Vitamin D supplementation for improving bone density in vitamin D-deficient children and adolescents: systematic review and individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin D supplements are widely used for improving bone health in children and adolescents, but their effects in vitamin D-deficient children are unclear. OBJECTIVES: This study aimed to examine whether the effect of vitamin D supplementation on bone mineral density (BMD) in children and adolescents differs by baseline vitamin D status and estimate the effect in vitamin D-deficient individuals. METHODS: This is a systematic review and individual participant data (IPD) meta-analysis. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, MBASE, CINAHL, AMED, and ISI Web of Science (until May 27, 2020) for randomized controlled trials (RCTs) of vitamin D supplementation reporting bone density outcomes after ≥6 mo in healthy individuals aged 1-19 y. We used two-stage IPD meta-analysis to determine treatment effects on total body bone mineral content and BMD at the hip, femoral neck, lumbar spine, and proximal and distal forearm after 1 y; examine whether effects varied by baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, and estimate treatment effects for each 25(OH)D subgroup. RESULTS: Eleven RCTs were included. Nine comprising 1439 participants provided IPD (86% females, mean baseline 25(OH)D = 36.3 nmol/L). Vitamin D supplementation had a small overall effect on total hip areal BMD (weighted mean difference = 6.8; 95% confidence interval: 0.7, 12.9 mg/cm2; I2 = 7.2%), but no effects on other outcomes. There was no clear evidence of linear or nonlinear interactions between baseline 25(OH)D and treatment; effects were similar in baseline 25(OH)D subgroups (cutoff of 35 or 50 nmol/L). The evidence was of high certainty. CONCLUSIONS: Clinically important benefits for bone density from 1-y vitamin D supplementation in healthy children and adolescents, regardless of baseline vitamin D status, are unlikely. However, our findings are mostly generalizable to White postpubertal girls and do not apply to those with baseline 25(OH)D outside the studied range or with symptomatic vitamin D deficiency (e.g., rickets). This study was preregistered at PROSPERO as CRD42017068772. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017068772.

Patient and Physician Decisional Factors Regarding Hypercalcemia of Malignancy Treatment: A Novel Mixed-Methods Study.

BACKGROUND: Integrating shared decision making between patients and physicians and incorporating their values and preferences in the development of clinical practice guidelines (CPGs) is of critical importance to optimize CPG implementation and treatment adherence. This applies to many debilitating diseases, including hypercalcemia of malignancy (HCM). OBJECTIVE: Evaluate patient and physician values, preferences, and attitudes to better inform CPGs to treat HCM in adults. METHODS: We followed a mixed-methods approach. We conducted a systematic review using 5 databases to identify studies reporting on patient and physician values, costs and resources, feasibility, acceptability, and equity regarding HCM treatment. We also gathered data from different countries on the cost of multiple treatment modalities. We collected data on outcome prioritization from the CPG Working Group. Similarly, we collected data from patients with HCM regarding outcome prioritization and administered a questionnaire to evaluate their attitudes and perceptions toward treatment as well as treatment acceptability and feasibility. RESULTS: In the systematic review, we included 2 cross-sectional surveys conducted on the same population of physicians who agreed that treating HCM alleviates symptoms and improves quality of life; however, harms and benefits should be thoroughly considered when deciding on the duration of treatment. We also included 2 studies on cost showing that intravenous (IV) bisphosphonate is more cost-effective than a combination of IV bisphosphonate and calcitonin and administration of IV zoledronic acid at home is more cost-effective than other IV bisphosphonates. The cost of zoledronic acid, denosumab, and cinacalcet varied widely among countries and types (brand vs generic). Both the CPG Working Group and patients with HCM agreed that the most important outcomes when deciding on treatment were survival and resolution of HCM, but there was some variability in the ratings for other outcomes. CONCLUSION: Using mixed methods, CPG developers can obtain meaningful information regarding evidence to decision criteria. In the case of HCM CPGs, this approach has provided the required contextual information and supported the development of evidence-based recommendations.

Effect of high dose vitamin D supplementation on indices of sarcopenia and obesity assessed by DXA among older adults: A randomized controlled trial.

