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Background: Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD)., Methods: Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n=329) was conducted., Results: After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI -0.027 to 0.100) g/cm 2 ) and femoral BMD (adjusted mean difference: 0.001 (-0.067 to 0.069) g/cm 2 ). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (-0.046 to 0.184) g/cm 2 ) or femoral BMD (adjusted mean difference: -0.055 (-0.139;0.029) g/cm 2 )., Conclusion: Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Worldwide, vitamin D deficiency is a common finding. Within individuals 25-hydroxyvitamin D (25OH)D) concentrations remain fairly stable over time although large differences in individual longitudinal changes exist. During aging vitamin D metabolism and activity changes in several different ways. Intestinal resistance to 1,25(OH)2D develops which hampers intestinal calcium uptake. Vitamin D receptor number decreases with aging in several organs involved in calcium metabolism and 1alpha-hydroxylase activity decreases mainly due to a decrease in renal function reducing vitamin D activation. Effects of 1,25(OH)2D on cell proliferation and differentiation may influence potential anti-cancer effects whereas regulation of telomere length may result in longevity. In older individuals, vitamin D supplementation has positive effects on fracture risk, number of falls and physical function. Supplementation in older populations warrants specific attention. Effects on "non-classical" outcomes may be revealed by ongoing large randomized clinical trials with high doses of vitamin D., (Copyright © 2017. Published by Elsevier B.V.)

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: Evidence regarding relationships of serum 25-hydroxyvitamin D (25(OH)D) with sex hormones and gonadotropin concentrations remains inconsistent. Polymorphisms in vitamin D-related genes may underly these relationships. Our aim was to examine the relationship of vitamin D status and polymorphisms in vitamin D-related genes with sex hormone and gonadotropin levels., Design and Measurements: We analysed data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals (65-89 years). We included data of men with measurements of serum 25-hydroxyvitamin D (25(OH)D) (n=643) and determination of vitamin D-related gene polymorphisms (n=459). 25(OH)D concentrations were classified into four categories: <25, 25-50, 50-75 and >75nmol/L. Outcome measures were total testosterone, calculated bioavailable and free fraction testosterone, SHBG, estradiol, LH and FSH concentrations. Hypogonadism was defined as a total testosterone level <8.0nmol/L., Results: Serum 25(OH)D was positively associated with total and bioavailable testosterone levels. After adjustments for confounders, men with serum 25(OH)D less than 25 (n=56), 25-50 (n=199) and 50-75nmol/L (n=240) had lower total testosterone levels compared to men with serum 25(OH)D higher than 75nmol/L (n=148) (β (95% confidence interval): -2.1 (-3.7 to -0.4nmol/L), -0.8 (-1.9 to 0.4nmol/L) and -1.4 (-2.4 to -0.3nmol/L), respectively). For bioavailable testosterone the association was significant only for men with serum 25(OH)D less than 25nmol/L (-0.8 (-1.4 to -0.1nmol/L)) compared to men with serum 25(OH)D >75nmol/L. Serum 25(OH)D was not related to SHBG, estradiol or gonadotropin levels. Hypogonadism (n=29) was not associated with lower serum 25(OH)D. No significant differences were found in hormone levels between the different genotypes of the vitamin D-related gene polymorphisms. Also, the polymorphisms did not modify the relationships of serum 25(OH)D with sex hormones or gonadotropins., Conclusion: Vitamin D status is positively associated with testosterone levels. No association was found between vitamin D-related gene polymorphisms and hormone levels., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: An increase in hospital admission rates in older people may reflect improved access to healthcare, but also declining health trends in the older population. Owing to a lack of individual-level data, the latter possibility has received little attention. The current study examines associations between health status and hospitalisation rates of older adults in the Netherlands., Design: Observational individual-level data linked to hospital register data., Setting: Data from 1995 to 2009 from the nationally representative Longitudinal Aging Study Amsterdam were linked to the Dutch Hospital Discharge Register., Participants: A total of 5681 observations of 2520 respondents across 4 measurement points (each with a follow-up of 36 months; ages 65-88 years)., Outcome Measures: The contribution of health, demographic, psychosocial and lifestyle characteristics to time trends in hospitalisation was assessed in multivariate models., Results: Between 1995 and 2009, the percentage with 1 or more overnight admissions (planned or acute) increased slightly from 38.1% to 39.7%. This was due to an increase in acute admission only (22.2-27.0%). Increased prevalences of chronic diseases, functional limitations and polypharmacy accounted for part of the observed increase in acute admissions. In addition, a more than doubled prevalence of day admissions over time was observed (12.3-28.3%), a trend that was unrelated to changes in individual characteristics., Conclusions: This trend study showed a contribution of declines in population health to increases in acute hospital admissions. Since these declines did not provide a full explanation, healthcare reforms and increases in treatment possibilities in this period are likely to have contributed as well., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 μg) and folic acid (400 μg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514., (© The Author(s) 2016.)

Paget's disease of bone is a focal disorder of bone remodelling that leads to changes in the shape and size of affected bones, and is associated with articular and vascular complications. The disorder is characterised by a localised increase in osteoclast number and activity in one or more affected sites while the rest of the skeleton remains unaffected. The excessive bone resorption leads to recruitment of osteoblasts to the remodelling sites, resulting in increased bone formation. This accelerated bone turnover causes deposition of bone with disorganised architecture and structural weakness. The precise aetiology is unknown. It is thought that the disease is caused by interactions between environmental and genetic factors; the nature of this interaction still has to be determined. The disease is progressive, but can be treated with a single infusion of zoledronic acid. In this manuscript three cases are described, along with a review of the current diagnostic tools and treatment.

Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow-up we determined bone measures-incident fractures and history of fractures, bone-mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow-up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia.

Background: Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients., Methods/design: We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate., Discussion: This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined., Trial Registration: This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

Introduction: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients., Methods: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12-50  μmol/l), treated with B-vitamins (500  μg vitamin B12 and 400  μg folic acid) or placebo for 2 years. In a subgroup (n = 569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima-media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured., Results: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6  μmol/l (P < 0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed., Discussion: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes.

