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Aim 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, or concentration change over time (delta) 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). Adjusted there were no significant associations between concentrations of SSRIs and fall risk. Also, for delta concentrations there was no association with fall risk in users. 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, replication in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Objectives Previous studies showed that high calcium intake may be associated with the reduced colorectal cancer (CRC) risk, but results were inconclusive. In this study, we evaluated whether calcium intake from diet and supplements, as well as the calcium levels itself, were associated with the CRC risk in middle-aged and older individuals. Also, we evaluated whether these associations were modified by genetic variation of calcium homeostasis. Design This study was embedded in the Rotterdam study, a prospective cohort study among adults aged 55 years and older without CRC at baseline, from the Ommoord district of Rotterdam, The Netherlands (N = 10 941). Effect modification by a predefined polygenetic risk score (PRS) from seven loci known to be associated with calcium concentrations, was evaluated. Results The incidence rate of CRC in the study population was 2.9 per 1000 person-years. Relative to the recommended dietary calcium intake, only higher than the recommended dietary calcium intake (≥1485 mg/day) was associated with a reduced risk of CRC [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.44-1.00]. No significant associations were found for calcium supplementation and only in the subgroup analysis, albumin-adjusted calcium levels were associated with an increased risk of CRC (HR = 1.11; 95% CI, 1.00-1.23). PRS showed effect modification in the association between calcium intake and CRC (P for interaction = 0.08). After stratification of PRS into low, intermediate and high, we found a lower CRC risk for low-weighted PRS per increase in calcium intake. Conclusion There is no consistent association between calcium indices on CRC. However, the association between calcium intake and CRC may be modified by genetic variation associated with serum calcium concentrations that deserves further replication in other studies with different population.

Purpose Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. Methods A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). Results Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI − 0.039; − 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI − 1.899; − 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. Conclusions Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition. Electronic supplementary material The online version of this article (10.1007/s00394-019-01985-8) contains supplementary material, which is available to authorized users.

Background & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk.Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 mg) and vitamin-B12 (500 mg) versus placebo (n = 2,919). Primary outcome was verified self reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease.Results: A total of 1,298 individuals (4 4.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic-and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 mmol/l). No age-dependent effects were present.Conclusions: This study supports and extends previous null -findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated. (c) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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.

The decreased risk of osteoporotic fractures in thiazide diuretics (TD) users is possibly not only caused by an increase in bone mineral density (BMD), but by an increase in other determinants of bone strength as well, such as the trabecular bone score (TBS). To test this hypothesis, we studied the association between TD use and both lumbar spine BMD (LS-BMD) and lumbar spine TBS (LS-TBS) cross-sectionally in 6096 participants from the Rotterdam Study, as well as the association between TD use and bone turnover estimated by serum osteocalcin levels. We found that past and current use of TD were associated with an increase of LS-BMD (β = 0.021 g/cm 2 (95% CI: 0.006;0.036) and β = 0.016 g/cm 2 (95% CI: 0.002;0.031), respectively). Use of ≥1 defined daily dose (DDD) (β = 0.028, 95% CI: 0.010;0.046; p for trend within DDD of use 365 days (β = 0.033, 95% CI: 0.014;0.052; p for trend within duration of use

Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002–2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20–50 nmol/l (β = − 0.036, 95% CI − 0.060; − 0.013 vs. β = − 0.012, 95% CI − 0.036; 0.013 and β = − 0.031, 95% CI − 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake.

