The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons.

Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11-2.16], p = .01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased ß1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.

Are higher antidepressant plasma concentrations associated with fall risk in older antidepressant users?

PURPOSE: Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. METHODS: For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC-MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. RESULTS: In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07-5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. CONCLUSION: There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Exploring the conceptual framework and measurement model of intrinsic capacity defined by the World Health Organization: A scoping review.

WHO has defined intrinsic capacity (IC) as the composite of all physical and mental capacities of an individual covering five subdomains: cognition, locomotion, sensory, vitality, and psychological. Despite this well accepted definition, the conceptual and measurement model of IC remains unclear, which hampers a standardized operationalization of the construct. We performed a scoping review to give a comprehensive overview of the extent to which the current literature of IC addresses and assumes the conceptual framework and measurement model of IC as reflective or formative. For inclusion, we considered all types of articles that were published in peer-reviewed journals except for protocol articles. A systematic search of 6 databases from different disciplines led to the inclusion of 31 papers. We found inconsistency and gaps in the descriptions of IC. Most of the papers did not define the measurement model. In the conceptual background and validation articles, we identified descriptions of both reflective and formative measurement models while in empirical studies applying IC measurements the underlying assumptions remained mainly unclear. Defining a measurement model is not merely a theoretical matter but influences the operationalization and validation processes of the construct. This study raised questions about the most fundamental features of the IC construct and discusses whether IC should be considered as an underlying latent trait of all capacities (reflective construct) or an aggregate summary measure of the subdomain capacities (formative construct).

Candidate genetic variants and antidepressant-related fall risk in middle-aged and older adults.

BACKGROUND: Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users. METHODS: The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated. RESULTS: In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00). CONCLUSION: This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.

A Propensity Score Matched Approach to Assess the Associations of Commonly Prescribed Medications with Fall Risk in a Large Harmonized Cohort of Older Ambulatory Persons.

INTRODUCTION: Several medication classes are considered to present risk factors for falls. However, the evidence is mainly based on observational studies that often lack adequate adjustment for confounders. Therefore, we aimed to assess the associations of medication classes with fall risk by carefully selecting confounders and by applying propensity score matching (PSM). METHODS: Data from several European cohorts, harmonized into the ADFICE_IT cohort, was used. Our primary outcome was time until the first fall within 1-year follow-up. The secondary outcome was a fall in the past year. Our exposure variables were commonly prescribed medications. We used 1:1 PSM to match the participants with reported intake of specific medication classes with participants without. We constructed Cox regression models stratified by the pairs matched on the propensity score for our primary outcome and conditional logistic regression models for our secondary outcome. RESULTS: In total, 32.6% of participants fell in the 1-year follow-up and 24.4% reported falling in the past year. ACE inhibitor users (prevalence of use 15.3%) had a lower fall risk during follow-up when matched to non-users, with a hazard ratio (HR) of 0.82 (95% CI 0.68-0.98). Also, statin users (prevalence of use 20.1%) had a lower risk, with an HR of 0.76 (95% CI 0.65-0.90). Other medication classes showed no association with risk of first fall. Also, in our secondary outcome analyses, statin users had a significantly lower risk. Furthermore, ß-blocker users had a lower fall risk and proton pump inhibitor use was associated with a higher risk in our secondary outcome analysis. CONCLUSION: Many commonly prescribed medication classes showed no associations with fall risk in a relatively healthy population of community-dwelling older persons. However, the treatment effects and risks can be heterogeneous between individuals. Therefore, focusing on identification of individuals at risk is warranted to optimize personalized falls prevention.

Accuracy of an algorithm to identify rheumatoid arthritis in the Longitudinal Ageing Study Amsterdam population: a validation study.