Objectives: Whereas evidence exists about the benefits of intensive exercise on cardiovascular outcomes in older adults, data are lacking regarding long-term effects of physical fitness and physical activity on cardiovascular health. Therefore, we aimed to investigate the longitudinal association of physical fitness, physical activity and muscle strength with arterial stiffness measures., Design: a longitudinal follow-up study (2 years) of data from the B-PROOF study., Setting: a subgroup of the B-PROOF study (n=497)., Participants: Four hundred ninety-seven participants with a mean age of 72.1 years (SD 5.4) of which 57% was male., Measurements: All performed at baseline and after two-year follow-up. Arterial stiffness was estimated by pulse wave velocity (PWV) measured with applanation tonometry. Furthermore, augmentation index (AIx) and aortic pulse pressure (PP) were assessed. Physical activity was estimated using a validated questionnaire regarding daily activities. Physical fitness was measured with a physical performance score, resulting from a walking, chair-stand and balance test. Muscle strength was assessed with hand-grip strength using a handheld dynamometer., Results: The median performance score was 9.0 [IQR 8.0-11.0], the mean physical activity was 744.4 (SD 539.4) kcal/day and the mean hand-grip strength was 33.1 (SD 10.2) kg. AIx differed between the baseline and follow-up measurement (26.2% (SD 10.1) vs. 28.1% (SD 9.9); p < 0.01), whereas PWV and aortic PP did not. In multivariable linear regression analysis, physical performance, physical activity and hand-grip strength at baseline were not associated with the amount of arterial stiffness after two years of follow-up., Conclusion: Physical fitness, activity and muscle strength were not associated with arterial stiffness. More research is warranted to elucidate the long-term effects of daily and intensive physical activity on arterial stiffness in an elderly population.

Context: Vitamin D is essential for bone health. In addition, vitamin D has recently been proposed to play a role in the pathophysiology of many chronic diseases. Despite the large number of studies published on vitamin D, the threshold for a sufficient serum 25-hydroxyvitamin D [25(OH)D] concentration is still debated and may differ according to outcomes and subgroups., Objective: The objective of the study was to estimate the thresholds for serum 25(OH)D concentration with respect to the different outcomes and for different subgroups., Design, Setting, and Participants: Observational data from the Longitudinal Aging Study Amsterdam, an ongoing population-based Dutch cohort study [n = 1164, mean (SD) age 75.2 (6.5) y], were used., Main Outcome Measures: Falling, fractures, hypertension, cardiovascular disease, blood pressure, PTH, grip strength, physical performance, functional limitations, body mass index (BMI), and mortality were measured. To determine thresholds, spline curves were used. Visual inspection and the statistical best fit of the spline regression models were used together to estimate the best estimate of the thresholds., Results: Thresholds for serum 25(OH)D concentrations in the whole sample ranged from 46 nmol/L (PTH) to 68 nmol/L (hypertension). On average, women, the oldest old (≥ 75 y), and individuals with a high BMI (>25 kg/m(2)) had lower thresholds compared with men, the youngest old (65-75 y), and individuals with a low to normal BMI (<25 kg/m(2))., Conclusion: The results indicate that thresholds for serum 25(OH)D may vary according to different outcomes and subgroups. This study does not support the high thresholds (>75 nmol/L) as advised by some experts, and the higher requirements in women, older persons, and those with high BMI.

Objective: Osteocalcin is a well-known marker of bone formation. Recently, mice lacking osteocalcin or its receptor were reported to be subfertile with low testosterone and high luteinizing hormone concentrations. In parallel, in humans, a loss-of-function mutation of the osteocalcin receptor was associated with hypergonadotropic hypogonadism. This suggests that osteocalcin is necessary for normal pituitary-gonadal axis function. Our objective was to determine the association between physiological variations in osteocalcin and the pituitary-gonadal axis in older men., Design and Patients: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a representative sample of the older Dutch population (65-88 years)., Measurements: Serum levels of total (T), free (FT) and bioavailable (bioT) testosterone, luteinizing hormone (LH) and osteocalcin were determined. Data were analysed using linear regression analyses and adjusted for age, BMI, 25-hydroxyvitamin D, parathyroid hormone and vitamin K antagonist use., Results: A total of 614 men participated in the study. The median age was 75·4 (69·8-81·2) years, and the median osteocalcin level was 1·8 (1·3-2·4) nmol/l. Serum osteocalcin was inversely associated with FT (adjusted B = -0·22 ± 0·09 ng/dl, P = 0·012) and bioT (adjusted B = -0·26 ± 0·08 nmol/l, P < 0·01), but not with total T. Furthermore, osteocalcin was positively associated with LH (adjusted B = 0·09 ± 0·03 U/l, P < 0·01)., Conclusions: Serum osteocalcin was negatively associated with free and bioavailable testosterone and positively with luteinizing hormone levels., (© 2014 John Wiley & Sons Ltd.)

The association of vitamin D status with bone mineral density (BMD) and Quantitative Ultrasound measurements (QUS) has been inconsistent in previous studies, probably caused by moderating effects. This study explored (1) the association of vitamin D status with QUS and BMD, and (2) whether these associations were modified by body mass index (BMI), age, gender, or physical activity. Two-independent cohorts of the Longitudinal Aging Study Amsterdam (LASA-I, 1995/1996, aged ≥65; LASA-II, 2008/2009, aged 61-71) and baseline measurement of the B-vitamins for the prevention of osteoporotic fractures (B-PROOF) study (2008-2011, aged 65+) were used. QUS measurements [broadband ultrasound attenuation (BUA) and speed of sound (SOS)] were performed at the calcaneus in all three cohorts (N = 1,235, N = 365, N = 1319); BMD was measured by Dual X-ray absorptiometry (DXA) in B-PROOF (N = 1,162 and 1,192 for specific sites) and LASA-I (N = 492 and 503). The associations of vitamin D status with BUA and BMD were modified by BMI. Only in persons with low-to-normal BMI (<25 kg/m(2)) and serum 25(OH)D <25 nmol/L was associated with lower BUA as compared to the reference group (≥50 nmol/L) in LASA-I and B-PROOF. Furthermore, in LASA-I, these individuals had lower BMD at the hip and lumbar spine. In LASA-II, no associations with BUA were observed. Vitamin D status was not associated with SOS, and these associations were not modified by the effect modifiers tested. The association between vitamin D status and BUA and BMD was modified by BMI in the older-aged cohorts: there was only an association in individuals with BMI <25 kg/m(2).