OBJECTIVES: To investigate the possible effects of the intervention with folic acid and vitamin B12 supplementation on fracture and cardiovascular disease risk: 5–7 years after the end of the intervention period of 2–3 years. METHODS: Extended follow-up of B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2–3 years daily supplementation with folic acid (400 µg) and vitamin-B12 (500 µg) versus placebo on fracture incidence. Fracture and cardiovascular outcomes were assessed by follow-up questionnaire. Fracture incidence (and a part of cardiovascular disease incidence) was verified by general practitioners (GPs). RESULTS: A total of 1298 individuals participated in the second follow-up round. Median age at baseline was 71.0 years [68.0–76.0] for both groups (n = 662 in the treatment group and n = 636 in the placebo group). No effect of the intervention on first osteoporotic fracture and other fracture risk after a follow up of 5–7 years was observed (HR: 0.99, 95% CI: 0.62; 1.59 and HR: 0.77; 95% CI: 0.50; 1.19, respectively) and also not for cardiovascular- or cerebrovascular disease (OR: 1.14; 95%CI: 0.74–1.74 and OR: 1.01; 95%CI: 0.76–1.33, respectively). Significant interaction for total homocysteine level was observed for osteoporotic- and any fracture (P = 0.10 and 0.06 resp.), which indicated a significantly lower risk of fracture in the intervention group with higher total homocysteine level. CONCLUSIONS: This study does not support a prolonged effect of supplementation of folic acid and vitamin B12 on fracture risk, or on cardiovascular disease in older individuals with elevated homocysteine concentration. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with higher total homocysteine levels. FUNDING SOURCES: The initial B-PROOF study has received funding so far by The Netherlands Organization for Health Research and Development (ZonMw), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovationn, the Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

Background: Symptoms of apathy are common in older persons. Negative effects on physical performance and fall risk are plausible, considering the pathophysiology of apathy. However, literature is scarce. Aim: To longitudinally assess the association between apathy and (1) decline of physical performance and (2) the number of falls in older community-dwelling persons. Methods: The ‘B vitamins for the PRevention Of Osteoporotic Fractures’ study provided data on 2919 older persons over a period of 2 years. Apathy was assessed using the Geriatric Depression Scale 3. A physical performance score (PPS) was calculated using three performance tests. Falls were registered prospectively. We calculated adjusted odds ratios (ORs), Incidence Rate Ratios (IRRs), and their 95% confidence intervals. Effect modification by age and gender was investigated. We also investigated mediation by baseline PPS for the association between apathy and the number of falls. Results: Apathy and decline of PPS were independently associated. After stratification, the effect only remained in men. Age was an effect modifier; higher ORs for decreasing age. Apathy was also independently associated with the number of falls. After stratification, women had higher IRRs than men. Age modified the association in the opposite direction: higher IRRs for increasing age. Baseline PPS was a mediator in the association. Conclusion: The impact of apathy on physical performance and fall incidents varied with age and gender. Potentially, in older individuals with apathy, fall risk is preceded by a decline in physical performance. In clinical practice, identifying apathy in older persons might be useful to target mobility preserving interventions.

Background: Elevated homocysteine levels are a risk indicator for cardiovascular disease, fractures and cognitive decline. Previous studies indicated associations between homocysteine levels and medication use, including antihypertensive, lipid-lowering and antidiabetic medication. However, results were often contradictory and inconclusive. Our objective was to study the associations established previously in more detail by sub-classifying medication groups, and investigate the potential mediating role of vitamin B12 and folate status. Materials and Methods: Baseline data from the B-PROOF (B-vitamins for the PRevention Of Osteoporotic Fractures) study were used. We included 2,912 participants aged ≥65 years, with homocysteine levels of 12-50 μmol/L and creatinine levels ≤150 μmol/L, for whom self-reported medication data were available. We used multivariable linear regression models and analysis of covariance to assess the association between medication use and plasma homocysteine levels, and the potential mediation by serum vitamin B 12 and folate. Results: The mean age was 74 years (standard deviation, 6.5), 50 % were women, and median homocysteine levels were 14 μmol/L [interquartile range, 13-17 μmol/L]. Higher mean homocysteine levels were observed in users vs. non-users for diuretics (15.2 vs. 14.9, p = 0.043), high-ceiling sulphonamide diuretics (16.0 vs. 14.9, p < 0.001), medication acting via the renin-angiotensin system (15.2 vs. 14.9, p = 0.029) and metformin (15.6 vs. 15.1, p = 0.006). Non-selective β-blocker use was associated with lower mean homocysteine levels (14.4 vs. 15.0, p = 0.019). Only this association was mediated by an underlying association with vitamin B 12 and folate levels. Conclusion: The associations between homocysteine levels and medication use appear to be fairly modest. Our results suggest that medication use is unlikely to contribute to clinically relevant changes in plasma homocysteine levels. © 2014 Springer International Publishing.

