Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP. METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures. DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients. TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL . CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.

Predictors of resilience in older adults with lower limb osteoarthritis and persistent severe pain.

BACKGROUND: Resilience refers to the process in which people function well despite adversity. Persistent severe pain may be considered an adversity in people with lower limb osteoarthritis (LLOA). The objectives of this study are: (1) to identify what proportion of older adults with LLOA and persistent severe pain show good functioning; and (2) to explore predictors of resilience. METHODS: Data from the European Project on OSteoArthritis (EPOSA) were used involving standardized data from six European population-based cohort studies. LLOA is defined as clinical knee and/or hip osteoarthritis. Persistent severe pain is defined as the highest tertile of the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index both at baseline and follow-up. Resilience is defined as good physical, mental or social functioning at follow-up despite having LLOA with persistent severe pain. RESULTS: In total, 95 (14.9%) out of 638 individuals with LLOA had persistent severe pain. Among these, 10 (11.0%), 54 (57.4%) and 49 (53.8%) had good physical, mental and social functioning, respectively. Only 4 individuals (4.5%) were resilient in all three domains of functioning. Younger age, male sex, higher education, higher mastery, smoking and alcohol use, higher physical activity levels, absence of chronic diseases, and more contacts with friends predicted resilience in one or more domains of functioning. CONCLUSIONS: Few people with LLOA and persistent severe pain showed good physical functioning and about half showed good mental or social functioning. Predictors of resilience differed between domains, and might provide new insights for treatment.

Long-Term Gender-Affirming Hormone Therapy and Cognitive Functioning in Older Transgender Women Compared With Cisgender Women and Men.

BACKGROUND: Long-term gender-affirming hormone therapy (GHT) in older transgender individuals could have beneficial effects on cognitive functioning. Cardiovascular risk factors and psychological factors are known determinants of cognition. Despite the rising number of older transgender individuals, only few studies have examined cognitive functioning in this population. AIM: We aimed to assess differences in cognitive functioning between transgender women, and non-transgender (cisgender) women and men, and investigated the contribution of cardiovascular risk factors and psychological factors on these differences. METHODS: In this study, 37 transgender women (age range 55 to 69) receiving GHT for at least ten years (range 10.2 to 41.6) were examined, and their cognitive functioning was compared to an age and education level matched cohort consisting of 222 cisgender women and men from the Longitudinal Aging Study Amsterdam. Linear regression analyses were performed. OUTCOMES: Cognitive functioning was assessed by neuropsychological tests including Mini-Mental State Examination (MMSE), Category Fluency animals, Letter Fluency D, 15-Word test (15WT) immediate and delayed recall. Additionally, cardiovascular risk factors and psychological factors such as cardiovascular disease, hypertension, antihypertensive use, statin use, diabetes mellitus, overweight, smoking, alcohol consumption, psychopharmaceutical use, anxiety and depression symptoms were collected. RESULTS: Transgender women had higher MMSE scores compared with cisgender women (+0.9, 95% CI 0.4 to 1.5), and cisgender men (+1.1, 95% CI 0.4 to 1.8). On all other tests transgender women performed similar to cisgender men. Transgender women performed at a lower level than cisgender women on 15WT immediate recall, -5.5, 95% CI -7.6 to -3.4, and 15WT delayed recall, -2.7, 95% CI -3.7 to -1.7, and equal to cisgender women on Fluency animals and Fluency D. Cardiovascular and psychological factors (i.e., cardiovascular disease and depression symptoms) partly explained differences on MMSE score between transgender women and cisgender-control groups. CLINICAL IMPLICATIONS: The results of this study do not indicate a need for tailored hormone treatment strategies for older transgender women, based on cognitive aspects after long-term GHT. STRENGTHS & LIMITATIONS: As one of the first studies, this study compared older transgender women to a large cohort of cisgender men and women regarding cognitive functioning and took into account numerous potential influencing factors. Limitations include difference in test procedures and the cross-sectional design of the study. CONCLUSION: Cognitive differences between transgender women and cisgender women and men were small, albeit significant. This may suggest that long-term GHT effects on cognitive functioning in older transgender women are minimal. van Heesewijk JO, Dreijerink KMA, Wiepjes CM, et al. Long-Term Gender-Affirming Hormone Therapy and Cognitive Functioning in Older Transgender Women Compared With Cisgender Women and Men. J Sex Med 2021;18:1434-1443.

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

The Effect of a Screening and Treatment Program for the Prevention of Fractures in Older Women: A Randomized Pragmatic Trial.

