. Self-reported falls and fractures for the preceding 12 months were registered through questionnaires. Group comparisons were done by chi-square test or logistic regression. RESULTS: The proportion of fallers among the total population was 16.5% in ages 65-69, 24.8% in ages 80-84 and 43.2% in ages above 90 (P <0.001). The corresponding proportions of recurrent fallers in the same age groups were 6.3%, 10.1% and 18.2%, respectively (P <0.001), and fallers with fractures 1.0%, 2.3% and 9.1%, respectively (P <0.001). The proportion of fallers was highest in the US, intermediate in Sweden and lowest in Hong Kong (in most age groups P <0.05). The proportion of fallers among white men in the US was higher than in white men in Sweden (all comparable age groups P <0.01) but there were no differences in the proportion of fallers in US men with different ethnicity. CONCLUSIONS: The proportion of fallers in older men is different in different countries, and data in this study corroborate with the view that society of residence influences fall prevalence more than ethnicity.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Prevalence and risk factors of radiographic vertebral fractures in elderly Chinese men and women: results of Mr. OS (Hong Kong) and Ms. OS (Hong Kong) studies.

UNLABELLED: This study investigated the prevalence of radiographic vertebral fractures using Genant's semiquantitative (SQ) scoring system in elderly Chinese men (n = 2,000; mean age, 72.4 years) and women (n = 2,000; mean age, 72.6 years). Vertebral deformities had similar prevalence in elderly men (14.9 %) and women (16.5 %). Majority of the deformities in men were mild (9.9 %, grade = 1). The prevalence of vertebral fractures (grade ≥ 2) was 5.0 % among men and 12.1 % among women. INTRODUCTION: Vertebral fracture is a serious consequence of osteoporosis and is often under-diagnosed. Researches on different ethnicities and territories to estimate the prevalence of vertebral fractures and to identify the risk factors are necessary. METHODS: Mr. OS (Hong Kong) and Ms. OS (Hong Kong) represent the first large-scale cohort studies ever conducted on bone health in elderly Chinese men (n = 2,000) and women (n = 2,000). The current study investigated the prevalence of radiographic vertebral fractures in these subjects using Genant's SQ scoring system and identified risk factors for vertebral fractures. RESULTS: The radiographs of all men (mean age, 72.4 years) and women (mean age, 72.6 years) were obtained. Six hundred twenty-seven subjects (15.7 %) had at least one vertebral deformity (SQ grade ≥ 1), including 297 men (14.9 %) and 330 women (16.5 %, p = 0.151). Three hundred forty-two participants (8.6 %) were defined as having at least one vertebra fracture (SQ grade ≥ 2), consisted of 100 men (5.0 %) and 242 women (12.1 %, p < 0.001). Older age, lower bone mineral density, lower physical activity, lower grip strength, fracture history, and low back pain were significantly associated with higher vertebral fracture rate for both men and women. CONCLUSION: Vertebral deformity had similar prevalence in older men and women, while vertebral fracture was more common in women. Majority of deformities in men was mild. The vertebral deformity prevalence of women from this study is similar to previous reports of other East Asian women and Latin American women.

Alterations of bone geometry, density, microarchitecture, and biomechanical properties in systemic lupus erythematosus on long-term glucocorticoid: a case-control study using HR-pQCT.

UNLABELLED: Compared to controls, HR-pQCT at distal radius of SLE patients on chronic glucocorticoid (SLE/GC) revealed reduced bone area, vBMD, deteriorated microarchitecture, and unevenly distributed stresses limited to cortical bone. Despite similar trabecular quality, whole bone strength decreased in patients. These alterations may partly explain high fracture rates in SLE/GC. INTRODUCTION: To assess bone geometric, densitometric, microarchitectural, and biomechanical properties in patients with systemic lupus erythematosus (SLE) on long-term glucocorticoid (GC) (SLE/GC) as compared with healthy controls. METHODS: A total of 180 female SLE patients and 180 healthy controls were in this cross-sectional study to assess areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) and microfinite element analysis (µFEA) was performed at distal radius. RESULTS: In addition to significantly lower aBMD at femoral neck, total hip and lumbar spine, cortical area, average volumetric BMD (vBMD) and cortical vBMD also significantly reduced by 5.3, 5.7, to 1.9 % in SLE patients, respectively. Deteriorations of cortical microarchitecture were pronounced in patients, with 6.3 % reduction in cortical thickness and 13.6 % higher in cortical porosity. Local stresses were more unevenly distributed through cortical bone in patients. SLE/GC patients had decreased whole bone stiffness, estimated failure load, and apparent modulus. Parameters related to trabecular bone density and microarchitecture were comparable between patients and controls. CONCLUSION: In SLE/GC patients, despite a reduction in bone area, vBMD and deteriorated microarchitecture and unevenly distributed stresses limited to the cortical compartment, whole bone strength decreased. HR-pQCT and µFEA were promising in elucidating the potential underlying pathophysiology of bone loss and propensity to fracture in SLE/GC and provide us additional information about alterations of bone quality which might better predict fracture risk beyond aBMD in SLE/GC.