BACKGROUND: Hypovitaminosis D is associated with Sarcopenic Obesity (SO), but evidence from randomized Vitamin D 3 (VD3) trials is scarce. OBJECTIVE: Compare the effect of VD3 supplementation, at two doses, on SO indices at 12 months. METHODS: Overweight older adults (>65 years) with baseline 25-hydroxyvitamin D (25OHD) of 10-30 ng/mL were recruited in this double-blind, randomized, controlled multicenter trial (clinicaltrial.gov identifier: NCT01315366). All subjects received 1000 mg calcium citrate/day and underwent total body Dual-energy X-ray Absorptiometry for body composition assessment. Low Dose Group (LDG) and High Dose Group (HDG) received 600 IU -Institute of Medicine (IOM) Recommended Dietary Allowance (RDA)- and 3750 IU VD3/day, respectively. RESULTS: Mean age was 71 ± 4.6 years, 55% females, BMI: 30.2 ± 4.5 Kg/m2, and 43% had metabolic syndrome. There were no differences in baseline characteristics between groups. At 12 months, 248 participants had body composition data, 122 in LDG and 126 in HDG. Proportions of patients with diminished muscle mass, muscle strength, and visceral adiposity did not differ between the 2 groups at baseline or 12 months. Similarly, no significant differences were noted in the proportion of patients with SO at study entry (1.8% in LDG vs 1.6% HDG; p = 0.99) and at 12 months (3.7% in LDG vs. 0.9% HDG; p = 0.18) across arms. CONCLUSIONS: Weekly VD3, at the daily equivalent of 3750 IU/day, did not improve indices of sarcopenia nor adiposity compared to the IOM RDA dose in adults.

Values and other decisional factors regarding treatment of hypercalcaemia of malignancy: a systematic review protocol.

INTRODUCTION: Hypercalcaemia of malignancy (HCM) is the second most common cause of hypercalcaemia and is associated with significant morbidity and mortality. Several treatment options are available including pharmacological therapy with bisphosphonates, denosumab, glucocorticoids and calcimimetics, as well as conventional therapy with hydration and possibly calcitonin. While guidelines have previously considered treatment effects, no guideline has yet considered a range of contextual factors impacting recommendations for the management. The aim of this study was to summarise the available evidence on important decisional factors for the development of guidelines for the treatment of HCM. These include patient's values and preferences, cost, acceptability, feasibility and equity. METHODS AND ANALYSIS: This protocol is registered in PROSPERO (registration number: CRD42021264371). This is a systematic review of observational studies, case series, trials, reviews and qualitative studies involving treatment of adult patients with HCM. We will develop and execute two independent search strategies using five databases: PubMed, Medline (OVID), Embase.com, CINAHL (EBSCO) and Cochrane, and review their combined output. Two reviewers will screen titles and abstracts and full texts and will implement data abstraction from relevant studies independently and in duplicate. The outcomes of interest are the decisional factors that influence drug selection, with possible subgroup summaries by drug class or aetiology of HCM. We will present the data collected in a narrative and thematic approach. ETHICS AND DISSEMINATION: Ethical approval is not applicable for our study, since we will only collect data from available literature. This systematic review will be submitted to a peer-reviewed journal when completed.

Vitamin D3 Dose Requirement That Raises 25-Hydroxyvitamin D to Desirable Level in Overweight and Obese Elderly.