Population screening for fracture risk may reduce the fracture incidence. In this randomized pragmatic trial, the SALT Osteoporosis Study (SOS), we studied whether screening for fracture risk and subsequent treatment in primary care can reduce fractures compared with usual care. A total of 11,032 women aged 65 to 90 years with ≥1 clinical risk factor for fractures were individually randomized to screening (n = 5575) or usual care (n = 5457). Participants in the screening group underwent a screening program, including bone densitometry and vertebral fracture assessment. Participants with a high 10-year fracture probability (FRAX) or a vertebral fracture were offered treatment with anti-osteoporosis medication by their general practitioner. Incident fractures as reported by questionnaires were verified with medical records. Follow-up was completed by 94% of the participants (mean follow-up = 3.7 years). Of the 5575 participants in the screening group, 1417 (25.4%) had an indication for anti-osteoporosis medication. Screening and subsequent treatment had no statistically significant effect on the primary outcome fracture (hazard ratio [HR] = 0.97; 95% confidence interval [CI] 0.87-1.08), nor on the secondary outcomes osteoporotic fractures (HR = 0.91; 95% CI 0.81-1.03), major osteoporotic fractures (HR = 0.91; 95% CI 0.80-1.04), hip fractures (HR = 0.91; 95% CI 0.71-1.15), falls (odds ratio [OR] = 0.91; 95% CI 0.72-1.15), or mortality (HR = 1.03; 95% CI 0.91-1.17). Post hoc explorative finding suggested that screening might be most effective after a recent fracture (HR = 0.65; 95% CI 0.44-0.96 for major osteoporotic fractures and HR = 0.38; 95% CI 0.18-0.79 for hip fractures). The results of this study might have been compromised by nonparticipation and medication nonadherence in the screening group. Overall, this study does not provide sufficient indications to consider screening for fracture prevention. However, we cannot exclude its clinical relevance to reduce (major) osteoporotic fractures and hip fractures because of the relatively small number of women with a treatment indication in the intervention group. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Changes of Vitamin D-Binding Protein, and Total, Bioavailable, and Free 25-Hydroxyvitamin D in Transgender People.

CONTEXT: Total 25-hydroxyvitamin D [25(OH)D] is mainly bound to vitamin d-binding protein (DBP). Bioavailable 25(OH)D consists of albumin-bound and free 25(OH)D and is available for metabolic processes. As sex steroids influence DBP, hormonal treatment (HT) in transgender people might affect DBP and consequently the available 25(OH)D. Total 25(OH)D might therefore not well represent bioavailable and free 25(OH)D. OBJECTIVE: To investigate the effects of HT on DBP, and total, bioavailable, and free 25(OH)D, and to assess whether total 25(OH)D well represents bioavailable and free 25(OH)D. DESIGN: A prospective study. SETTING: A university hospital. PARTICIPANTS: Twenty-nine transwomen and 30 transmen. INTERVENTION: Estradiol and cyproterone acetate in transwomen, and testosterone in transmen. MAIN OUTCOME MEASURES: DBP, total 25(OH)D, free 25(OH)D, and albumin were measured at baseline and after 3 months of HT, and deseasonalized total 25(OH)D and bioavailable 25(OH)D were calculated. RESULTS: DBP changed with +5% (95% CI, -0% to 10%; P = 0.06) in transwomen and with -3% (95% CI: -9% to 3%; P = 0.34) in transmen. No significant changes were found in total 25(OH)D, free, and bioavailable 25(OH)D concentrations. Total 25(OH)D was well correlated with bioavailable (R2, 0.75) and free (R2, 0.76) 25(OH)D. CONCLUSIONS: DBP tended to increase in transwomen, but did not change in transmen. HT did not influence free 25(OH)D, total 25(OH)D, and bioavailable 25(OH)D concentrations in transwomen and transmen. As total 25(OH)D represents bioavailable and free 25(OH)D well, HT in transgender people does not interfere with the assessment of vitamin D status.

Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial.

BACKGROUND: Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial. METHODS: Long-term follow-up of B-PROOF trial participants (N = 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 µg) and vitamin B12 (500 µg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00-C97 for all cancers (except C44 for skin cancer), and C18-C20 for colorectal cancer. RESULTS: Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53, P = 0.05]. B vitamins were significantly associated with a higher risk of colorectal cancer [43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08-2.90, P = 0.02]. CONCLUSIONS: Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer. IMPACT: Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.

Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10-≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 µg (400-800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Trends in lifestyle among three cohorts of adults aged 55-64 years in 1992/1993, 2002/2003 and 2012/2013.