Objective: In view of global ageing and the scarcity of knowledge about disease determinants in older individuals with rheumatoid arthritis (RA), an algorithm with optimal diagnostic accuracy was developed to identify RA patients in the Longitudinal Ageing Study Amsterdam (LASA).Method: Four case ascertainment algorithms were constructed and assessed for validity in LASA, an ongoing cohort study (≥ 55 years) representing the general older population of the Netherlands. Data sources used to identify the diagnosis RA were: self-reported morbidity, specialist diagnosis, and medication. A validation subsample of LASA participants was taken to verify RA diagnosis by a standard procedure using a checklist.Results: Data from 272/300 (91%) participants were verified. Four algorithms were developed: 'treatment', 'diagnosis', 'treatment or diagnosis', and 'treatment and diagnosis'. The algorithm 'treatment and diagnosis' showed the best measurement properties: specificity 100%, positive predictive value 100%, and area under the receiver operating characteristics curve 0.72. Applying this algorithm in the LASA sample (mean age 71 years) revealed a prevalence of RA of 1.0% (19/1908 participants).Conclusion: An algorithm for RA identification in the LASA population was developed, with high diagnostic accuracy. It provides an accurate tool to identify older adults with RA in LASA and, after validation, may be applicable in other large population-based studies.

Clinical osteoarthritis of the hip and knee and fall risk: The role of low physical functioning and pain medication.

OBJECTIVE: Several studies have found an increased fall risk in persons with osteoarthritis (OA). However, most prospective studies did not use a clinical definition of OA. In addition, it is not clear which factors explain this risk. Our objectives were: (1) to confirm the prospective association between clinical OA of the hip and knee and falls; (2) to examine the modifying effect of sex; and (3) to examine whether low physical performance, low physical activity and use of pain medication are mediating these relationships. METHODS: Baseline and 1-year follow-up data from the European Project on OSteoArthritis (EPOSA) were used involving pre-harmonized data from five European population-based cohort studies (ages 65-85, n = 2535). Clinical OA was defined according to American College of Rheumatology (ACR) criteria. Falls were assessed using self-report. RESULTS: Over the follow-up period, 27.7% of the participants fell once or more (defined as faller), and 9.8% fell twice or more (recurrent faller). After adjustment for confounding, clinical knee OA was associated with the risk of becoming a recurrent faller (relative risk=1.55; 95% confidence interval: 1.10-2.18), but not with the risk of becoming a faller. No associations between clinical hip OA and (recurrent) falls were observed after adjustment for confounding. Use of opioids and analgesics mediated the associations between clinical OA and (recurrent) falls, while physical performance and physical activity did not. CONCLUSION: Individuals with clinical knee OA were at increased risk for recurrent falls. This relationship was mediated by pain medication, particularly opioids. The fall risk needs to be considered when discussing the risk benefit ratio of prescribing these medications.

A comprehensive assessment of risk factors for falls in middle-aged adults: co-ordinated analyses of cohort studies in four countries.

We identified demographic, health and lifestyle factors associated with falls in adults aged 50-64 years from Australia, The Netherlands, Great Britain and Ireland. Nearly all factors were associated with falls, but there were differences between countries and between men and women. Existing falls prevention programs may also benefit middle-aged adults. INTRODUCTION: Between ages 40-44 and 60-64 years, the annual prevalence of falls triples suggesting that middle age may be a critical life stage for preventive interventions. We aimed to identify demographic, health and lifestyle factors associated with falls in adults aged 50-64 years. METHODS: Harmonised data were used from four population-based cohort studies based in Australia (Australian Longitudinal Study on Women's Health, n = 10,641, 51-58 years in 2004), Ireland (The Irish Longitudinal Study on Ageing, n = 4663, 40-64 years in 2010), the Netherlands (Longitudinal Ageing Study Amsterdam, n = 862, 55-64 years in 2012-13) and Great Britain (MRC National Survey of Health and Development, n = 2987, 53 years in 1999). Cross-sectional and prospective associations of 42 potential risk factors with self-reported falls in the past year were examined separately by cohort and gender using logistic regression. In the absence of differences between cohorts, estimates were pooled using meta-analysis. RESULTS: In cross-sectional models, nearly all risk factors were associated with fall risk in at least one cohort. Poor mobility (pooled OR = 1.71, CI = 1.34-2.07) and urinary incontinence (OR range = 1.53-2.09) were consistently associated with falls in all cohorts. Findings from prospective models were consistent. Statistically significant interactions with cohort and sex were found for some of the risk factors. CONCLUSION: Risk factors known to be associated with falls in older adults were also associated with falls in middle age. Compared with findings from previous studies of older adults, there is a suggestion that specific risk factors, for example musculoskeletal conditions, may be more important in middle age. These findings suggest that available preventive interventions for falls in older adults may also benefit middle-aged adults, but tailoring by age, sex and country is required.