CONTEXT: Guidelines for the dosage of vitamin D supplementation vary widely globally. OBJECTIVE: To investigate the impact of 2 vitamin D doses, bracketed between the IOM recommended dietary allowance (RDA) and the upper tolerable limit, on vitamin D nutritional status in elderly individuals. METHODS: This post hoc analysis of data collected from a 12-month, double-blind, randomized control trial included 221 ambulatory participants (≥ 65 years) with a mean BMI of 30.2 kg/m2 and a mean baseline serum 25-hydroxyvitamin D [25(OH)D] level of 20.4 ±â€…7.4 ng/mL, who were recruited from 3 outpatient centers in Lebanon. All participants received 1000 mg of elemental calcium daily from calcium citrate plus the daily equivalent of either 600 IU or 3750 IU of vitamin D3. RESULTS: Mean 25(OH)D level at 12 months was 26.0 ng/mL with low dose and 36.0 ng/mL with high dose vitamin D3. The proportion of participants reaching a value ≥ 20 ng/mL was 86% in the low dose, and 99% in the high dose arms, with no gender differences. The increment of 25(OH)D per 100 IU/day was 1 ng/mL with the low dose, and 0.41 ng/mL with the high dose. Serum 25(OH)D levels at 1 year were highly variable in both treatment arms. Baseline 25(OH)D level and vitamin D dose-but not age, BMI, gender, or season-were significant predictors of serum 25(OH)D level post-intervention. CONCLUSION: The IOM Recommended Dietary Allowance (RDA) of 600 IU/day does not bring 97.5% of ambulatory elderly individuals above the desirable threshold of 20 ng/mL. Country-specific RDAs are best derived taking into account the observed variability and predictors of achieved 25(OH)D levels.

The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

Total, Bioavailable, and Free 25(OH)D Relationship with Indices of Bone Health in Elderly: A Randomized Controlled Trial.

CONTEXT: Questions regarding the superiority of free and bioavailable 25-hydroxyvitamin D [25(OH)D] in predicting health outcomes remain unresolved. OBJECTIVE: This study investigates the impact of vitamin D variables-total, bioavailable, or free 25(OH)D-on indices of bone and mineral metabolism, at baseline and in response to 2 vitamin D doses. DESIGN: Our objectives are implemented as exploratory analyses on data collected in a 1-year, double-blind, randomized controlled trial completed in July 2014. SETTING: Participants were recruited from 3 major hospitals in an ambulatory setting. PARTICIPANTS: Participants were >65 years of age, overweight, and had a baseline serum 25(OH)D between 10 and 30 ng/mL. A total of 221 participants completed the study. INTERVENTION: Subjects were randomized to receive calcium and oral vitamin D3 (600 IU/day or 3750 IU/day) supplementation. RESULTS: Participants who received the higher vitamin D dose had levels that were 1.3- to 1.4-fold higher than those taking the lower dose, for all variables (P value < 0.001). Serum values of bioavailable and free 25(OH)D were associated with total 25(OH)D, with r values of 0.942 and 0.943, respectively (P value < 0.001). Parathyroid hormone (PTH) was negatively associated with all vitamin D variables, with correlation coefficients ranging from -0.22 to -0.25, while calcium and bone turnover markers (carboxy-terminal collagen crosslinks and osteocalcin) did not. Only total 25(OH)D had a positive relationship with % change bone mineral density (BMD) at the femoral neck at 12 months, while only free and bioavailable 25(OH) had a positive relationship with % change total body BMD at 12 months. CONCLUSION: Calculated free and bioavailable 25(OH)D do not appear to be superior to total 25(OH)D in predicting indices of bone health in an elderly population.

Delta-like 1 (DLK1) is a possible mediator of vitamin D effects on bone and energy metabolism.

Vitamin D effects on bone and mineral metabolism are well recognized, and its anti-inflammatory actions are gaining particular interest. Delta-like 1 (DLK1) is a protein, expressed by progenitor cells of different tissues, and increases the size of progenitor cell population during the inflammatory phase of tissue regeneration. DLK1 also plays a role in energy metabolism as it antagonizes insulin signaling in bone. In this one-year randomized clinical trial of overweight elderly individuals that received either 600 or 3750 IU daily cholecalciferol we assessed the effect of vitamin D supplementation on pre-specified secondary outcomes: DLK1, leptin, adiponectin, C-Reactive Protein (CRP) and Vascular Cell Adhesion Molecule (VCAM). We also examined correlations between DLK1 and bone (BMD, bone markers), fat (adipokines, body composition), insulin sensitivity and inflammatory markers. Multivariate analyses were conducted to further explore these associations. Overall, there was a significant increase in serum DLK1 and leptin and a decrease in VCAM, but no change in CRP, after 12 months of vitamin D supplementation. DLK1 was negatively correlated with BMD and positively correlated with bone markers, associations that persisted after adjusting for age, gender and BMI. DLK1 was also positively associated with indices of insulin resistance and negatively with indices of insulin sensitivity. Correlations between DLK1 and fat parameters, such as adipokines, and DXA derived fat mass were less consistent. There were no correlations between DLK1 and inflammatory markers. In conclusion, twelve months supplementation of vitamin D3 increased serum DLK1. DLK1 was negatively associated with indices of bone health and fuel metabolism, and with 1,25(OH)2D levels. Similar to the role of DLK1 in animal models, our findings support the hypothesis that DLK1 can be targeted to regulate bone and energy metabolism and develop drugs to improve BMD and insulin sensitivity. However, further studies are needed to explore the role of DLK1 and its relationship to vitamin D metabolites in vivo.