Background: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population., Design: cross-sectional., Setting/subjects: a subgroup of the B-PROOF study was included to determine associations between serum 25(OH)D and arterial stiffness and atherosclerosis (n = 567, 57% male, age 72.6 ± 5.6 years, mean serum 25(OH)D 54.6 ± 24.1 nmol/l)., Methods: carotid intima media thickness (IMT) was assessed using ultrasonography and pulse wave velocity (PWV) was determined with applanation tonometry. Associations were tested using multivariable restricted cubic spline functions and stratified linear regression analysis., Results: the associations between serum 25(OH)D and carotid IMT or PWV were non-linear. Spline functions demonstrated a difference between 25(OH)D deficient and sufficient individuals. In serum 25(OH)D sufficient participants (≥50 nmol/l; n = 287), a positive association with IMT and serum 25(OH)D was present (β 1.24; 95%CI [0.002; 2.473]). PWV levels were slightly lower in vitamin D deficient individuals, but the association with 25(OH)D was not significant., Conclusion: our study demonstrates that associations of serum 25(OH)D and PWV and IMT in an elderly population are not linear. In particular from serum 25(OH)D levels of 50 nmol/l and up, there is a slight increase of IMT with increasing 25(OH)D levels., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Vitamin D deficiency has been associated with impaired physical functioning, depression, and several chronic diseases and might thereby affect quality of life and self-rated health., Objective: The aim of this study was to assess relationships of serum 25-hydroxyvitamin D [25(OH)D] with quality of life and self-rated health and to examine whether physical performance, depressive symptoms, and number of chronic diseases mediate these relationships., Design: We analyzed data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals., Main Outcome Measures: Serum 25(OH)D was classified into the following categories: less than 25, 25-50, and 50 nmol/L or greater. We assessed quality of life (QOL) using the Short Form-12 Health Survey (SF-12; n = 862) and self-rated health (SRH) with a single question, dichotomized into good vs poor SRH (n = 1248)., Results: Individuals with serum 25(OH)D less than 25 nmol/L scored lower on the physical component score of the SF-12 and had a lower odds on good SRH score compared with individuals with serum 25(OH)D greater than 50 nmol/L (β (95% confidence interval) -3.9 (-6.5 to -1.3) for SF-12, and odds ratio [95% confidence interval) 0.50 (0.33-0.76) for SRH]. Physical performance, depressive symptoms, and the number of chronic diseases were associated with vitamin D status, QOL, and SRH. Adding all these potential mediators to regression models attenuated associations of 25(OH)D less than 25 nmol/L with QOL with 78% and SRH with 32%., Conclusion: Lower 25(OH)D status is related to lower scores on QOL and SRH. A large part of the association with QOL can statistically be explained by physical performance, depressive symptoms, and the number of chronic diseases.

Background and Aims: Hyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated., Methods and Results: Baseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine-gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels., Conclusion: Homocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate which parameters of physical functioning are associated with bone quality and fracture risk and whether gender-specific differences exist within these associations. We studied 1,486 participants of the Longitudinal Aging Study Amsterdam. As measures of physical functioning, handgrip strength, physical performance, and level of physical activity were assessed. To assess bone quality, broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at baseline using quantitative ultrasound and bone mineral density (BMD) at baseline and after 3 years by dual-energy X-ray absorptiometry. In addition, fracture incidence over 6 years was assessed. After adjustment for confounders (age, serum 25[OH]D, smoking, and body weight), in men, physical performance was positively related to BUA, SOS, and BMD cross-sectionally and to BMD longitudinally. Using Cox proportional hazards model, in men higher handgrip strength and physical performance were associated with reduced fracture risk after adjustment for confounders (hazard ratio [HR] 0.96, 95 % confidence interval [CI] 0.92-0.99, and HR 0.89, 95 % CI 0.80-0.98, respectively). In women, a moderate level of physical activity was related to reduced fracture risk (HR 0.57, 95 % CI 0.33-0.99). In conclusion, in men, higher handgrip strength and physical performance are related to higher bone quality and reduced fracture risk, whereas in women, a moderate to high level of physical activity is associated with reduced fracture risk. These measurements may contribute to the identification of individuals at high fracture risk. Both the causality of and explanations for gender-specific differences in these relationships remain subject to further studies.

Background: Vitamin D status is currently diagnosed by measuring serum 25-hydroxyvitamin D [25(OH)D]., Objective: This study aimed to develop a risk profile that can be used to easily identify older individuals at high risk of vitamin D deficiency., Design: This study was performed within the Longitudinal Aging Study Amsterdam, an ongoing cohort study in a representative sample of the Dutch older population (n = 1509 for the development sample and n = 1100 for the validation sample). Prediction models for serum 25(OH)D concentrations <50 and <30 nmol/L were developed by using backward logistic regression. Risk scores were calculated by dividing the individual regression coefficients by the regression coefficient with the lowest β to create simple scores., Results: Serum 25(OH)D concentrations <50 and <30 nmol/L were present in 46.2% and 17.5% of participants, respectively. The model for the prediction of concentrations <50 nmol/L consisted of 13 easily assessable predictors, whereas the model for concentrations <30 nmol/L contained 10 predictors. The resulting areas under the curve (AUCs) were 0.78 and 0.80, respectively. The AUC in the external validation data set was 0.71 for the <50-nmol/L model. At a cutoff of 58 in total risk score (range: 8-97), the model predicted concentrations <50 nmol/L with a sensitivity of 61% and a specificity of 82%, whereas these values were 61% and 84%, respectively, at a cutoff of 110 in the total risk score (range: 6-204) in the model for concentrations <30 nmol/L., Conclusions: Two total risk scores, including 13 or 10 predictors that can easily be assessed, were developed and are able to predict serum 25(OH)D concentrations <50 and <30 nmol/L accurately. These risk scores may be useful in clinical practice to identify persons at risk of vitamin D deficiency.

Vitamin D status can be assessed by measuring concentrations of 25-hydroxyvitamin D (25(OH)D). Sunlight is the most important source of vitamin D and stimulates the production of vitamin D3 in the skin during the summer, depending on age, skin pigmentation, clothing style, and sunscreen use. Seasonal variation in serum 25(OH)D is between 10 and 20 nmol/L in adults and almost absent in nursing home residents. Sunscreen use decreases, but does not abolish, vitamin D production in the skin. Clothing style has a large influence on vitamin D production. Furthermore, vitamin D status can be improved by ingestion of fatty fish and the fortification of milk or orange juice. A high dietary calcium intake has a vitamin D-sparing effect, because it increases the half-life of 25(OH)D. A combination of sunlight exposure, nutrition, food fortification, and supplements is desirable to obtain sufficient vitamin D status in the population of most countries throughout the year., (© 2014 New York Academy of Sciences.)