Background: Unhealthy lifestyle factors, such as obesity, smoking, excessive alcohol consumption and physical inactivity, are associated with increased morbidity and mortality risk, even in older age. We investigated trends in lifestyle among three cohorts of adults aged 55-64 years from the Netherlands. Methods: Data from the Longitudinal Aging Study Amsterdam were used. This study consisted of three randomly selected samples of men and women. Lifestyle data were collected in 1992/1993 (cohort 1, n = 988), in 2002/2003 (cohort 2, n = 1002) and in 2012/2013 (cohort 3, n = 1023). Trends in lifestyle across cohorts were tested using multivariable regression analyses. Results: Complete lifestyle data were available for 834 participants from cohort 1, 861 from cohort 2 and 845 from cohort 3. Among men, but not in women, mean BMI and prevalence of obesity increased over time. The mean minutes per day spent being physically active decreased among both men and women, from 130 ± 107 and 230 ± 122 (1992/1993) to 114 ± 100 and 192 ± 109 (2002/2003), and 126 ± 98 and 187 ± 112 (2012/2013), respectively. The percentage of men and women defined as excessive drinkers (>7 alcoholic consumptions per week) increased from 54.9%, 62.3% to 65.4% (men) and 22.7%, 36.1% to 37.4% (women), in 1992/1993, 2002/2003 and 2012/2013, respectively. The percentage of non-smoking men and women increased over time. Conclusion: The lifestyle of Dutch adults aged 55-64 years was less healthy in 2012/2013 compared with 2002/2003 and 1992/1993. Political attention regarding healthy ageing should target the prevention of overweight, physical inactivity and excessive alcohol consumption in middle-aged persons.

Patient satisfaction with information on oral anticancer agent use.

Adequate information on oral anticancer agent (OACA) use is an essential element of optimal cancer care. The present study aimed to get insight into the experiences of patients with information on OACA treatment and their characteristics regarding information dissatisfaction. Patients of four Dutch university hospitals using OACA participated in this observational study and completed the Satisfaction with Information about Medicines Scale (SIMS), EORTC Quality of Life Questionnaire-C30, Brief Illness Perception Questionnaire, and Beliefs about Medicines Questionnaire-Specific. Logistic regression analyses were used to determine factors associated with dissatisfaction with information. Patients (n = 208) using capecitabine (35%), lenalidomide (15%), imatinib (14%), temozolomide (12%), sunitinib (11%), thalidomide (5%), dasatinib (4%), erlotinib (2%), and nilotinib (2%) participated. Information on the following SIMS-items was inadequate: how OACA elicit their effect, how long it takes before treatment works, how to conclude that treatment is effective, the risk of side effects and its management, interference with sex life, drowsiness, interference with other medication and alcohol and what to do in case of a missed dose. Younger age, hematological malignancy, dyspnoea, positive perception of consequences of the cancer, low perception of treatment control, and indifferent attitude towards OACA were associated with dissatisfaction with information. In conclusion, a considerable number of patients would have appreciated receiving more information on specific issues relating to the consequences of OACA treatment such as the effects and side effects of OACA and the interference of treatment with various aspects of their daily life. Oncologists, hematologists, lung-oncologists and pharmacists may reconsider the provision of information on OACA treatment.

Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data.

BACKGROUND: A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation. METHODS AND FINDINGS: We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses. CONCLUSIONS: Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

Changes in vitamin D endocrinology during aging in adults.

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.

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.

BACKGROUND: Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS: In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS: We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00-1.29), 1.33 (1.16-1.51), and 1.67 (1.44-1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. INTERPRETATION: In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study.

Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12-50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0-12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95% CI 0.9-1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95% CI 1.1-1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies.

Vitamin D, PTH and the risk of overall and disease-specific mortality: Results of the Longitudinal Aging Study Amsterdam.

Observational studies suggest that low concentrations of serum 25-hydroxyvitamin D (25(OH)D) and high concentrations of parathyroid hormone (PTH) are associated with a higher risk of mortality. The aim of this study was to examine whether 25(OH)D and PTH concentrations are independently associated with overall and disease-specific (cardiovascular and cancer-related) mortality in a large, prospective population-based cohort of older adults. Data from 1317 men and women (65-85 years) of the Longitudinal Aging Study Amsterdam were used. Cox proportional hazard analyses were used to examine whether 25(OH)D and PTH at baseline were associated with overall mortality (with a follow-up of 18 years) and disease-specific mortality (with a follow-up of 13 years). Compared to persons in the reference category of ≥75nmol/L, persons with serum 25(OH)D <25nmol/L (HR 1.46; 95% CI: 1.12-1.91) and 25-49.9nmol/L (HR 1.24; 95% CI: 1.01-1.53) had a significantly higher risk of overall mortality, as well as men with baseline PTH concentrations ≥7pmol/L (HR 2.54 (95% CI: 1.58-4.08)), compared to the reference category of <2.33pmol/L. The relationship of 25(OH)D with overall mortality was partly mediated by PTH. Furthermore, men with PTH concentrations of ≥7pmol/L (HR 3.22; 95% CI: 1.40-7.42) had a higher risk of cardiovascular mortality, compared to the reference category. No significant associations of 25(OH)D or PTH with cancer-related mortality were observed. Both 25(OH)D and PTH should be considered as important health markers.