Time trends and predictors of hypovitaminosis D across the life course: 2009-2016.

PURPOSE: We investigated prevalence, determinants, seasonal changes, and time trends in hypovitaminosis D. We derived a desirable serum 25-hydroxy-vitamin D (25OHD) level in adults/elderly by evaluating the 25OHD-parathyroid hormone (PTH) exponential relationship. METHODS: We analyzed serum 25OHD data from a large laboratory database (N = 151,705), from a major academic medical center in Lebanon, from 2009 to 2016. We used cross calibration formulas to convert measured 25OHD levels to LC-MS/MS equivalents based on our external quality assurance protocols. RESULTS: 6% of the population were children (mean age 11 ±â€¯5 years, 56% girls), 68% were adults (44 ±â€¯13 years, 71% women), and 25% were elderly (74 ±â€¯6 years, 59% women). The prevalence of hypovitaminosis D, in the entire population, was 39%, 29% and 23% at 25OHD cutoffs of 20 ng/ml, 15 ng/ml, and 12 ng/ml, respectively, across all years. Using multivariate analysis, predictors of 25OHD levels below 12, 15 and 20 ng/ml were younger age, male sex, winter months, and inpatient status both in adults and elderly. In children, older age, female sex, winter months, and inpatient status, predicted levels below 15 ng/ml and 20 ng/ml, but only older age, female sex, and winter months predicted levels below 12 ng/ml. There was a significant steady annual increase in 25OHD levels between 2009 and 2016 of 0.9 ng/ml/year (95% CI: 0.7, 1.0) in children, 1.2 ng/ml/year (1.2, 1.3) in adults and 2.6 ng/ml/year (2.6, 2.8) in the elderly. Using best fit non-linear regression models, on a subset of adults and elderly in whom concomitant 25OHD and PTH data was available (N = 4025), PTH levels plateaued at a serum 25OHD level of 26.1 ng/ml. CONCLUSION: Secular increase in serum 25OHD levels is observed in Lebanon, but hypovitaminosis D is still prevalent. Our data provides basis for a desirable 25OHD level above 26 ng/ml in adult and elderly Lebanese individuals.

Impact of vitamin D supplementation on falls and fractures-A critical appraisal of the quality of the evidence and an overview of the available guidelines.

INTRODUCTION: The beneficial effect of vitamin D supplementation on musculo-skeletal outcomes have been recently questioned and recommendations regarding supplementation vary widely. The aim of this paper is to systematically assess the quality of the evidence evaluating the effect of vitamin D supplementation on falls and fractures. METHODS: We conducted a systematic search in Medline, PubMed, and Embase and selected systematic reviews (SRs) / meta-analyses (MAs) of randomized controlled trials (RCTs) on vitamin D supplementation and falls or fracture, published between 2012 - 2018. We identified 5 MAs of RCTs on falls, 4 on fractures and 4 on both outcomes. We applied the critical appraisal tool "A MeaSurement Tool to Assess systematic Reviews 2" - AMSTAR 2 - to assess the quality of the identified MAs. RESULTS: Vitamin D and calcium supplementation (CaD), compared to calcium only or placebo, may reduce the risk of falls, in institutionalized individuals and/or those from the community, but the data is inconsistent. The largest and most consistent evidence for a protective effect of CaD, compared to placebo or control, is in reducing the risk of hip fracture, by 16-33%, and any fracture, by 5-19%. This effect was demonstrated when combining trials in community-dwelling and institutionalized individuals, potentially driven by data from institutionalized individuals as shown in 3 SRs/MAs. Major limitations to the quality of the evidence include variability in the methodology of MAs, but more importantly, differences between trials in terms of subjects' characteristics, vitamin D regimens, outcome definition and ascertainment, risk of bias, trial duration and/or low power. The quality of the included MAs was moderate to critically low. CONCLUSIONS: While the effect on falls is inconsistent, CaD reduces the risk of fracture (hip and any fracture), as shown in meta-analyses pooling data of studies combining institutionalized and community individuals. The evidence is however limited by major shortcomings and heterogeneity.