Reference values of PTH depend on vitamin D status of the reference population. This is often not described in package inserts. The aim of the present study was therefore to calculate assay specific PTH reference levels in EDTA plasma for the Architect (Abbott) in relation to 25-hydroxyvitamin D (25OHD) levels. The relation between PTH levels, 25OHD, BMI, age, gender and kidney function was determined in a cohort of older individuals from the Longitudinal Aging Study Amsterdam (LASA, n = 738, age 55-65 years) and in a cohort of healthy individuals from the Netherlands Study of Depression and Anxiety (NESDA, n = 633, 18-65 years). The LASA cohort is a representative sample of the Dutch older population. As expected, PTH reference values were significantly lower in 25OHD sufficient subjects (25OHD>50 nmol/L) than in 25OHD deficient and insufficient subjects. The 97.5th percentile of PTH in 25OHD sufficient subjects was 10 pmol/L (94.3 pg/mL), which was higher than the upper limit stated by the manufacturer (7.2 pmol/L or 68.3 pg/mL). The relation between vitamin D and PTH was independent of age, gender, BMI and kidney function. In conclusion, we have shown that it is important to establish PTH reference values in a local reference population taking 25OHD status into account., (© 2013.)

Context: Vitamin D is known to influence muscle health. A reduction in muscle mass increases the risk of functional limitations among older individuals., Objective: The aim of this study was to examine the relationship between vitamin D status and functional limitations., Design, Setting, and Participants: Two independent cohorts of the Longitudinal Aging Study Amsterdam were used. Participants were aged 65 to 88 years (older cohort, n = 1237; baseline 1995) and 55 to 65 years (younger cohort, n = 725; baseline 2002)., Main Outcome Measures: Questions on the ability and degree of difficulty to perform 6 functions of daily life were asked., Results: Of the participants, 56% in the older cohort and 30% in the younger cohort had ≥1 limitation. Vitamin D deficiency (25-hydroxyvitamin D level of <20 ng/mL) compared with the value in the reference group (>30 ng/mL) was related to the presence of functional limitations at baseline (odds ratio [OR] = 1.7; 95% confidence interval [CI], 1.2-2.5 and OR = 2.2; 95% CI 1.3-3.7 for the older and younger cohorts, respectively). In the older cohort, vitamin D deficiency was associated with an increase in limitations at 3 years (OR = 2.0; 95% CI, 1.1-3.5), whereas vitamin D deficiency in the younger cohort was associated with an increase in limitations at 6 years (OR = 3.3; 95% CI, 1.1-10.1). Analyses were adjusted for confounders., Conclusion: Vitamin D status is associated with functional limitations cross-sectionally and longitudinally in individuals aged 55 to 65 years and those 65 years and older. The possible association of vitamin D with functional limitations is present after a shorter follow-up time in the oldest age group compared with the younger age group.

Background/objectives: Physical activity (PA) may have an impact on vitamin D status. The aim of the present study is to assess the contribution of different characteristics of PA (duration, intensity as estimated by energy expenditure, location) to vitamin D status., Subjects/methods: The study was conducted in 1255 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA). Cross-sectional relationships between PA and serum 25-hydroxyvitamin D (25(OH)D) concentrations were examined., Results: Total PA, both indoor and outdoor PA, expressed in kcal/d was positively associated with 25(OH)D in women (P<0.05) but not in men. The total time spent on these activities was not associated. As compared with the lowest tertile, both men and women in the highest tertile of cycling activity (≈ 6.4 min/d or 34.7 kcal/d) had a ≥ 6 nmol/l higher 25(OH)D (P<0.05). For men and women in the highest tertile of gardening (≥ 8.6 min/d or 87.6 kcal/d), these levels were 14.2 nmol/l (P<0.001) and 5.8 nmol/l 25(OH)D (P<0.05), respectively. Walking showed no association., Conclusions: Daily time spent on total PA is often included when studying the association between sum of PA and 25(OH)D, while our study showed that energy expenditure might be a better unit. Individual types of outdoor PA with a high intensity, such as gardening and cycling, were associated with 25(OH)D.

Unlabelled: This study, on the association between vitamin D status and physical performance and its decline, shows that vitamin D status is associated with physical performance in several older age groups. However, vitamin D status does not predict a decline in physical performance in individuals aged 55-65 years., Introduction: Previous research in the Longitudinal Aging Study Amsterdam (LASA) showed an association of vitamin D status with physical performance and its decline in persons aged 65 years and older. The current study aims to determine these associations in younger individuals and to replicate previous research of LASA., Methods: Data from three independent cohorts were used: two cohorts of LASA (LASA-II with measurements in 2002 (n = 707) and 2009 (n = 491), LASA-I-2009 (n = 355)) and the baseline measurement of the B-Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) study (n = 2,813). Participants performed three tests (walking test, chair stands, and tandem stand; range total score 0-12), except in LASA-II-2002 (only walking and chair stands tests; range total score 0-8). Multiple linear and logistic regression were used to assess whether vitamin D status was associated with total physical performance and its decline, respectively., Results: The mean age of the participants was 60.0 (SD 3.0), 65.9 (2.9), 78.4 (5.3), and 74.4 (6.8) years for LASA-II-2002, LASA-II-2009, LASA-I-2009, and B-PROOF, respectively. Vitamin D status was not predictive of a clinical decline in total physical performance score in the LASA-II-2002 cohort (aged 55-65 years). After adjustment for confounding, participants with serum 25(OH)D < 50 nmol/L scored 0.8 (95 % confidence interval 0.4-1.2), 0.9 (0.3-1.5), 1.5 (0.8-2.3), and 0.6 (0.3-0.9) points lower on total physical performance than participants with serum 25(OH)D ≥ 75 nmol/L., Conclusion: Our study confirmed that serum 25(OH)D is associated with physical performance. However, vitamin D status did not predict a clinical decline in physical performance in individuals aged 55-65 years.

Hypophosphatemia is an important finding in the evaluation of patients with chronic bone pain. Fibroblast-growth factor 23 (FGF23) plays a role in the differential diagnosis of hypophosphatemia. A 34-year-old man had progressive pain in both shoulders and hips due to hypophosphatemic osteomalacia. He had elevated FGF23 levels, induced by a FGF23-producing tumour in the right acetabulum. Thus, he had tumour-induced hypophosphatemic osteomalacia. A 50-year-old man had had bowed legs and joint pains since his youth due to osteomalacia. Several family members also had osteomalacia. His phosphate concentration was low. Genetic testing revealed a mutation on the PHEX gene which results in high FGF23 levels. Thus, he had X-linked hereditary hypophosphatemic osteomalacia. In patients with bone pain, the measurement of a phosphate concentration is important. In renal phosphate loss, the measurement of FGF23 is an important next step if parathormone concentrations are low or normal.