Association of renal function with bone mineral density and fracture risk in the Longitudinal Aging Study Amsterdam.

Early renal dysfunction is associated with a 38% increased fracture risk in individuals aged 65 years and older. In men but not women, early renal dysfunction is associated with decreased femoral neck bone mineral density (BMD) which can be partially explained by increased parathyroid hormone (PTH) concentrations. INTRODUCTION: It is uncertain whether early renal dysfunction is associated with osteoporosis and increased fracture risk. The aim of this study was to determine the relationship of decreased renal function with BMD and fracture risk and the role of PTH therein. METHODS: We analyzed data of participants aged 65 years and older from the Longitudinal Aging Study Amsterdam. A 6-year fracture follow-up was obtained in 1477 participants. BMD was measured by dual-energy x-ray absorptiometry (n = 535) and vertebral fractures by lateral spinal radiograph (n = 527) in a subsample at baseline. Glomerular filtration rate (eGFR) was estimated according to the modification of diet in renal disease equation and assessed by the five stages of chronic kidney disease (CKD). RESULTS: In men and women, eGFR < 57 ml/min/1.73 m2 (lowest quartile) compared to eGFR > 74 ml/min/1.73 m2 (highest quartile) was associated with a 38% increase in fracture risk after adjustment for relevant confounders [hazard ratio (95%CI): 1.38 (1.17 to 1.61)]. Also, CKD stages 3a and 3b were associated to a 28 and 46% increase in fracture risk, respectively, as compared to CKD stages 1 and 2 together (eGFR > 60 ml/min/1.73 m2) after adjustment for confounders. Renal function was not associated with prevalent vertebral fractures. In men, but not women, lowest quartile of eGFR was related to lower femoral neck BMD as compared to the highest quartile eGFR [unstandardized B (95%CI) - 0.052 g/cm2 (- 0.098 to - 0.006)], after adjustment for relevant confounders. Further adjustment for PTH attenuated this relationship by 27%. CONCLUSIONS: In men and women, early decreased renal function (eGFR < 60 ml/min/1.73 m2) was related to increased incident any fracture risk but not with increased prevalence of vertebral fractures. In men, but not women, early renal dysfunction was related to lower femoral neck BMD which could statistically be partially explained by increased PTH concentrations.

Prediction of insufficient serum vitamin D status in older women: a validated model.

We developed an externally validated simple prediction model to predict serum 25(OH)D levels < 30, < 40, < 50 and 60 nmol/L in older women with risk factors for fractures. The benefit of the model reduces when a higher 25(OH)D threshold is chosen. INTRODUCTION: Vitamin D deficiency is associated with increased fracture risk in older persons. General supplementation of all older women with vitamin D could cause medicalization and costs. We developed a clinical model to identify insufficient serum 25-hydroxyvitamin D (25(OH)D) status in older women at risk for fractures. METHODS: In a sample of 2689 women ≥ 65 years selected from general practices, with at least one risk factor for fractures, a questionnaire was administered and serum 25(OH)D was measured. Multivariable logistic regression models with backward selection were developed to select predictors for insufficient serum 25(OH)D status, using separate thresholds 30, 40, 50 and 60 nmol/L. Internal and external model validations were performed. RESULTS: Predictors in the models were as follows: age, BMI, vitamin D supplementation, multivitamin supplementation, calcium supplementation, daily use of margarine, fatty fish ≥ 2×/week, ≥ 1 hours/day outdoors in summer, season of blood sampling, the use of a walking aid and smoking. The AUC was 0.77 for the model using a 30 nmol/L threshold and decreased in the models with higher thresholds to 0.72 for 60 nmol/L. We demonstrate that the model can help to distinguish patients with or without insufficient serum 25(OH)D levels at thresholds of 30 and 40 nmol/L, but not when a threshold of 50 nmol/L is demanded. CONCLUSIONS: This externally validated model can predict the presence of vitamin D insufficiency in women at risk for fractures. The potential clinical benefit of this tool is highly dependent of the chosen 25(OH)D threshold and decreases when a higher threshold is used.

