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.
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.
Aims
To investigate the association between use of β‐blockers and β‐blocker characteristics – selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism – and ...fall risk.
Methods
Data from two prospective studies were used, including community‐dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B‐PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time‐varying β‐blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β‐blocker use, their characteristics – selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism – and fall risk. The results of the studies were combined using meta‐analyses.
Results
In total 2917 participants encountered a fall during a total follow‐up time of 89 529 years. Meta‐analysis indicated no association between use of any β‐blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 95% confidence interval (CI) 0.88–1.06. Use of a selective β‐blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83–1.01). Use of a nonselective β‐blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01–1.48). Other β‐blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk.
Conclusion
Our study suggests that use of a nonselective β‐blocker, contrary to selective β‐blockers, is associated with an increased fall risk in an older population. In clinical practice, β‐blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β‐blocker in this age group, and the pros and cons for β‐blocker classes should be taken into consideration.
High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B
12
...and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B
12
, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all
p
< 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (
p
= 0.24), LS-BMD (
p
= 0.16), SOS (
p
= 0.67), and BUA (
p
= 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group,
p
= 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B
12
and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone ...mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•45% of this Dutch older population had serum 25(OH)D concentrations <50nmol/L.•Only 6% of the participants with a vitamin D deficiency used vitamin D supplements.•Sun habits are still an important ...determinant of 25(OH)D status in older adults.•35% of the variation in serum 25(OH)D was explained by the determinants under study.
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.
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).
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).
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.
OBJECTIVE:Homocysteine has been shown to be a more accurate predictor of cardiovascular mortality in very old persons than models based on classical risk factors. Arterial stiffening is a structural ...abnormality involved in the pathway of cardiovascular disease. We expect this underlying pathophysiology to be a possible explanation for the association between homocysteine and cardiovascular risk, particularly in older populations.
METHODS:Baseline cross-sectional data of the B-PROOF study were used to determine associations between homocysteine and outcomes of vascular function and structure. The cardiovascular subgroup of the B-PROOF study was included n = 560, 58% men, age 72.6 ± 5.5 years, median homocysteine level 14.2 μmol/l (IQR 13.0–16.6). We assessed carotid distensibility coefficient, carotid compliance coefficient, aortic pulse wave velocity (aPWV), augmentation index (AIx) and aortic pulse pressure (aortic PP). Associations were tested using linear regression analysis and ANCOVA and were adjusted for possible confounders including age, sex, renal function, mean arterial pressure and heart rate.
RESULTS:Ln-homocysteine was strongly associated with aPWV β 0.005 95% confidence interval (0.001–0.009). Furthermore, this association was shown to be age-dependent (P = 0.02) and it was most strong in the upper tertile of age (77–98 years). No significant associations with ln-homocysteine were observed for AIx, carotid distensibility coefficient and compliance coefficient and aortic PP. Sex stratification shows the association between ln-homocysteine and aPWV is only significant in men.
CONCLUSION:In older persons, homocysteine is associated with aortic stiffness, predominantly in the oldest old. This suggests that the strong association between homocysteine and cardiovascular mortality in the elderly may be mediated by aortic stiffness.
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 B
12
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.
We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B
status and brain volumes. We furthermore compared brain volumes of participants who ...received daily folic acid and vitamin B
supplementation with participants who did not.
Participants of the B-PROOF study (
= 2919) were assigned to 400 µg folic acid and 500 µg vitamin B
, or a placebo. After two years of intervention, T₁-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (
= 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B
, holotranscobalamin, and methylmalonic acid concentrations were measured.
Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (β = -0.91, 95% CI -1.85-0.03;
= 0.06) and between serum folate and TBV (β = -0.20, 95% CI -0.38, -0.02;
= 0.03). No significant associations were observed for serum vitamin B
and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL,
= 0.03).
Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B
supplementation will be beneficial above and beyond normal dietary intake for brain health.
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives ...for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10−8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10−14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10−6 also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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