Context: To our knowledge, no previous studies examined the longitudinal relationship between vitamin D status and pulmonary function in a population-based sample of older persons., Objective: Our objective was to examine the cross-sectional as well as the longitudinal relationship between vitamin D status and peak expiratory flow rate (PEFR) in a representative sample of the Dutch older population., Design, Setting, and Participants: Participants included men and women in the Longitudinal Aging Study Amsterdam, an ongoing cohort study in older people., Main Outcome Measure: PEFR was measured using the mini-Wright peak flow meter., Results: Men with serum 25-hydroxyvitamin D (25-OHD) levels below 10 ng/ml (25 nmol/liter) had a significantly lower PEFR in the cross-sectional analyses, and men with serum 25-OHD levels below 20 ng/ml (50 nmol/liter) had a significantly lower PEFR in the longitudinal analyses as compared with men with serum 25-OHD levels above 30 ng/ml (75 nmol/liter) (cross-sectional: β = -47.0, P = 0.01 for serum 25-OHD <10 ng/ml; longitudinal: β = -45.0, P < 0.01 for serum 25-OHD <10 ng/ml; and β = -20.2, P = 0.03 for serum 25-OHD = 10-20 ng/ml in the fully adjusted models). Physical performance (β = -32.5, P = 0.08 for serum 25-OHD <10 ng/ml) and grip strength (β = -40.0, P = 0.03 for serum 25-OHD <10 ng/ml) partly mediated the cross-sectional associations but not the longitudinal associations. In women, statistically significant associations between 25-OHD and PEFR were observed in the cross-sectional analyses after adjustment for age and season of blood collection but not in the fully adjusted models or in the longitudinal analyses., Conclusions: A strong relationship between serum 25-OHD and PEFR was observed in older men, both in the cross-sectional as well as longitudinal analyses, but not in older women. The association in men could partly be explained by physical performance and muscle strength.

Objectives: to compare the incidence of recurrent falls in older people with and without diabetes, and to examine diabetes- and fall-related risk factors explaining the increased risk of recurrent falls associated with diabetes., Methods: population-based cohort study of 1,145 (85 with diabetes) community-dwelling participants, aged ≥65 years, from The Longitudinal Aging Study Amsterdam (LASA). Falls were assessed prospectively (every 3 months) during a 3-year follow-up period. Incidence of recurrent falls was estimated with Poisson regression analyses. The associations between diabetes and time to recurrent falls, defined as at least two falls occurring within a 6-month period, and the potential explanatory role of several risk factors herein, were analysed with the use of Cox-regression models., Results: during a mean follow-up of 139 weeks, 30.6% of the individuals with and 19.4% of the individuals without diabetes fell recurrently [incidence rate of 129.7 versus 77.4 per 1,000 persons-years, respectively, HR = 1.67 (95% CI: 1.11-2.51)]. Adjustments for potential confounders did not change the increased risk associated with diabetes [HR = 1.63 (1.06-2.52)]. Factors that partly explained this increased risk were: greater number of medication, higher levels of pain, poorer self-perceived health, lower physical activity and grip strength, more limitations in ADLs, lower-extremity physical performance and cognitive impairment. Altogether, these variables accounted for 47% of the increased risk of recurrent falls associated with diabetes [adjusted HR = 1.30 (0.79-2.11)]., Conclusion: fall prevention efforts targeting the factors identified above may need to be incorporated into the care and treatment of older individuals with diabetes.

Objective: Vitamin D deficiency and polypharmacy are common in the elderly. However, knowledge on the associations between the use of specific medicines and serum 25-hydroxyvitamin D (25(OH)D) is limited. The aim of this study was to (better) define the associations between the use of specific medicines and serum 25(OH)D., Methods: Two different cohorts (1995/1996 and 2002/2003) from the Longitudinal Aging Study Amsterdam (LASA) were used for cross-sectional analyses. LASA is based on an age and sex-stratified random sample of the Dutch older population. Study participants were aged 65-88 years in the first cohort (n = 1301) and 55-65 years in the second cohort (n = 736). Serum 25(OH)D of users of several groups of medicines were compared with levels of non-users using multiple linear regression analysis., Results: Of all participants, 75.4% (first cohort) and 61.1% (second cohort) were using at least one medicine. In both cohorts, the number of medicines was associated with lower serum 25(OH)D. In the first cohort, after adjustment for confounding, users of any kind of medicine, loop diuretics and inhaled corticosteroids (only men) had respectively 4.4 nmol/l (P<0.01), 4.7 nmol/l (P = 0.04) and 7.3 nmol/l (P = 0.02) lower serum 25(OH)D than non-users. In the second cohort, the use of oral antidiabetics, calcium-channel blockers and angiotensin-converting enzyme inhibitors was associated with respectively 7.4 nmol/l (P = 0.04), 7.7 nmol/l (P = 0.01) and 7.6 nmol/l (P<0.01) lower serum 25(OH)D., Conclusions: These data show that users of several medicines have lower serum 25(OH)D than non-users. Vitamin D supplementation may be considered in patients with chronic use of medicines.

Objective: To what extent endogenous subclinical thyroid disorders contribute to impaired physical and cognitive function, depression, and mortality in older individuals remains a matter of debate., Design: A population-based, prospective cohort of the Longitudinal Aging Study Amsterdam., Methods: TSH and, if necessary, thyroxine and triiodothyronine levels were measured in individuals aged 65 years or older. Participants were classified according to clinical categories of thyroid function. Participants with overt thyroid disease or use of thyroid medication were excluded, leaving 1219 participants for analyses. Outcome measures were physical and cognitive function, depressive symptoms (cross-sectional), and mortality (longitudinal), Results: Sixty-four (5.3%) individuals had subclinical hypothyroidism and 34 (2.8%) individuals had subclinical hyperthyroidism. Compared with euthyroidism (n=1121), subclinical hypo-, and hyper-thyroidism were not significantly associated with impairment of physical or cognitive function, or depression. On the contrary, participants with subclinical hypothyroidism did less often report more than one activity limitation (odds ratio 0.44, 95% confidence interval (CI) 0.22-0.86). After a median follow-up of 10.7 years, 601 participants were deceased. Subclinical hypo- and hyper-thyroidism were not associated with increased overall mortality risk (hazard ratio 0.89, 95% CI 0.59-1.35 and 0.69, 95% CI 0.40-1.20 respectively)., Conclusions: This study does not support disadvantageous effects of subclinical thyroid disorders on physical or cognitive function, depression, or mortality in an older population.

