E. Sohl

Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial

BACKGROUND Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures. Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk. OBJECTIVE This study [B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF)] aimed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals. DESIGN This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations (12-50 μmol/L). Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3. The primary endpoint was time to first osteoporotic fracture. Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per-protocol principles. RESULTS Osteoporotic fractures occurred in 61 persons (4.2%) in the intervention group and 75 persons (5.1%) in the placebo group. Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses (HR: 0.84; 95% CI: 0.58, 1.21) or per-protocol analyses (HR: 0.81; 95% CI: 0.54, 1.21). For persons aged >80 y, in per-protocol analyses, osteoporotic fracture risk was lower in the intervention group than in the placebo group (HR: 0.27; 95% CI: 0.10, 0.74). The total number of adverse events (including mortality) did not differ between groups. However, 63 and 42 participants in the intervention and placebo groups, respectively, reported incident cancer (HR: 1.56; 95% CI: 1.04, 2.31). CONCLUSIONS These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population. Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged >80 y. However, treatment was also associated with increased incidence of cancer, although the study was not designed for assessing cancer outcomes. Therefore, vitamin B-12 plus folic acid supplementation cannot be recommended at present for fracture prevention in elderly people. The B-PROOF study was registered with the Netherlands Trial Register (trialregister.nl) as NTR1333 and at clinicaltrials.gov as NCT00696414.

Vitamin D Status Is Associated With Functional Limitations and Functional Decline in Older Individuals

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.

Prediction of vitamin D deficiency by simple patient characteristics

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.

Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population

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 impact of medication on vitamin D status in older individuals

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.

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.

Thresholds for Serum 25(OH)D Concentrations With Respect to Different Outcomes

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.

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.

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) (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.

Effects of Two-Year Vitamin B12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations: Additional Results from the B-PROOF Study, an RCT

Lowering elevated plasma homocysteine (Hcy) concentrations by supplementing vitamin B12 and folic acid may reduce depressive symptoms and improve health-related quality of life (HR-QoL) in older adults. This study aimed to test this hypothesis in a randomized controlled trial. Participants (N = 2919, ≥65 years, Hcy concentrations ≥12 µmol/L) received either 500 µg vitamin B12 and 400 µg folic acid daily or placebo for two years. Both tablets contained 15 µg vitamin D3. Depressive symptoms were measured with the Geriatric Depression Scale-15 (GDS-15). HR-QoL was assessed with the SF-12 Mental and Physical component summary scores and the EQ-5D Index score and Visual Analogue Scale. Differences in two-year change scores were analyzed with Analysis of Covariance (ANCOVA). Hcy concentrations decreased more in the intervention group, but two-year change scores of the GDS-15 and three of four HR-QoL measures did not differ between groups. The EQ-5D Index score declined less in the intervention group than in the placebo group (mean change 0.00 vs. −0.02, p = 0.004). In conclusion, two-year supplementation with vitamin B12 and folic acid in older adults with hyperhomocysteinemia showed that lowering Hcy concentrations does not reduce depressive symptoms, but it may have a small positive effect on HR-QoL.