Vertebral fracture is one of the major adverse clinical consequences of osteoporosis; however, there are few data concerning the incidence of vertebral fracture in population samples of men and ...women. The aim of this study was to determine the incidence of vertebral fracture in European men and women. A total of 14,011 men and women aged 50 years and over were recruited from population‐based registers in 29 European centers and had an interviewer‐administered questionnaire and lateral spinal radiographs performed. The response rate for participation in the study was approximately 50%. Repeat spinal radiographs were performed a mean of 3.8 years following the baseline film. All films were evaluated morphometrically. The definition of a morphometric fracture was a vertebra in which there was evidence of a 20% (+4 mm) or more reduction in anterior, middle, or posterior vertebral height between films—plus the additional requirement that a vertebra satisfy criteria for a prevalent deformity (using the McCloskey‐Kanis method) in the follow‐up film. There were 3174 men, mean age 63.1 years, and 3614 women, mean age 62.2 years, with paired duplicate spinal radiographs (48% of those originally recruited to the baseline survey). The age standardized incidence of morphometric fracture was 10.7/1000 person years (pyr) in women and 5.7/1000 pyr in men. The age‐standardized incidence of vertebral fracture as assessed qualitatively by the radiologist was broadly similar—12.1/1000 pyr and 6.8/1000 pyr, respectively. The incidence increased markedly with age in both men and women. There was some evidence of geographic variation in fracture occurrence; rates were higher in Sweden than elsewhere in Europe. This is the first large population‐based study to ascertain the incidence of vertebral fracture in men and women over 50 years of age across Europe. The data confirm the frequent occurrence of the disorder in men as well as in women and the rise in incidence with age.
Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing ...antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.
One of the key research problems in stellar physics is to decipher the small-scale magnetic activity of the quiet solar atmosphere. Recent magneto-convection simulations that account for small-scale ...dynamo action have provided three-dimensional (3D) models of the solar photosphere characterized by a high degree of small-scale magnetic activity, similar to that found through theoretical interpretation of the scattering polarization observed in the Sr i 4607 line. Here we present the results of a novel investigation of the Hanle effect in this resonance line based on 3D radiative transfer calculations in a high-resolution magneto-convection model having most of the convection zone magnetized close to the equipartition and a surface mean field strength G. The Hanle effect produced by the model's magnetic field depolarizes the zero-field scattering polarization signals significantly, to the extent that the center-to-limb variation (CLV) of the calculated spatially averaged polarization amplitudes is compatible with the observations. The standard deviation of the horizontal fluctuations of the calculated scattering polarization signals is very sensitive to the model's magnetic field, and we find that the predicted spatial variations are sufficiently sizable so as to be able to detect them, especially with the next generation of solar telescopes. We find that at all on-disk positions, the theoretical scattering polarization signals are anticorrelated with the continuum intensity. To facilitate reaching new observational breakthroughs, we show how the theoretically predicted polarization signals and spatial variations are modified when deteriorating the signal-to-noise ratio and the spectral and spatial resolutions of the simulated observations.
The aim was to evaluate changes of bone mineral density (BMD) and markers of bone turnover in healthy adolescents, and in adolescent users of combined oral contraceptives (COCs) with different ...ethinylestradiol (EE) contents.
In this prospective crossover study, 56 healthy females (15-19.5 years) with desire to use hormonal contraception were randomized to COC with either 30 or 15 μg of EE in crossover design of 9-month intervention each in reverse order. Nonusers of the same age (n=28) served as controls. BMD at lumbar spine (LS), total femur, femoral neck, distal radius, and total body, and serum markers (N-propeptide of type I procollagen, and type I collagen C-telopeptide) were measured at baseline and after 9 and 18 months.
In COC nonusers, BMD significantly increased at LS and radius, while markers decreased. In COC users, BMD did not increase, with the exception of LS BMD in the 30 μg COC group (P<0.05). In the crossover design, a difference between the low- and very low-dose COC users was found in LS BMD changes (P<0.05), where increase in BMD was more impaired in the 15 μg COC users. The skeletal effects of COC remained significant after adjustments for age and smoking status. Markers declined faster in COC users during the first period, while they remained stable or even increased during the second 9 months.
Physiological acquisition of LS BMD during adolescent age may be prevented by use of COC, especially those containing very low dose of EE.