Vitamin D status in relation to physical performance, falls and fractures in the Longitudinal Aging Study Amsterdam: A reanalysis of previous findings using standardized serum 25-hydroxyvitamin D values.

The Longitudinal Aging Study Amsterdam (LASA) is an ongoing prospective cohort study in a representative sample of Dutch older persons. In previous LASA studies, lower serum 25-hydroxyvitamin D (25(OH)D) values, as assessed by a competitive protein binding assay or radioimmunoassay, have been associated with decreased physical functioning, falls and fractures. Recently, serum 25(OHD) values in LASA were standardized using the Vitamin D Standardization Program (VDSP) protocol as part of the European ODIN project. In the current manuscript, the influence of standardizing serum 25(OH)D values will be discussed using the associations with physical functioning, falls and fractures as examples.

Vitamin B12 Intake and Related Biomarkers: Associations in a Dutch Elderly Population.

BACKGROUND: Vitamin B12 status is measured by four plasma/ serum biomarkers: total vitamin B12 (total B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and homocysteine (tHcy). Associations of B12 intake with holoTC and tHcy and associations between all four biomarkers have not been extensively studied. A better insight in these associations may contribute to an improved differentiation between vitamin B12 deficiency and a normal vitamin B12 status. OBJECTIVE: This study investigates associations between vitamin B12 intake and biomarkers and associations between biomarkers. DESIGN: In this cross-sectional observational study, levels of total B12, HoloTC, MMA and tHcy were determined in participants of the B-PROOF study: 2919 elderly people (≥65 years, with a mean age of 74.1 years, a mean BMI of 27.1 and 50% women) with elevated tHcy levels (≥12 µmol/L). B12 intake was assessed in a subsample. We assessed the association between intake and status with multivariate regression analysis. We explored the dose-response association between B12 intake and biomarkers and the association of total B12 and holoTC with tHcy and MMA with restricted cubic spline plots. RESULTS: A doubling of B12 intake was associated with 9% higher total B12, 15% higher HoloTC, 9% lower MMA and 2% lower tHcy. Saturation of biomarkers occurs with dietary intakes of >5 µg B12. Spline regression showed that levels of MMA and tHcy started to rise when vitamin B12 levels fall below 330 pmol/L and with HoloTC levels below 100 pmol/L, with a sharp increase with levels of B12 and HoloTC below 220 and 50 pmol/L respectively. CONCLUSIONS: In this study we observed a significant association between vitamin B12 intake and vitamin B12 biomarkers and between the biomarkers. The observed inflections for total B12 and holoTC with MMA and tHcy could indicate cut-off levels for further testing for B12 deficiency and determining subclinical B12 deficiency.

Design of the SALT Osteoporosis Study: a randomised pragmatic trial, to study a primary care screening and treatment program for the prevention of fractures in women aged 65 years or older.

BACKGROUND: Several drugs have become available for the treatment of osteoporosis. However, screening and treatment of patients with a high fracture risk is currently not recommended in the Netherlands, because the effectiveness of bone sparing drugs has not been demonstrated in the general primary care population. Here we describe the design of the SALT Osteoporosis study, which aims to examine whether the screening and treatment of older, female patients in primary care can reduce fractures, in comparison to usual care. METHODS: A randomised pragmatic trial has been designed using a stepwise approach in general care practices in the Netherlands. Women aged ≥65 years, who are not prescribed bone sparing drugs or corticosteroids are eligible for the study. First, women with at least one clinical risk factor for fractures, as determined by questionnaires, are randomly assigned to the intervention or control group. Second, women in the intervention group having a high fracture risk according to our screening program, including an adapted fracture risk assessment (FRAX) tool, combined with dual-energy x-ray absorptiometry (DXA), and instant vertebral assessment (IVA), are offered a structured treatment program. The women in the control group receive care as usual and will undergo the same screening as the intervention group at the end of the trial. The follow-up duration will be three years and the primary outcome is time to first incident fracture and the total number of fractures. DISCUSSION: The results of the current study will be very important for underpinnings of the prevention strategy of the osteoporosis guidelines. TRIAL REGISTRATION: ID NTR2430 . Registered 26 July 2010.