Limitations of platform assays to measure serum 25OHD level impact on guidelines and practice decision making.

CONTEXT: Liquid Chromatography Mass Spectroscopy (LC-MS/MS) is the preferred method to measure 25 hydroxyvitamin D (25OHD) levels, but laboratories are increasingly adopting automated platform assays. OBJECTIVE: We assessed the performance of commonly used automated immunoassays, with that of LC-MS/MS, and the National Institute of Standards and Technology (NIST) reference values, to measure 25OHD levels. METHODS/SETTING: We compared serum 25OHD levels obtained from 219 elderly subjects, enrolled in a vitamin D trial, using the Diasorin Liaison platform assay, and the tandem LC-MS/MS method. We also assessed the performance of the Diasorin and Roche automated assays, expressed as mean % bias from the NIST standards, based on the vitamin D External Quality Assessment Scheme (DEQAS) reports, from 2013 to 2017. RESULTS: Serum 25OHD levels were significantly lower in the Diasorin compared to LC-MS/MS assay at baseline, 18.5 ±â€¯7.8 vs 20.5 ±â€¯7.6 ng/ml (p < 0.001), and all other time points. Diasorin (25OHD) = 0.76 × LC-MS/MS (25OHD) + 4.3, R2 = 0.596. The absolute bias was independent of 25OHD values, and the pattern unfit for any cross-calibration. The proportion of subjects considered for vitamin D treatment based on pre-set cut-offs differed significantly between the 2 assays. There also was wide variability in the performance of both automated assays, compared to NIST reference values. CONCLUSION: The performance of most widely used automated assays is sub-optimal. Our findings underscore the pressing need to re-consider current practices with regard to 25OHD measurements, interpretation of results from research studies, meta-analyses, the development of vitamin D guidelines, and their relevance to optimizing health.

Vitamin D in the Middle East and North Africa.

PURPOSE: The Middle East and North Africa (MENA) region registers some of the lowest serum 25­hydroxyvitamin D [25(OH)D] concentrations, worldwide. We describe the prevalence and the risk factors for hypovitaminosis D, completed and ongoing clinical trials, and available guidelines for vitamin D supplementation in this region. METHODS: This review is an update of previous reviews published by our group in 2013 for observational studies, and in 2015 for randomized controlled trials (RCTs) from the region. We conducted a comprehensive search in Medline, PubMed, and Embase, and the Cochrane Library, using MeSH terms and keywords relevant to vitamin D, vitamin D deficiency, and the MENA region, for the period 2012-2017 for observational studies, and 2015-2017 for RCTs. We included large cross-sectional studies with at least 100 subjects/study, and RCTs with at least 50 participants per arm. RESULTS: We identified 41 observational studies. The prevalence of hypovitaminosis D, defined as a 25­hydroxyvitamin D [25(OH)D] level below the desirable level of 20 ng/ml, ranged between 12-96% in children and adolescents, and 54-90% in pregnant women. In adults, it ranged between 44 and 96%, and the mean 25(OH)D varied between 11 and 20 ng/ml. In general, significant predictors of low 25(OH)D levels were female gender, increasing age and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude.We retrieved 14 RCTs comparing supplementation to control or placebo, published during the period 2015-2017: 2 in children, 8 in adults, and 4 in pregnant women. In children and adolescents, a vitamin D dose of 1000-2000 IU/d was needed to maintain serum 25(OH)D level at target. In adults and pregnant women, the increment in 25(OH)D level was inversely proportional to the dose, ranging between 0.9 and 3 ng/ml per 100 IU/d for doses ≤2000 IU/d, and between 0.1 and 0.6 ng/ml per 100 IU/d for doses ≥3000 IU/d. While the effect of vitamin D supplementation on glycemic indices is still controversial in adults, vitamin D supplementation may be protective against gestational diabetes mellitus in pregnant women. In the only identified study in the elderly, there was no significant difference between 600 IU/day and 3750 IU/day doses on bone mineral density. We did not identify any fracture studies.The available vitamin D guidelines in the region are based on expert opinion, with recommended doses between 400 and 2000 IU/d, depending on the age category, and country. CONCLUSION: Hypovitaminosis D is prevalent in the MENA region, and doses of 1000-2000 IU/d may be necessary to reach a desirable 25(OH)D level of 20 ng/ml. Studies assessing the effect of such doses of vitamin D on major outcomes, and confirming their long term safety, are needed.