Abstract We collected population-based young normal hip and spine BMD data from 17 centres across Europe to assess between centre differences and to compare reference values with the US NHANES-III ...data. There was strong evidence of between country heterogeneity, but not between centres within countries. Hip BMD mean values were lower in European women, but SD's differed little from the NHANES-III USA results in both sexes. It may be necessary to adjust NHANES-III based T-scores by adding/subtracting a country-specific adjustment factor. Introduction It remains unclear whether young normal BMD reference values specific to an American population can be validly used for T-score calculation in Europeans. Methods We collected population based BMD data from 1163 men and 329 women aged 19-29 years from 17 centres across Europe to compare mean and SD values with the NHANES-III study USA results. BMD(g/cm2 ) was measured at the hip and spine using DXA densitometers cross-calibrated with the European Spine Phantom (ESP). The only exclusions were for technically inadequate scans. A linear regression model was used to derive reference values. To allow for direct comparison with published NHANES III study data, the cross-calibrated BMD values were converted using the ESP equations to Hologic QDR 1000 units. Results In men, the overall mean(SD) BMD values expressed in Hologic-QDR1000 units of measurement, were: femoral neck 0.912(0.132); trochanter 0.793(0.124); and L2-L4 spine 1.027(0.123). The respective estimates in women were: 0.826(0.115); 0.670(0.093); and 0.983(0.107). However the I2 statistic for heterogeneity indicated moderate to strong evidence of between-centre heterogeneity. There was, however, no significant heterogeneity observed between centres within countries, suggesting that this variation arose from national differences. Compared to the NHANES III population-based US data, the mean values in women were significantly lower at both sites due to some lower national European means. However, at all sites and in both sexes the SD's were very similar between the US and Europe. There was some evidence that recruiting volunteers resulted in biased values in women. Conclusion Our T-score normal values for the lumbar spine (L2-L4) should be more reliable for spine-specific risk assessment than some non-representative normal ranges, and should be evaluated for that purpose in Europe. If T-scores are to be used to compare individual data with ranges seen in normal young subjects of the same nationality, it may be necessary to adjust femoral NHANES III-based T-scores by adding (or subtracting) a country-specific adjustment factor. In risk assessment it is probably sufficient to use NHANES III–based hip T-scores, as supplied for the hip by densitometer manufacturers, interpreting them in light of recent international meta-analysis data on the relationship between BMD and fracture risk.
Hip geometry and bone mineral density (BMD) have previously been shown to relate independently to hip fracture risk. Our objective was to determine by how much hip geometric data improved the ...identification of hip fracture. Lunar pencil beam scans of the proximal femur were obtained. Geometric and densitometric values from 800 female controls aged 60 years or more (from population samples which were participants in the European Prospective Osteoporosis Study, EPOS) were compared with data from 68 female hip fracture patients aged over 60 years who were scanned within 4 weeks of a contralateral hip fracture. We used Lunar DPX 'beta' versions of hip strength analysis (HSA) and hip axis length (HAL) applied to DPX(L) data. Compressive stress (Cstress), calculated by the HSA software to occur as a result of a typical fall on the greater trochanter, HAL, body mass index (BMI: weight/(height)2) and age were considered alongside femoral neck BMD (FN-BMD, g/cm2) as potential predictors of fracture. Logistic regression was used to generate predictors of fracture initially from FN-BMD. Next age, Cstress (as the most discriminating HSA-derived parameter), HAL and BMI were added to the model as potentially independent predictors. It was not necessary to include both HAL and Cstress in the logistic models, so the entire data set was examined without excluding the subjects missing HAL measurements. Cstress combined with age and BMI provided significantly better prediction of fracture than FN-BMD used alone as is current practice, judged by comparing areas under receiver operating characteristic (ROC) curves (p<0.001, deLong's test). At a specificity of 80%, sensitivity in identification was improved from 66% to 81%. Identifying women at high risk of hip fracture is thus likely to be substantially enhanced by combining bone density with age, simple anthropometry and data on the structural geometry of the hip. HSA might prove to be a valuable enhancement of DXA densitometry in clinical practice and its use could justify a more pro-active approach to identifying women at high risk of hip fracture in the community.
Context. Interpreting the Stokes profiles observed in quiet regions of the solar chromosphere is a challenging task. The Stokes Q and U profiles are dominated by the scattering polarisation and the ...Hanle effect, and these processes can only be correctly quantified if 3D radiative transfer effects are taken into account. Forward-modelling of the intensity and polarisation of spectral lines using a 3D model atmosphere is a suitable approach in order to statistically compare the theoretical and observed line profiles. Aims. Our aim is to present novel observations of the Ca II 8542 Å line profiles in a quiet region at the centre of the solar disc and to quantitatively compare them with the theoretical Stokes profiles obtained by solving the problem of the generation and transfer of polarised radiation in a 3D model atmosphere. We aim at estimating the reliability of the 3D model atmosphere, excluding its known lack of dynamics and/or insufficient density, using not only the line intensity but the full vector of Stokes parameters. Methods. We used data obtained with the ZIMPOL instrument at the Istituto Ricerche Solari Locarno (IRSOL) and compared the observations with the theoretical profiles computed with the PORTA radiative transfer code, using as solar model atmosphere a 3D snapshot taken from a radiation-magnetohydrodynamics simulation. The synthetic profiles were degraded to match the instrument and observing conditions. Results. The degraded theoretical profiles of the Ca II 8542 line are qualitatively similar to the observed ones. We confirm that there is a fundamental difference in the widths of all Stokes profiles: the observed lines are wider than the theoretical lines. We find that the amplitudes of the observed profiles are larger than those of the theoretical ones, which suggests that the symmetry breaking effects in the solar chromosphere are stronger than in the model atmosphere. This means that the isosurfaces of temperature, velocity, and magnetic field strength and orientation are more corrugated in the solar chromosphere than in the currently available 3D radiation-magnetohydrodynamics simulation.
