Hannes B. Staehelin

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.

BACKGROUND Antifracture efficacy with supplemental vitamin D has been questioned by recent trials. METHODS We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial. RESULTS The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation. CONCLUSION Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial

IMPORTANCE Vitamin D deficiency has been associated with poor physical performance. OBJECTIVE To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline. DESIGN, SETTING, AND PARTICIPANTS One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. INTERVENTIONS Three study groups with monthly treatments, including a low-dose control group receiving 24,000 IU of vitamin D3 (24,000 IU group), a group receiving 60,000 IU of vitamin D3 (60,000 IU group), and a group receiving 24,000 IU of vitamin D3 plus 300 μg of calcifediol (24,000 IU plus calcifediol group). MAIN OUTCOMES AND MEASURES The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index. RESULTS The study cohort comprised 200 participants (men and women ≥ 70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60,000 IU and 24,000 IU plus calcifediol were more likely than 24,000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60,000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24,000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24,000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60,000 IU group (mean, 1.47) and the 24,000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24,000 IU group (mean, 0.94) (P = .09). CONCLUSIONS AND RELEVANCE Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01017354.

Severe vitamin D deficiency in Swiss hip fracture patients

BACKGROUND Most clinical guidelines for the prevention of hip fractures recommend 800 IU vitamin D per day. This dose shifted serum 25-hydroxyvitamin D levels (25(OH)D) in previous studies to between 60 and 100 nmol/l. AIM To measure 25(OH)D levels and prevalence of vitamin D supplementation in individuals age 65+ with acute hip fracture. METHODS 222 consecutive hip fracture patients were investigated over a 12 month period. Mean age of patients was 86 years and 77% were women. RESULTS Mean serum 25(OH)D levels were low among hip fracture patients admitted from home (34.6 nmol/l), from assisted living (27.7 nmol/l), and from nursing homes (24 nmol/l). Severe vitamin D deficiency below 30 nmol/l was present in 60%, 80% were below 50 nmol/l, and less than 4% reached desirable levels of at least 75 nmol/l. Consistently, only 10% of hip fracture patients had any vitamin D supplementation on admission to acute care with significantly higher 25(OH)D levels among individuals supplemented with 800-880 IU/day (63.5 nmol/l). Controlling for age and gender, vitamin D supplementation, type of dwelling, and season were independently and significantly associated with 25(OH)D levels. CONCLUSION These data provide evidence that current guidelines for the prevention of hip fractures need further effort to be translated into clinical practice.

Milk intake and risk of hip fracture in men and women: A meta-analysis of prospective cohort studies

Milk contains calcium, phosphorus, and protein and is fortified with vitamin D in the United States. All these ingredients may improve bone health. However, the potential benefit of milk on hip fracture prevention is not well established. The objective of this study was to assess the association of milk intake with risk of hip fracture based on a meta‐analysis of cohort studies in middle‐aged or older men and women. Data sources for this study were English and non‐English publications via Medline (Ovid, PubMed) and EMBASE search up to June 2010, experts in the field, and reference lists. The idea was to compare prospective cohort studies on the same scale so that we could calculate the relative risk (RR) of hip fracture per glass of milk intake daily (approximately 300 mg calcium per glass of milk). Pooled analyses were based on random effects models. The data were extracted by two independent observers. The results show that in women (6 studies, 195,102 women, 3574 hip fractures), there was no overall association between total milk intake and hip fracture risk (pooled RR per glass of milk per day = 0.99; 95% confidence interval [CI] 0.96–1.02; Q‐test p = .37). In men (3 studies, 75,149 men, 195 hip fractures), the pooled RR per daily glass of milk was 0.91 (95% CI 0.81–1.01). Our conclusion is that in our meta‐analysis of cohort studies, there was no overall association between milk intake and hip fracture risk in women but that more data are needed in men.

Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH(2)-terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland (N=1334) and Israel (N=923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC (P=0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (DeltaTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (DeltaTC=0.06 mmol/l, 1.4%; P=0.334; N=1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia.

Pharmacokinetics of oral vitamin D3 and calcifediol

AIM Long-term pharmacokinetics after supplementation with vitamin D3 or calcifediol (the 25-hydroxyvitamin D3 metabolite) are not well studied. Additionally, it is unclear whether bolus doses of vitamin D3 or calcifediol lead to 25(OH)D3 plasma concentrations considered desirable for fracture prevention (30ng/mL). We therefore investigated plasma pharmacokinetics of 25(OH)D3 during different vitamin D3 and calcifediol supplementation regimens. METHODS In this seven-arm, randomised, double-blind, controlled parallel-group study, 35 healthy females aged 50 - 70years (5 per group) received 20μg calcifediol or vitaminD3 daily, 140μg calcifediol or vitaminD3 weekly, for 15weeks, or a single bolus of either 140μg calcifediol, or vitaminD3, or both. 25(OH)D3 plasma concentrations were quantified using LC-MS/MS in 14 clinical visits among all participants. RESULTS For daily (weekly) dosing, the area under the concentration-time curve (AUC0-24h), which is the measure for exposure, was 28% (67%) higher after the first dose of calcifediol than after the first dose of vitaminD3. After 15weeks, this difference was 123% (178%). All women in the daily and weekly calcifediol groups achieved 25(OH)D3 concentrations >30ng/mL (mean, 16.8days), but only 70% in the vitaminD3 daily or weekly groups reached this concentration (mean, 68.4days). A single dose of 140μg calcifediol led to 117% higher 25(OH)D3 AUC0-96h values than 140μg vitaminD3, while the simultaneous intake of both did not further increase exposure. CONCLUSIONS Calcifediol given daily, weekly, or as a single bolus is about 2-3 times more potent in increasing plasma 25(OH)D3 concentrations than vitamin D3. Plasma 25(OH)D3 concentrations of 30ng/mL were reached more rapidly and reliably with calcifediol.