Vitamin D Metabolism in Bariatric Surgery.

Hypovitaminosis D is common in obese patients and persists after roux-en-Y gastric bypass and sleeve gastrectomy. Several societies recommend screening for vitamin D deficiency before bariatric surgery, and replacement doses of 3000 IU/d and up to 50,000 IU 1 to 3 times per week, in case of deficiency, with periodic monitoring. These regimens are mostly based on expert opinion. Large trials are needed to assess the vitamin D dose response, by type of bariatric surgery, and evaluate the effect on surrogate markers of skeletal outcomes. Such data are essential to derive desirable vitamin D levels in this population.

Impact of Calcium and Two Doses of Vitamin D on Bone Metabolism in the Elderly: A Randomized Controlled Trial.

The optimal dose of vitamin D to optimize bone metabolism in the elderly is unclear. We tested the hypothesis that vitamin D, at a dose higher than recommended by the Institute of Medicine (IOM), has a beneficial effect on bone remodeling and mass. In this double-blind trial we randomized 257 overweight elderly subjects to receive 1000 mg of elemental calcium citrate/day, and the daily equivalent of 3750 IU/day or 600 IU/day of vitamin D3 for 1 year. The subjects' mean age was 71 ± 4 years, body mass index 30 ± 4 kg/m2 , 55% were women, and 222 completed the 12-month follow-up. Mean serum 25 hydroxyvitamin D (25OHD) was 20 ng/mL, and rose to 26 ng/mL in the low-dose arm, and 36 ng/mL in the high-dose arm, at 1 year (p < 0.05). Plasma parathyroid hormone, osteocalcin, and C-terminal telopeptide (Cross Laps) levels decreased significantly by 20% to 22% in both arms, but there were no differences between the two groups for any variable, at 6 or 12 months, with the exception of serum calcitriol, which was higher in the high-dose group at 12 months. Bone mineral density (BMD) increased significantly at the total hip and lumbar spine, but not the femoral neck, in both study arms, whereas subtotal body BMD increased in the high-dose group only, at 1 year. However, there were no significant differences in percent change BMD between the two study arms at any skeletal site. Subjects with serum 25OHD <20 ng/mL and PTH level >76 pg/mL showed a trend for higher BMD increments at all skeletal sites, in the high-dose group, that reached significance at the hip. Adverse events were comparable in the two study arms. This controlled trial shows little additional benefit in vitamin D supplementation at a dose exceeding the IOM recommendation of 600 IU/day on BMD and bone markers, in overweight elderly individuals. © 2017 American Society for Bone and Mineral Research.

Effect of vitamin D replacement on indexes of insulin resistance in overweight elderly individuals: a randomized controlled trial.