Relative importance of summer sun exposure, vitamin D intake, and genes to vitamin D status in Dutch older adults: The B-PROOF study.

BACKGROUND/OBJECTIVES: The prevalence of vitamin D deficiency among seniors is high. Whereas sun exposure, vitamin D intake, genes, demographics, and lifestyle have been identified as being important determinants of vitamin D status, the impact of these factors is expected to differ across populations. To improve current prevention and treatment strategies, this study aimed to explore the main determinants of vitamin D status and its relative importance in a population of community-dwelling Dutch older adults. METHODS/SUBJECTS: Serum 25-hydroxyvitamin D (25(OH)D) was measured in 2857 adults aged ≥65 years. Sun exposure was assessed with a structured questionnaire (n=1012), vitamin D intake using a Food Frequency Questionnaire (n=596), and data on genetic variation that may affect 25(OH)D status was obtained for 4 genes, DHCR7 (rs12785878), CYP2R1 (rs10741657), GC (rs2282679), and CYP24A1 (rs6013897) (n=2530). RESULTS: Serum 25(OH)D concentrations <50nmol/L were observed in 45% of the population; only 6% of these participants used vitamin D supplements. Sun exposure (being outside daily during summer: 66±25nmol/L vs not being outside daily during summer: 58±27nmol/L, P=0.02) and vitamin D intake (per unit µg/day during winter/spring: 3.1±0.75nmol/L, P<0.0001) were associated with higher 25(OH)D concentrations. Major allele carriers of SNPs related to DHCR7, CYP24A1, and GC, as well as CYP2R1 minor allele carriers had the highest 25(OH)D concentrations. Together, sun (R2=0.29), vitamin D intake (R2=0.24), and genes (R2=0.28) explained 35% (R2=0.35) of the variation in 25(OH)D concentrations during summer/autumn period, when adjusted for age, sex, BMI, education, alcohol consumption, smoking, physical activity, and self-rated health status (n=185). CONCLUSION: The investigated determinants explained 35% of 25(OH)D status. Of the three main determinants under study, sun exposure still appeared to be an important determinant of serum 25(OH)D in older individuals, closely followed by genes, and vitamin D intake. Given the low frequency of vitamin D supplement use in this population, promoting supplement use may be an inexpensive, easy, and effective strategy to fight vitamin D deficiency.

Vitamin D supplementation to prevent depression and poor physical function in older adults: Study protocol of the D-Vitaal study, a randomized placebo-controlled clinical trial.

BACKGROUND: Depressive symptoms and decreased physical functioning are interrelated conditions and common in older persons, causing significant individual and societal burden. Evidence suggests that vitamin D supplementation may be beneficial for both mental and physical functioning. However, previous randomized controlled trials have yielded inconsistent results and often had suboptimal designs. This study examines the effect of vitamin D supplementation on both depressive symptoms and physical functioning in a high-risk population of older persons with low vitamin D status. METHODS/DESIGN: The D-Vitaal study is a randomized, double-blind, placebo-controlled trial investigating the effects of a daily dose of 1200 IU vitamin D3 versus placebo for one year on depressive symptoms and physical functioning (primary outcomes) in older adults. Participants (N = 155, age 60-80 years) were recruited from the general population. Eligibility criteria included the presence of depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D levels between 15 and 50/70 nmol/L (depending on season). Secondary outcomes include incidence of major depressive disorder, anxiety symptoms, health-related quality of life, cognitive function and cost-effectiveness of the intervention. DISCUSSION: With this study, we aim to elucidate the effects of vitamin D supplementation on depressive symptoms and physical functioning in older persons who are at high risk of developing more substantial mental and physical problems. If effective, vitamin D supplementation can be a preventive intervention strategy that is easy to implement in the primary care setting. TRIAL REGISTRATION: Netherlands Trial Register NTR3845. Registered 6 February 2013.