Vitamin B12, homocysteine and depressive symptoms: a longitudinal study among older adults.

BACKGROUND/OBJECTIVES: The roles of vitamin B12 and homocysteine concentration in depression are not clear. We investigated cross-sectional and prospective associations of serum vitamin B12 and plasma homocysteine with depressive symptoms in Dutch older adults. SUBJECTS/METHODS: In the Longitudinal Aging Study Amsterdam (LASA), blood was collected in 1995/1996 among 1352 men and women aged ⩾65 years. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) six times from 1995/1996 to 2011/2012. Multiple linear regression and mixed models were used to assess whether vitamin B12 and homocysteine were associated with severity at baseline and course of depressive symptoms over 16 years. Cox regression analyses were performed for the associations with incidence of depression (CES-D ⩾16 and/or antidepressant use). All analyses were adjusted for sociodemographic characteristics and lifestyle factors. RESULTS: Vitamin B12 was neither cross-sectionally (n=1205) nor prospectively (n=1012) associated with depressive symptoms (adjusted ß for CES-D over time, lowest versus highest quartile: -0.04 (95% confidence interval (CI): -0.15-0.06)). We also found no association with incident depression (n=853), except for a higher risk of depression over time in younger participants (aged 64.8-73.4 years; continuous vitamin B12, adjusted hazard ratio per s.d.: 1.38 (95% CI: 1.10-1.72)). For homocysteine, no associations were found, except for a lower risk of depression in younger participants. CONCLUSIONS: Our study did not confirm earlier shown associations of serum vitamin B12 and plasma homocysteine with severity and course of depressive symptoms and incidence of depression in older adults. Further research into the influence of homocysteine metabolism on mental health is needed.

Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning.

BACKGROUND: Vitamin D deficiency is common in older persons. The objectives of this study were: To examine the cross-sectional and longitudinal association between serum 25-hydroxyvitamin D (25(OH)D) and cognitive functioning in older persons; and to explore the optimal cut-off for serum 25(OH)D. METHODS: Data of the Longitudinal Aging Study Amsterdam (LASA) were used. Serum 25(OH)D was determined using a competitive protein binding assay in 1995/6 (n = 1,320). Cognitive functioning was assessed in 1995/6 and 1998/9 using the Mini-Mental State Examination (MMSE, general cognitive functioning), Raven's Colored Progressive Matrices (RCPM, ability of nonverbal and abstract reasoning), the Coding Task (CT, information processing speed), and the 15 Words Test (15WT, immediate memory and delayed recall). The data were analyzed using linear regression analyses and restricted cubic spline functions. The MMSE was normalized using ln(31-MMSE). RESULTS: Mean serum 25(OH)D was 53.7 nmol/L. After adjustment for confounding, patients with serum 25(OH)D levels below 30 nmol/L had significantly lower general cognitive functioning (beta of ln(31-MMSE) = 0.122; p = 0.046) and slower information processing speed (beta = -2.177, p = 0.001) as compared with patients having serum 25(OH)D levels ≥ 75 nmol/L in the cross-sectional analyses. For both outcomes, the optimal cut-off was about 60 nmol/L. No other significant associations were observed. CONCLUSIONS: A lower serum 25(OH)D was significantly associated with lower general cognitive functioning and slower information processing speed, but not with a faster rate of cognitive decline.

Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men.

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) (ß (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.

Low vitamin D status is associated with more depressive symptoms in Dutch older adults.