Mild to moderate cognitive impairment is a major risk factor for mortality and nursing home admission in the first year after hip fracture.

BACKGROUND It is not well established if and to what extent mild to moderate cognitive impairment predicts mortality and risk of nursing home admission after hip fracture. OBJECTIVE To investigate prospectively whether and to what extent mild to moderate cognitive impairment, contributes to mortality and admission to nursing home in the first year after acute hip fracture. METHODS We enrolled 173 patients with acute hip fracture age 65 and older who reached a Mini-Mental State Examination (MMSE) score of at least 15 during acute care after hip fracture repair. An MMSE score of 15 to 24 (median) was classified as mild to moderate cognitive impairment. Primary outcomes were mortality in all and admission to nursing home among seniors who lived at home prior to their hip fracture. Follow-up was 12 months with clinical visits at baseline, 6, and 12 months, plus monthly phone calls. We used Cox proportional hazards models controlling for age, sex, body mass index, baseline number of comorbidities and 25-hydroxyvitamin D status, and severe incident infections to assess the risk of mortality and nursing home admission. Because the study population was enrolled in a factorial design clinical trial testing high dose vitamin D and/or an exercise home program, all analyses also controlled for these treatment strategies. RESULTS Of 173 acute hip fracture patients enrolled, 79% were women, 77% were admitted from home, and 80% were vitamin D deficient (<20ng/ml). Mean age was 84 years. 54% had mild to moderate cognitive impairment. Over the 12-month follow-up, 20 patients died (27% of 173) and 47 (35% of 134) were newly admitted to a nursing home. Mild to moderate cognitive impairment was associated with a more than 5-fold increased risk of mortality (HR=5.77; 95% CI: 1.55-21.55) and a more than 7-fold increased risk of nursing home admission (HR=7.37; 95% CI: 1.75-30.95). Additional independent risk factors of mortality were male gender (HR=3.55; 95% CI: 1.26-9.97), low BMI (HR=7.25; 95% CI: 1.61-33.74), and baseline 25-hydroxyvitamin D level (per 1ng/ml: HR=0.93; 95% CI: 0.87-0.998; p=0.04). CONCLUSIONS Mild to moderate cognitive impairment in patients with acute hip fracture is associated with a high risk of mortality and nursing home admission during the first year after hip fracture. Female gender, a greater BMI and a higher 25-hydroxyvitamin D status may protect against mortality after hip fracture independent of cognitive function.

Importance of Vitamin D and Calcium at Older Age

We review the potential of vitamin D for the prevention of falls and fractures. Evidence from randomized-controlled trials will be reviewed for both endpoints, as well as epidemiologic data that correlates higher 25-hydroxyvitamin D status with better bone and muscle health. This review summarizes the compelling dual benefit of vitamin D on bone and muscle health, a concept that is unique and important for optimal fracture prevention at higher age. We will review sources of vitamin D and calcium and also outline why calcium supplementation alone may not contribute to fracture prevention at higher age. This review concludes that vitamin D at a dose of at least 800 IU per day should be provided to all postmenopausal women and everybody starting at age 60 for optimal bone and muscle health. In combination with a vitamin D supplement, dairy products may be an optimal source of calcium at higher age as milk provides both calcium and protein.

No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits

A 30 cM broad genomic region on the long arm of chromosome 10 at 80 cM shows significant and consistent linkage with AD and with plasma concentration of the β‐amyloid peptide 1–42 (Aβ42). The PLAU gene, which is involved in the production and degradation of Aβ42, maps to that region and is therefore a strong positional candidate for association with sporadic AD. We analyzed the non‐synonymous single nucleotide polymorphism (SNP) rs2227564 in two independent case‐control series from Switzerland and Greece and investigated the influence of this SNP on cognition in elderly individuals. Because PLAU modulates the cleavage of the amyloid precursor protein (APP) and the degradation of Aβ, we also determined the levels of Aβ in the brain, plasma and in the cerebrospinal fluid (CSF). We found no evidence for association of this SNP with AD or with AD‐related traits such as β‐amyloid load in the medial temporal lobe or Aβ42 concentration in the CSF and in plasma. Our findings do not support a major role of PLAU polymorphisms as susceptibility factors for AD and suggest that large‐scale association studies which combine genetic information from populations with similar genetic background might prevent the generation of spurious associations. Although PLAU may be pathophysiologially related to AD, the contribution of common genetic variants of this gene to the risk for developing AD is likely to be low.