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.

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.

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.

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.

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.

Physical Fitness, Activity and Hand-Grip Strength Are Not Associated with Arterial Stiffness in Older Individuals.

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

The association between vitamin D status and parameters for bone density and quality is modified by body mass index.

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

The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons.

INTRODUCTION: High plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density. METHODS: Cross-sectional data of the B-PROOF study (n=1227) and of two cohorts of the Rotterdam Study (RS-I (n=2850) and RS-II (n=2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual-energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters. RESULTS: Natural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B=-0.025, p=0.004 and B=-0.024, p=0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B=-0.032, p=0.010) and lumbar spine (B=-0.098, p=0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B=-3.7, p=0.009) and speed of sound in both B-PROOF (B=-8.9, p=0.001) and RS-I (B=-14.5, p=0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B=-13.1, p=0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively. DISCUSSION: In this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence.

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness.

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

Homocysteine and the methylenetetrahydrofolate reductase 677C-->T polymorphism in relation to muscle mass and strength, physical performance and postural sway.

BACKGROUND/OBJECTIVES: Elevated plasma homocysteine has been linked to reduced mobility and muscle functioning in the elderly. The relation of methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism with these associations has not yet been studied. This study aimed to investigate (1) the association of plasma homocysteine and the MTHFR 677C-->T polymorphism with muscle mass, handgrip strength, physical performance and postural sway; (2) the interaction between plasma homocysteine and the MTHFR 677C-->T polymorphism. SUBJECTS/METHODS: Baseline data from the B-PROOF study (n=2919, mean age=74.1±6.5) were used. Muscle mass was measured using dual X-ray absorptiometry, handgrip strength with a handheld dynamometer, and physical performance with walking-, chair stand- and balance tests. Postural sway was assessed on a force platform. The data were analyzed using regression analyses with plasma homocysteine levels in quartiles. RESULTS: There was a significant inverse association between plasma homocysteine and handgrip strength (quartile 4: regression coefficient B=-1.14, 95% confidence interval (CI)=-1.96; -0.32) and physical performance score (quartile 3: B=-0.53, 95% CI=-0.95; -0.10 and quartile 4: -0.94; 95% CI=-1.40; -0.48) in women only, independent of serum vitamin B12 and folic acid. No association was observed between the MTHFR 677C-->T polymorphism and the outcomes. High plasma homocysteine in the 677CC and 677CT genotypes, but not in the 677TT genotype, was associated with lower physical performance. CONCLUSIONS: Elevated plasma homocysteine concentrations are associated with reduced physical performance and muscle strength in older women. There is an urgent need for randomized controlled trials to examine whether lowering homocysteine levels might delay physical decline.

5-HIAA excretion is not associated with bone metabolism in carcinoid syndrome patients.

In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N-terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50 µmol/24 h, so-called "hyper-secretors") and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout differentiation as well as mineralization. In conclusion, the current study in a unique group of untreated carcinoid patients could not demonstrate a major role for circulating serotonin in the control of bone metabolism.