PURPOSE: The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged ≥65 years. METHODS: 25-Hydroxyvitamin D (25(OH)D) was measured, and five 'vitamin D-related genes' were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. RESULTS: A clear cross-sectional and prospective association between serum 25(OH)D and depressive symptom score was observed. Fully adjusted models indicated a 22 % (RR 0.78, 95 % CI 0.68-0.89), 21 % (RR 0.79, 95 % CI 0.68-0.90), and 18 % (RR 0.82, 95 % CI 0.71-0.95) lower score of depressive symptoms in people in the second, third, and fourth 25(OH)D quartiles, when compared to people in the first quartile (P for trend <0.0001). After 2 years of daily 15 µg vitamin D supplementation, similar associations were observed. 25(OH)D concentrations did not significantly interact with the selected genes. CONCLUSION: Low serum 25(OH)D was associated with higher depressive symptom scores. No interactions between 25(OH)D concentrations and vitamin D genetic make-up were observed. In view of the probability of reverse causation, we propose that the association should be further examined in prospective studies as well as in randomized controlled trials.

Impact of clinical osteoarthritis of the hip, knee and hand on self-rated health in six European countries: the European Project on OSteoArthritis.

PURPOSE: Osteoarthritis (OA) has been shown to be associated with decreased physical function, which may impact upon a person's self-rated health (SRH). Only a few studies have examined the association between OA and SRH in the general population, but to date none have used a clinical definition of OA. The objectives are: (1) To examine the cross-sectional association between clinical OA and fair-to-poor SRH in the general population; (2) To examine whether this association differs between countries; (3) To examine whether physical function is a mediator in the association between clinical OA and SRH. METHODS: Baseline data of the European Project on OSteoArthritis (EPOSA) were used, which includes pre-harmonized data from six European cohort studies (n = 2709). Clinical OA was defined according to the American College of Rheumatology criteria. SRH was assessed using one question: How is your health in general? Physical function was assessed using the Western Ontario and McMaster Universities OA Index and Australian/Canadian OA Hand Index. RESULTS: The prevalence of fair-to-poor SRH ranged from 19.8 % in the United Kingdom to 63.5 % in Italy. Although country differences in the strength of the associations were observed, clinical OA of the hip, knee and hand were significantly associated with fair-to-poor SRH in five out of six European countries. In most countries and at most sites, the association between clinical OA and fair-to-poor SRH was partly or fully mediated by physical function. CONCLUSIONS: Clinical OA at different sites was related to fair-to-poor SRH in the general population. Most associations were (partly) mediated by physical functioning, indicating that deteriorating physical function in patients with OA should be a point of attention in patient care.

Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population.

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.

BMI and Body Fat Mass Is Inversely Associated with Vitamin D Levels in Older Individuals.

OBJECTIVE: To assess the association between obesity (measured by Body Mass Index (BMI) and fat percentage) and serum 25(OH)D levels in older persons. DESIGN: Cross-sectional analysis of data from 'the B-PROOF study' (B-vitamins for the Prevention Of Osteoporotic Fractures). PARTICIPANTS: 2842 participants aged 65 years and older. MEASUREMENTS: BMI and fat percentage, measured by Dual Energy X-ray, and serum 25(OH)D levels. RESULTS: Mean age was 74 years (6.5 SD), with 50% women. Mean serum 25(OH)D levels were 55.8 nmol/L (25 SD). BMI and total body fat percentage were significant inversely associated with serum 25(OH)D levels after adjustment for confouders (ß-0.93; 95% CI [-1.15; -0.71], p<0.001 and ß-0.84; 95% CI [-1.04; -0.64], p<0.001). This association was most prominent in individuals with a BMI in the 'overweight' and 'obesity' range (ß -1.25 and -0.96 respectively) and fat percentage in the last two upper quartiles (ß-1.86 and -1.37 respectively). CONCLUSION: In this study, higher BMI and higher body fat percentage were significantly associated with lower serum 25(OH)D levels in older persons. This association was particularly present in individuals with overweight, and higher fat percentages, suggesting that these persons are at increased risk of vitamin D insufficiency.