Context: Vitamin D receptor (VDR) polymorphisms are associated with a variety of diseases, which may translate into an effect on mortality., Objective: To investigate the associations between VDR gene variants and mortality among older people., Design: The analyses were conducted in a population-based, prospective cohort of the Longitudinal Aging Study Amsterdam. Adequate DNA analysis was performed in 923 men and women (≥65 years). We aimed to assess the associations between mortality and the VDR polymorphism FokI, three haplotypes of the Cdx2 and GATA polymorphisms, and three haplotypes of the BsmI, ApaI, and TaqI polymorphisms., Results: During the median follow-up of 10.7 years, 480 participants deceased (51%). Homozygosity for the Cdx2-GATA haplotype 1 allele was associated with a 30% higher mortality risk compared to the absence of alleles (hazard ratios (HR) 1.30, 95% confidence intervals (CI) 1.01-1.68). Adjustment for cardiovascular risk factors and 25-hydroxyvitamin D levels did not affect this HR. The number of copies of the Cdx2-GATA haplotype 1 allele was associated, although not significantly, with an increased risk of osteoporotic fractures (0 copies=reference, HR, 95% CI: 1 copy 2.01, 0.99-4.07 and 2 copies 1.81, 0.87-4.18). After adjustment for osteoporotic fractures, homozygosity for the Cdx2-GATA haplotype 1 allele was no longer associated with higher mortality risk (HR 1.08, 95% CI 0.83-1.41)., Conclusions: The Cdx2-GATA haplotype 1 allele was related to increased mortality risk, which may be partly explained by osteoporotic fractures. As the biological mechanism is uncertain and this study size is limited, our results should be interpreted as hypothesis generating.

Context: Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity., Objective: The objective of the study was to investigate whether insulin sensitivity and insulin's effects on the microcirculation are impaired in normal-weight and obese women with PCOS., Design and Population: Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia., Main Outcome Measures: Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity)., Results: Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups., Conclusion: PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases.

The association between birth weight and blood pressure is well established but at present unexplained. According to the Borst-Guyton concept, chronic hypertension can occur only with a shift in the renal pressure-natriuresis relationship resulting in increased salt sensitivity of blood pressure. We assessed salt sensitivity of blood pressure in a group of 27 healthy adults whose birth weight was available. Birth weight was ascertained from birth certificates or announcements. Salt sensitivity of blood pressure was determined as difference in mean arterial pressure (MAP) between a 1-week high-salt ( approximately 235 mmol NaCl/d) versus low-salt diet ( approximately 55 mmol NaCl/d). Creatinine clearance was estimated according to the formula of Cockcroft and Gault. Birth weight was negatively associated with salt sensitivity of blood pressure (r=-0.60, P=0.002). The creatinine clearance was positively associated with birth weight (r=0.53; P=0.008) but did not influence the association between birth weight and salt sensitivity of blood pressure. Birth weight is associated with salt sensitivity of blood pressure, and this may play a role in the maintenance of elevated blood pressure in individuals with a low birth weight.

Our study aim is to investigate whether obesity is characterized by an impairment of insulin-mediated vasodilatory effects and by a modification of basal vasomotion in the skin microvasculature. Forty healthy obese and forty healthy lean women were included. Microvascular effects of insulin as compared to a control substance were measured by cathodal iontophoresis combined with laser Doppler flowmetry. Vasomotion was examined by Fourier transform analyses of skin laser Doppler flow at rest. Locally administered insulin, as compared to the control substance, induced a microvascular vasodilatory response in lean (median (interquartile range): 31.6 (17.1-43.9) vs. 22.9 (16.4-36.7) perfusion units, P=0.04), but not in obese women (28.1 (14.4-47.1) vs. 27.5 (17.5-48.2) perfusion units, P=0.7). The relative insulin-induced increase in blood flow corrected for the control substance was higher in lean than obese women (ANOVA for repeated measures F=3.93, P=0.05). The contribution of the total frequency spectrum 0.01-1.6 Hz and of the frequency intervals 0.01-0.02 Hz and 0.02-0.06 Hz (representative of endothelial and neurogenic activity, respectively) to basal microvascular vasomotion was lower in obese than in lean women (P<0.05 for all). These findings show that obesity is characterized by an impaired direct microvascular vasodilatory effect of insulin and by decreased skin microvascular vasomotion in a way that is suggestive for alterations of endothelial and neurogenic activity.

Objective: Generalized microvascular dysfunction may contribute to the development of salt sensitivity, insulin resistance and hypertension, and may thus link these cardiovascular risk factors. To test this hypothesis, we examined skin microvascular function, salt sensitivity, insulin sensitivity and blood pressure in 27 normotensive and 26 hypertensive individuals., Methods: Capillary density was examined by videomicroscopy during venous congestion and postocclusive reactive hyperaemia. Endothelium-(in)dependent vasodilation was assessed by iontophoresis of acetylcholine and sodium nitroprusside and by laser Doppler flowmetry. Salt sensitivity was determined as the difference in mean arterial pressure (MAP) between a 1-week high-salt diet (approximately 235 mmol NaCl/day) versus low-salt diet (approximately 55 mmol NaCl/day). Insulin sensitivity was measured with the hyperinsulinaemic, euglycaemic clamp, and blood pressure was assessed by 24-h ambulatory blood pressure monitoring., Results: Salt sensitivity of blood pressure was inversely associated with postocclusive capillary recruitment and endothelium-dependent vasodilation (r=-0.67, P<0.001 and r=-0.60, P<0.01, respectively), but not with capillary density during venous congestion or endothelium-independent vasodilation. Salt sensitivity was negatively associated with insulin sensitivity (r=-0.55, P<0.001) and positively with MAP (r=0.58, P<0.001). Multiple regression analyses suggested that associations between salt sensitivity and both insulin sensitivity and MAP were dependent on microvascular function., Conclusion: Our results suggest a close inverse association between skin microvascular function and salt sensitivity and a role for generalized microvascular defects as a link between salt sensitivity, insulin resistance and hypertension.

Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension.

The relationships of cortisol with elevated blood pressure and insulin resistance are likely to be the result of a complex interplay of different mechanisms. We hypothesize that cortisol is associated with impaired microvascular function and that this contributes to cortisol-associated high blood pressure and insulin resistance. We examined 24 h urinary free cortisol excretion in 56 healthy adults (26 women). Blood pressure was assessed by 24 h ambulatory measurements. Insulin sensitivity was determined using the hyperinsulinaemic euglycaemic clamp technique. Skin capillary recruitment after arterial occlusion was visualized with videomicroscopy and endothelium-(in)dependent vasodilation was evaluated with iontophoresis of acetylcholine and sodium nitroprusside combined with laser Doppler fluxmetry. Men were characterized by higher urinary cortisol excretion [median (interquartile range), 162 (130-194) compared with 118 (99-156) nmol/24 h, P<0.05]. In women, but not in men, urinary cortisol excretion was associated with impaired capillary recruitment (r=-0.66, P<0.001), higher systolic blood pressure (r=0.64, P<0.001) and lower insulin sensitivity (r=-0.43, P<0.05). Urinary cortisol excretion was not associated with endothelium-(in)dependent vasodilation in men or women. Regression analysis demonstrated that capillary recruitment statistically explained 37% of the association between urinary cortisol and blood pressure in women. Capillary recruitment did not explain part of the association between urinary cortisol and insulin sensitivity. In conclusion, urinary cortisol excretion is inversely associated with capillary recruitment in women, but not in men, and capillary recruitment explains part of the cortisol-blood pressure relationship. These data suggest that, in women, impairment of capillary function mediates some of the adverse effects of cortisol and thus may provide a target to prevent such adverse effects.