BACKGROUND: It is unclear whether and at what dose vitamin D supplementation affects insulin resistance (IR). OBJECTIVE: We sought to investigate whether vitamin D at doses higher than currently recommended decreases indexes of IR in an ambulatory population of overweight elderly subjects. DESIGN: This double-blind, randomized, controlled multicenter trial enrolled 257 elderly overweight individuals aged ≥65 y with baseline 25-hydroxyvitamin D [25(OH)D] concentrations between 10 and 30 ng/mL. All subjects received 1000 mg calcium citrate/d, with vitamin D administered weekly at an equivalent dose of 600 or 3750 IU/d. The homeostasis model assessment (HOMA) of IR index at 1 y was the primary outcome. We also assessed the McAuley index. RESULTS: In total, 222 subjects (55% women) with a mean ± SD age and body mass index (BMI; in kg/m(2)) of 71 ± 4 y and 30 ± 4, respectively, completed the study. Subjects' baseline characteristics, including IR indexes, were similar across groups: 69% had prediabetes, 54% had hypertension (47% were taking antihypertensive medications), and 60% had hyperlipidemia, nearly half of whom were receiving lipid-lowering drugs. At 1 y, mean ± SD serum 25(OH)D increased from 20 ± 7 to 26 ± 7 ng/mL in the low-dose arm (P < 0.0001) and from 21 ± 8 to 36 ± 10 ng/mL in the high-dose arm (P < 0.001). Median HOMA-IR indexes did not change compared with baseline concentrations and were similar in the high- [2.2 (IQR: 1.5, 2.9)] and low-dose [2.3 (IQR: 1.6, 3.3] treatment groups. Adjusted analyses showed that HOMA-IR was predicted by the baseline HOMA index and BMI but not by vitamin D dose, baseline serum 25(OH)D, or change in 25(OH)D. CONCLUSION: Vitamin D3 at 3750 IU/d did not improve HOMA-IR compared with the Institute of Medicine Recommended Dietary Allowance of 600 IU/d in elderly overweight individuals. This trial was registered at clinicaltrials.gov as NCT01315366.

Effects of hormone therapy on blood pressure.

OBJECTIVE: Although hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies. METHODS: Comprehensive Ovid MEDLINE searches were conducted for the terms "hypertension" and either of the following "hormone therapy and menopause" or "selective estrogen receptor modulator" from year 2000 to November 2013. RESULTS: In vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women. CONCLUSIONS: Large randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment.

Hypovitaminosis D in the Middle East and North Africa: Prevalence, risk factors and impact on outcomes.

BACKGROUND: The Middle East and North Africa (MENA) region registers some of the highest rates of hypovitaminosis D worldwide.   AIM: We systematically reviewed the prevalence of hypovitaminosis D, rickets and osteomalacia, their predictors and impact on major outcomes, in the region. METHODS: Medline, Pubmed and Embase search engines, entering keywords and concepts, combined with individual countries of interest, were used. Search was limited years 2000-2012; and review articles were used for the period preceding year 2000. RESULTS: Rickets and osteomalacia still occur in this sunny region. Hypovitaminosis D prevails, with rates varying 30-90%, considering a desirable serum 25 hydroxy-vitamin D [25(OH)D] of 20 ng/ml. Advancing age, female gender, multi-parity, clothing style, season, socio-economic status and urban living are recognized predictors of hypovitaminosis D in adults. Prolonged breastfeeding without vitamin D supplementation and low dietary calcium intake are the recognized risk factors for rickets and hypovitaminosis D in children.. Associations with pain score and disease activity in rheumatologic disorders, viral load and interleukins in hepatitis C, BMI, lipids and insulin sensitivity, blood pressure, heart failure and mortality are described. Sun exposure in adults decreased prevalence of metabolic syndrome in one study. Few randomized vitamin D trials revealed that the majority of mothers or children failed to achieve a desirable 25(OH)D level, even with doses by far exceeding current recommendations. A trial in adolescent girls reveals substantial bone and lean mass increments. CONCLUSION: Hypovitaminosis D is prevalent in MENA. The lack of populations based studies, gaps in studies in infants, pre-pubertal children and pregnant women, hinder the development of region specific guidelines and constitute a major obstacle to impact this chronic and most often subclinical disease.