SLE disease per se contributes to deterioration in bone mineral density, microstructure and bone strength.

OBJECTIVE: The objective of this report is to assess the effect of systemic lupus erythematosus (SLE) disease itself on deterioration of bone mineral density (BMD), microstructure and bone strength. METHOD: Thirty age-matched SLE patients on long-term glucocorticoids (GC) (SLE/GC), 30 SLE patients without GC (SLE/non-GC) and 60 healthy controls were examined. Areal BMD (aBMD) was measured by dual-energy X-ray absorptiometry. Bone geometry, volumetric BMD (vBMD), and architectural parameters at the nondominant distal radius were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Bone strength was estimated by HR-pQCT-based micro-finite element analysis. RESULTS: Adjusted for menopausal status and adjusted calcium level, when compared with controls, SLE/non-GC patients had significantly lower aBMD at femoral neck and total hip, and diminished radial total vBMD, cortical area, vBMD and thickness, respectively, by 8.3%, 8%, 2.7% and 9.2%, as well as significant compromised bone strength (stiffness, failure load and apparent modulus) by 8.3%, 9.1% and 9.5%, respectively. Similar alterations were also found in SLE/GC patients when compared to controls. In the premenopausal subgroup analysis, when compared with controls, total hip aBMD and radial cortical area were significantly lower in SLE/non-GC patients, and cortical area and thickness were significantly deficit in SLE/GC patients. However, no significant difference in any bone variables was present between SLE/GC and SLE/non-GC patients in the entire cohort or in the premenopausal subgroup. CONCLUSION: SLE disease per se contributes to the deterioration in bone density, cortical microstructure and bone strength. This might help to explain the considerably higher fracture risk seen in SLE patients.

Racial/ethnic differences in bone mineral density among older women.

The epidemiologic information regarding international differences in bone mineral density (BMD) in women is currently insufficient. We compared BMD in older women across five racial/ethnic groups in four countries. The femoral neck, total hip, and lumbar spine BMD were measured in women (aged 65-74 years) from the Study of Osteoporotic Fractures (SOF) (5,035 Caucasian women and 256 African American women in the US), the Tobago Women's Health Study (116 Afro-Caribbean women), the Ms Os Hong Kong Study (794 Hong Kong Chinese women) and the Namwon Study (1,377 South Korean women). BMD was corrected according to the cross-site calibration results for all scanners. When compared with US Caucasian women, the age adjusted mean BMD measurements at the hip sites were 21-31 % higher among Tobago Afro-Caribbean women and 13-23 % higher among African American women. The total hip and spine BMD values were 4-5 % lower among Hong Kong Chinese women and 4-7 % lower among South Korean women compared to US Caucasians. The femoral neck BMD was similar in Hong Kong Chinese women, but higher among South Korean women compared to US Caucasians. Current/past estrogen use was a significant contributing factor to the difference in BMD between US versus non-US women. Differences in body weight partially explained the difference in BMD between Asian versus non-Asian women. These findings show substantial racial/ethnic differences in BMD even within African or Asian origin individuals, and highlight the contributing role of body weight and estrogen use to the geographic and racial/ethnic variation in BMD.

Molecular studies of the congenital malformation induced by Largehead Atractylodes Rhizome, the most commonly used Chinese medicine for threatened miscarriage.