Context: Central adiposity is associated with cardiovascular risk independently of total adiposity. Microvascular dysfunction is thought to contribute to obesity-associated insulin resistance and hypertension and may thus link central adiposity with cardiovascular risk., Objective: Our objective was to investigate how body fat distribution relates to microvascular function and the role of adipocytokines in these relationships., Design, Setting, and Participants: We cross-sectionally studied 51 healthy adults and 29 of their prepubertal children born at the VU University Medical Center in Amsterdam., Main Outcome Measures: We measured visceral and abdominal sc adiposity with magnetic resonance imaging and truncal and peripheral sc adiposity with skinfold thickness. Postocclusive skin capillary recruitment was assessed with videomicroscopy. Concentrations of C-reactive protein, IL-6, and TNF-alpha were combined in an inflammation score., Results: In adults, visceral adipose tissue and trunk/extremity skinfold ratio were inversely associated with capillary recruitment (partial correlation coefficients, -0.32, P = 0.03, and -0.37, P < 0.01, respectively). The inflammation score was inversely associated with capillary recruitment (r = -0.50; P < 0.01) and statistically explained 41% of the association between visceral adipose tissue and capillary recruitment. In children, trunk/extremity skinfold ratio was inversely associated with capillary recruitment (r = -0.49; P = 0.01), but other measures of adiposity were not., Conclusion: Our data in adults suggest a role for visceral adiposity and its associated proinflammatory state in capillary dysfunction and its possible sequelae such as hypertension and insulin resistance. Also, our findings in children and adults suggest that truncal sc adiposity is detrimental for capillary perfusion and that this process may start before puberty.

Obesity and obesity-associated clinical disorders are becoming an increasing public health burden. In this perspective, we postulate that impairment of microvascular function links obesity with insulin resistance and hypertension. Obesity is characterized by generalized microvascular dysfunction, which is associated with, and may precede, the development of insulin resistance and hypertension. Understanding of mechanisms involved in obesity-associated microvascular dysfunction may reveal new therapeutic targets. In obesity, cellular regulatory mechanisms of vasoreactivity are shifted towards vasoconstriction, with an increased role for endothelin-1 and a decreased role for nitric oxide. In addition, communicative pathways between adipose tissue and the microvasculature comprise increased release of adipokines and increased sympathetic activity. Although one mechanism may dominate, microvascular defects in obesity are probably caused by an integrated response consisting of endocrine, vasocrine and neurogenic mechanisms. This remains a fruitful area for future research.

The metabolic syndrome defines a clustering of metabolic risk factors that confers an increased risk for type 2 diabetes and cardiovascular disease. The metabolic syndrome seems to have multiple etiological factors and microvascular dysfunction may be one potential factor explaining the clustering of multiple metabolic risk factors including hypertension, obesity, insulin resistance and glucose intolerance. Microvascular dysfunction may increase not only peripheral vascular resistance and blood pressure, but may also decrease insulin-mediated glucose uptake in muscle. The present article summarizes some of the data concerning the role of microvascular dysfunction in the metabolic syndrome.

The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.

To test the hypothesis that free fatty acids (FFAs) modulate microvascular function and that this contributes to obesity-associated insulin resistance, hypertension, and microangiopathy, we examined the effects of both FFA elevation in lean women and FFA lowering in obese women on skin microvascular function. A total of 16 lean and 12 obese women underwent, respectively, Intralipid plus heparin (or saline) infusion and overnight acipimox (or placebo) treatment. We measured capillary recruitment with capillaroscopy and endothelium-(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside before and during hyperinsulinemia (40 mU . m(-2) . min(-1)). FFA elevation impaired capillary recruitment and acetylcholine-mediated vasodilation before (44.6 +/- 16.8 vs. 56.9 +/- 18.9%, P < 0.05; and 338 +/- 131 vs. 557 +/- 162%, P < 0.01, respectively) and during (54.0 +/- 21.3 vs. 72.4 +/- 25.4%, P < 0.01; and 264 +/- 186 vs. 685 +/- 199%, P < 0.01, respectively) hyperinsulinemia. FFA lowering improved capillary recruitment before (50.9 +/- 14.6 vs. 37.4 +/- 9.3%, P < 0.01) and during (66.8 +/- 20.6 vs. 54.8 +/- 15.4%, P < 0.05) hyperinsulinemia. Changes in FFA levels were inversely associated with changes in capillary recruitment and insulin sensitivity in lean (r = -0.46, P = 0.08; and r = -0.56, P = 0.03) and in obese (r = -0.70, P = 0.02; and r = -0.62, P = 0.04) women. Regression analyses showed that changes in capillary recruitment statistically explained approximately 29% of the association between changes in FFA levels and insulin sensitivity. In conclusion, FFA levels modulate microvascular function and may contribute to obesity-associated insulin resistance, hypertension, and microangiopathy.

Aims/hypothesis: Insulin possesses vasodilatory actions that may be important in regulating its access to insulin-sensitive tissues. Our study aims to directly measure changes in response to insulin in the human skeletal muscle microcirculation. Measurement was by an implanted laser Doppler probe., Methods: We investigated changes in intramuscular and skin microvascular perfusion in 12 healthy individuals during a hyperinsulinaemic and a control clamp. We determined leg blood flow with plethysmography, finger skin functional capillary recruitment with capillaroscopy, endothelium-(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside, and leg intramuscular reactive hyperaemia and vasomotion with laser Doppler measurements., Results: Compared to the control study, hyperinsulinaemia (416+/-82 pmol/l) caused: (i) an increase in leg blood flow (1.0+/-1.0 vs 0.1+/-0.6 ml.min(-1).100 ml, p<0.05); (ii) an increase in finger skin capillary recruitment (14.9+/-10.1 vs -5.6+/-11.0%, p<0.01); (iii) no change in baseline laser Doppler perfusion either in finger skin or leg muscle; (iv) a tendency to increase acetylcholine-mediated vasodilation (475+/-534 vs 114+/-337%, p=0.07) with no change in sodium-nitroprusside-mediated vasodilation ( p=0.2) in finger skin; (v) an increase in intramuscular reactive hyperaemia (423+/-507 vs 0+/-220%, p<0.01); and (vi) a decrease in time needed to reach peak intramuscular perfusion (-3.6+/-3.0 vs 1.1+/-3.1 s, p<0.01). In addition, hyperinsulinaemia induced an increase in intramuscular vasomotion by increasing the contribution of frequencies between 0.01 and 0.04 Hz ( p<0.05 for all), which probably represents increased endothelial and neurogenic activity., Conclusions/interpretation: Physiological hyperinsulinaemia not only stimulates total blood flow and skin microvascular perfusion, but also augments human skeletal muscle microvascular recruitment and vasomotion as detected directly by laser Doppler measurements.