Objective: Music interventions are widely used, but have not yet gained a place in guidelines for pediatric surgery or pediatric anesthesia. In this systematic review and meta-analysis we examined the effects of music interventions on pain, anxiety and distress in children undergoing invasive surgery. Data Sources: We searched 25 electronic databases from their first available date until October 2014. Study Selection: Included were all randomized controlled trials with a parallel group, crossover or cluster design that included pediatric patients from 1 month to 18 years old undergoing minimally invasive or invasive surgical procedures, and receiving either live music therapy or recorded music. Data Extraction and Synthesis: 4846 records were retrieved from the searches, 26 full text reports were evaluated and data was extracted by two independent investigators. Main Outcome Measures: Pain was measured with the Visual Analogue Scale, the Coloured Analogue Scale and the Facial Pain Scale. Anxiety and distress were measured with an emotional index scale (not validated), the Spielberger short State Trait Anxiety Inventory and a Facial Affective Scale. Results: Three RCTs were eligible for inclusion encompassing 196 orthopedic, cardiac and day surgery patients (age of 1 day to 18 years) receiving either live music therapy or recorded music. Overall a statistically significant positive effect was demonstrated on postoperative pain (SMD -1.07; 95%CI-2.08; -0.07) and on anxiety and distress (SMD -0.34 95% CI -0.66; -0.01 and SMD -0.50; 95% CI -0.84; - 0.16. Conclusions and Relevance: This systematic review and meta-analysis indicates that music interventions may have a statistically significant effect in reducing post-operative pain, anxiety and distress in children undergoing a surgical procedure. Evidence from this review and other reviews suggests music therapy may be considered for clinical use.

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 (beta-0.93; 95%CI [-1.15; -0.71], p < 0.001 and beta-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 (beta-1.25 and -0.96 respectively) and fat percentage in the last two upper quartiles (beta-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.

Background Medication use is a potentially modifiable risk factor for falling; psychotropic and cardiovascular drugs have been indicated as main drug groups that increase fall risk. However, evidence is mainly based on studies that recorded falls retrospectively and/or did not determine medication use at the time of the fall. Therefore, we investigated the associations indicated in the literature between medication use and falls, using prospectively recorded falls and medication use determined at the time of the fall. Methods Data from the B-PROOF (B-vitamins for the prevention of osteoporotic fractures) study were used, concerning community-dwelling elderly aged >= 65 years. We included 2,407 participants with pharmacy dispensing records. During the 2- to 3-year follow-up, participants recorded falls using a fall calendar. Cox proportional hazard models were applied, adjusting for potential confounders including age, sex, health status variables and concomitant medication use. Results During follow-up, 1,147 participants experienced at least one fall. Users of anti-arrhythmic medication had an increased fall risk (hazard ratio [HR] 1.61; 95 % confidence interval [CI] 1.12-2.32) compared with non-users. Similarly, non-selective beta-blocker use was associated with an increased fall risk (HR 1.41 [95 % CI 1.12-1.78]), while statin use was associated with a lower risk (HR 0.81 [95 % CI 0.71-0.94]). Benzodiazepine use (HR 1.32 [95 % CI 1.02-1.71]), and antidepressant use (HR 1.40 [95 % CI 1.07-1.82]) were associated with an increased fall risk. Use of other cardiovascular and psychotropic medication was not associated with fall risk. Conclusion Our results strengthen the evidence for an increased fall risk in community-dwelling elderly during the use of anti-arrhythmics, non-selective beta-blockers, benzodiazepines, and antidepressant medication. Clinicians should prescribe these drugs cautiously and if possible choose safer alternatives for older patients.