Largehead Atractylodes Rhizome (LAR) is the most commonly used Chinese herbal medicine for threatened miscarriage. Potential reproductive toxicity of LAR was identified in early pregnancy in animals. Skeletal anomalies including loss of ulna and distal digits, shortening of humerus and radius were observed in higher clinical dose groups. Here, we aimed to study the molecular mechanism of the congenital malformation induced by LAR. In vitro whole mouse embryo culture was used to confirm the embryotoxicity effects of LAR on developing limb buds during early organogenesis. A pregnant mouse model was employed to study the developmental gene expression by quantitative PCR and whole hybridization and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling staining, in the forelimbs and hindlimbs during development in vivo. Severe growth retardation, multiple embryonic malformations and delayed limb bud development were observed. Limb-specific Tbx gene expressions in both developing forelimbs and hindlimbs were significantly decreased. Increased developmental apoptosis in apical ectodermal ridge and mesenchymal mesoderm of the developing limb buds was identified. Overexpressions of Tbx2 and Tbx3 in embryos in vitro rescued LAR-induced abnormal limb development and reduced apoptosis in the developing forelimb buds. In conclusion, LAR affects limb development by suppressing the expression of limb developmental genes and disturbing programmed cell death during limb formation in mice.

Predictive values of calcaneal quantitative ultrasound and dual energy X ray absorptiometry for non-vertebral fracture in older men: results from the MrOS study (Hong Kong).

UNLABELLED: Calcaneal QUS is comparable to DXA in predicting non-vertebral fractures in older Chinese men. INTRODUCTION: The predictive values of calcaneal quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA) for non-vertebral fractures in older Chinese men were examined. METHODS: One thousand nine hundred twenty-one Chinese men aged 65-92 years had calcaneal QUS and axial DXA bone mineral density (BMD) measurements. The incidence of non-vertebral fractures was documented. Cox regression and receiver operating curve (ROC) analysis were used to examine the associations of QUS parameters and BMD with the incidence of non-vertebral fractures. RESULTS: The duration of follow-up was (mean ± SD) 6.5 ± 1.7 years. One hundred thirty-one non-vertebral fractures were recorded, 71 of which were major fragility fractures. Broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) were significantly associated with non-vertebral fractures and major fragility fractures, with age and fracture history-adjusted hazard ratio (95% CI) of 1.23 (1.03, 1.47) and 1.32 (1.10, 1.59) per standard deviation reduction, respectively, for non-vertebral fractures; 1.32 (1.04, 1.68) and 1.43 (1.11, 1.84), respectively, for major fragility fractures. Age and fracture history-adjusted areas under ROC curves of hip or spine BMDs were significantly greater than that of BUA or QUI in predicting major fragility fractures, but not in predicting all non-vertebral fractures. The addition of BUA or QUI had no effect on AUCs of total hip BMD alone. CONCLUSIONS: The ability of calcaneal QUS to predict non-vertebral fractures was comparable to that of axial BMD by DXA, but was inferior to BMD in predicting major fragility fractures in older Chinese men.

Sex steroids and bone health in older Chinese men.

UNLABELLED: This study examines the association between sex steroids, bone mineral density (BMD), and incident fractures in 1,489 community-living Chinese men aged 65 and over. Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians. INTRODUCTION: This study examines the association between serum total testosterone (TT), free testosterone (free T), estradiol (E(2)), bioavailable estradiol (bioE(2)), sex hormone binding globulin (SHBG), BMD, and incident fractures. METHODS: This is a cohort study with 4-year follow-up in the community in Hong Kong SAR, China. One thousand four hundred eighty-nine community-living Chinese men aged 65 and over participated. Sex steroid levels and BMD were measured at baseline; BMD was repeated after 4 years of follow-up, and fracture incidence from ascertainment from hospital databases was determined over 4 years of follow-up. RESULTS: The strongest age-adjusted positive association with total hip and femoral neck BMD was with bioE(2), followed by E(2). Greater bone loss occurred in the lowest quartile of E(2) and bioE(2). The lowest quartile of free T and bioE(2) and the two highest quartile of SHBG were associated with the highest percentage of participants with incident fractures. Those in the lowest quartile of E(2) and bioE(2) had approximately a 50% increased risk of incident fractures compared with the other three quartiles. This relationship remains significant for nonvertebral incident fractures (hip, radius, pelvis, and humerus) for E(2) only, but not bioE(2). Compared with the group with the three highest quartiles of TT and E(2), the group with the lowest quartile of both had approximately twice the risk of nonvertebral osteoporosis-related incident fractures. CONCLUSION: Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians.

Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?

UNLABELLED: In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss. INTRODUCTION: Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men. METHODS: Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study-The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4. RESULTS: Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm(2)) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss. CONCLUSION: Use of ACE inhibitors but not ARB may marginally increase bone loss in older men.