This randomised double-blind, placebo-controlled, clinical trial investigated the effect of 3 months of treatment with calcium dobesilate on endothelium-dependent vasodilation, markers of endothelial function, blood pressure, and markers of oxidation in obese, male smokers. Vascular effects may depend on the type of vessel and we, therefore, investigated both smaller arteries, i.e. resistance arteries and small arterioles, and large conduit arteries. Vascular function was measured by acetylcholine- and sodium-nitroprusside-mediated vasodilation, and capillary recruitment, in the skin microcirculation; by forearm blood flow (FBF) responses to several agonists and to N-G-monomethyl L-arginine (L-NMMA) in the forearm vascular bed; by flow-mediated vasodilation in the brachial artery; and by determination of soluble levels of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin. Twenty-eight individuals received dobesilate and 24 placebo. No effect of calcium dobesilate on endothelial function, blood pressure or markers of oxidation was observed compared with placebo. The difference in acetylcholine-mediated vasodilation in the microcirculation was -52.1%-point (95% confidence interval -132.8 to 28.1); in sodium-nitroprusside-mediated vasodilation in the microcirculation, 2.6%-point (-95.1 to 100.2); in capillary recruitment, 2.5%-point (-6.8 to 11.7); in acetylcholine-induced increases in FBF (n=28), 23%-point (-173 to 126); in L-NMMA-induced reduction of basal FBF, -2.8%-point (-29.3 to 23.8); in flow-mediated vasodilation of the brachial artery, 0.3%-points (-2.7 to 3.3); in 24-h systolic blood pressure, 2.1 mmHg (-1.3 to 5.5); in soluble VCAM-1, 54 ng/ml (-8 to 115); in soluble ICAM-1, 9 ng/ml (-49 to 67); in sE-selectin, -17 ng/ml (-44 to 11); in ketocholesterol 5 nM (-17 to 26); and in oxidised LDL -1.6 U/l (-6.7 to 3.5). We have shown that endothelial function, blood pressure, and markers of oxidation were not affected by 3 months of treatment with calcium dobesilate in mildly obese, smoking men. Thus, our data provide no evidence of an effect on vascular function of calcium dobesilate in humans.

Background: To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk., Materials and Methods: Forty-six healthy White individuals aged 30-70 years were studied. Coronary heart disease risk was assessed with the use of the CHD risk score according to the Framingham Heart Study, which is based on the risk factors age, blood pressure, cigarette smoking, total cholesterol, HDL cholesterol and diabetes. Endothelium-dependent and -independent vasodilation in skin were evaluated with laser Doppler after iontophoresis of acetylcholine and sodium nitroprusside. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion., Results: Coronary heart disease risk score (i.e. the 10-year probability of CHD) varied from 1-37%. Microvascular function decreased with increasing quartiles of CHD risk (for acetylcholine-mediated vasodilation: 687, 585, 420 and 326%, P = 0.002; for nitroprusside-mediated vasodilation: 776, 582, 513 and 366%, P = 0.02; for capillary recruitment: 49.9, 44.6, 27.2 and 26.7%, P = 0.001). These trends were similar in men and women (P for interaction > 0.2) and independent of body mass index., Conclusions: Increased CHD risk is associated with an impaired endothelium-dependent vasodilatation and capillary recruitment in skin, suggesting that microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function.

An effect on microvascular function has been proposed as a possible mechanism explaining the association of acute smoking with increased blood pressure and decreased insulin sensitivity. However, the effects of smoking on microvascular function have not been studied. We have investigated the acute effects of smoking on microvascular function in 12 healthy smokers. Before and after smoking a cigarette, we measured heart rate, blood pressure and capillary recruitment during peak reactive hyperaemia. We also measured endothelium-dependent and endothelium-independent vasodilatation of the skin microcirculation with iontophoresis of acetylcholine and sodium nitroprusside respectively combined with laser Doppler fluxmetry. To exclude non-specific changes, a control study with sham smoking was performed. The smoking and sham smoking studies were conducted in a randomized order. Compared with sham smoking, acute smoking caused increases in heart rate (smoking, 9.3+/-4.1 beats/min; sham, -1.3+/-3.0 beats/min; P < 0.001) and systolic blood pressure (smoking, 6.3+/-8.8 mmHg; sham, 0.8+/-4.4 mmHg; P < 0.05); decreases in absolute (smoking, -4.9+/-6.9 per mm(2); sham, 0.8+/-2.1 per mm(2); P = 0.01) and relative (smoking, -13.8+/-21.4%; sham, 1.9+/-6.9%; P = 0.02) capillary recruitment during peak reactive hyperaemia; and decreases in absolute [smoking, -62.4+/-47.7 perfusion units (PU); sham, -30.8+/-32.6 PU; P = 0.04] and relative (smoking, -147+/-163%; sham, 32+/-225%; P = 0.07) vasodilatation caused by acetylcholine. Absolute (smoking, -31.6+/-58.5 PU; sham, -8.4+/-44.0 PU; P = 0.3) and relative (smoking, -50.2+/-219.0%; sham, -17.1+/-139%; P = 0.7) vasodilatation caused by sodium nitroprusside were not affected. Thus acute smoking is associated with impaired capillary recruitment during peak reactive hyperaemia and impaired microvascular endothelium-dependent vasodilatation. These findings may explain the increased blood pressure and decreased insulin sensitivity that have been observed after acute smoking.

Background: Severe hypoglycaemic episodes are an important source of morbidity in people with Type 1 diabetes. The occurrence of severe hypoglycaemia is strongly related to the frequency of low blood glucose readings. The aim of this exploratory study was to identify determinants of the frequency of mild, biochemical hypoglycaemia in patients with Type 1 diabetes treated with multiple insulin injection therapy., Methods: We studied 31 patients with Type 1 diabetes in reasonable glycaemic control (HbA(1c)