Juvenile idiopathic arthritis (JIA) is a disease associated with loss of bone mass, deterioration in bone mass quality and an increased risk of fractures. The objective of this study was to evaluate ...factors that predict bone mineral density (BMD) alterations in young adult patients with active JIA before and during therapy with tumour necrosis factor α (TNFα) inhibitors.
Thirty-one patients (twelve males and nineteen females; mean age =25.1 ± 6.1 years) with active JIA (mean Disease Activity Score in 28 joints (DAS28) =6.36 ± 0.64; mean high-sensitivity C-reactive protein (hsCRP) =18.36 ± 16.95 mg/L) were investigated. The control group consisted of 84 healthy individuals matched by sex and age. BMD, bone turnover markers and serum concentrations of soluble receptor activator of nuclear factor κB ligand, osteoprotegerin, dickkopf Wnt signalling pathway inhibitor 1 (Dkk1) and sclerostin were evaluated.
Baseline BMD values in the lumbar spine, proximal femur, femoral neck and distal radius were significantly lower in patients with JIA compared to healthy control participants. Baseline sclerostin serum concentrations were significantly higher in patients with JIA compared to control participants. After 2 years of treatment with TNFα inhibitors, BMD was significantly increased in the lumbar spine. This increase correlated with a drop in DAS28 score. A statistically significant correlation between hsCRP and Dkk1 was found at baseline, as well as during the 2-year follow-up period. A significant reduction in serum sclerostin after 1 year of therapy was predictive of a drop in DAS28 score observed with a 1-year delay after reduction of serum sclerostin.
A significant correlation between the sclerostin serum concentration and the number of tender and swollen joints, but not BMD, supports the hypothesis that chondrocytes and cells of the subchondral bone may contribute to circulating sclerostin in JIA.
Abstract Introduction While the determinants of BMD change have been studied in women, there have been few longitudinal studies in men. As part of the Network in Europe for Male Osteoporosis (NEMO) ...study, data were analysed from 1337 men and 1722 women aged 50–86y (mean = 67 years) from 13 centres across Europe to assess determinants of BMD change and between-gender contrasts. Methods BMD was measured at the femoral neck, trochanter and/or L2–L4 spine on 2 occasions 0.8–8 years apart (mean = 3.5 years) using DXA densitometers manufactured by Hologic ( n = 6), Lunar ( n = 5) and Norland ( n = 2). Each was cross-calibrated using the European Spine Phantom and annual rates of BMD change (g/cm2 /year) were calculated from the standardised paired BMD values. The EPOS risk factor questionnaire was administered at baseline. Results In multivariate linear regression models, there were large between centre differences in the mean rates of BMD change in all 3 sites for both genders ( P < 0.0001) with the standard deviation of the between centre heterogeneity in the adjusted means being 0.005 g/cm2 /year at the femoral neck. The overall adjusted mean annual rates of BMD change in g/cm2 /year (95% CI) pooled across centres by random effects meta-analysis in men were: femoral neck − 0.005 (− 0.009, − 0.001); trochanter − 0.003 (− 0.006, − 0.001); and spine 0.000 (− 0.004, 0.004). In women the respective estimates were: − 0.007 (− 0.009, − 0.005); − 0.004 (− 0.006, − 0.003); and − 0.005 (− 0.008, − 0.001). The I2 statistic for heterogeneity was between 81% and 94%, indicating strong evidence of between centre heterogeneity. Higher baseline BMD value was associated with subsequent greater decline in BMD ( P < 0.001). Preserved BMD was associated with higher baseline body weight in all 3 sites in men ( P < 0.012) but not in women. Weight gain preserved BMD ( P < 0.039) in all 3 sites for both genders, except the male spine. Increasing age was associated with faster BMD decline at the trochanter in both genders ( P < 0.026) and with a slower rate of decline at the female spine ( P = 0.002). Effects of lifestyle, physical activity, medications, and reproductive factors were not consistent across sites or between genders. Conclusion These results show major geographic variations in rates of BMD change in men and women over 50 years of age across diverse European populations and demonstrate that body weight and weight gain are key determinants of BMD change in men.
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