Assessment of the Methods Used to Develop Vitamin D and Calcium Recommendations-A Systematic Review of Bone Health Guidelines.

BACKGROUND: There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. METHODS: We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure; assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development; and, identified types identified types of evidence underpinning the recommendations. RESULTS: we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600-4000 IU/day) and 70% provided calcium (600-1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9-12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. CONCLUSIONS: There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health.

Assessment of eldecalcitol and alendronate effect on postural balance control in aged women with osteoporosis.

INTRODUCTION: Older people aged over 75 are more prone to falls because physical functions become deteriorated along with aging, and also fracture risk is strongly correlated with age. We evaluated the effects of anti-osteoporosis agents, eldecalcitol (ELD) and alendronate (ALN) on physical functions by assessing dynamic and static postural balance in aged patients with osteoporosis. MATERIALS AND METHODS: A randomized, open-label, controlled clinical trial has been conducted with 124 female patients aged 65 or over with osteoporosis. Patients were randomly assigned to receive either 0.75 µg of ELD once-a-day or 35 mg of ALN once-a-week for 24 weeks. The primary endpoint was the change in a postural balance index, adjusted composite equilibrium score (CES) of sensory organization test (SOT). The SOT equilibrium scores, leg muscle strength, and other physical functions were also evaluated. RESULTS: The Adjusted CES increased from baseline by 6.10% in the ELD group and 6.28% in the ALN group. There was no statistically significant difference between the two groups. The static postural balance at fixed platform were maintained in the ELD group, but declined in the ALN group. The dynamic postural balance at swaying platform and knee extension power increased from baseline in both groups. CONCLUSIONS: These results suggest that ELD and ALN treatments may each be beneficial to improve postural balance control in older patients with osteoporosis via different mechanisms of action.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Vitamin D supplementation as a potential cause of U-shaped associations between vitamin D levels and negative health outcomes: a decision tree analysis for risk of frailty.

BACKGROUND: A recent controversy in vitamin D research is a "U-shaped association", with elevated disease risks at both high and low 25-hydroxyvitamin D (25 (OH) D) levels. METHODS: This is a cross-sectional study of 238 male nursing home veterans in Hawaii. Classification and regression tree (CART) analysis identified groups based on 25 (OH) D and vitamin D supplementation for frailty risk. Characteristics were examined and compared across the groups using logistic regression and receiver operating characteristic (ROC) curve analyses. RESULTS: CART analysis identified three distinct groups: vitamin D supplement users (n = 86), non-users with low vitamin D (n = 55), and non-users with high vitamin D (n = 97). Supplement users were the most frail, but had high mean 25 (OH) D of 26.6 ng/mL, which was compatible with 27.1 ng/mL in non-users with high vitamin D, while mean 25 (OH) D of non-users with low vitamin D was 11.7 ng/mL. Supplement users and non-users with low vitamin D were significantly more likely to be frail (odds ratio (OR) = 9.90, 95% CI = 2.18-44.86, p = 0.003; OR = 4.28, 95% CI = 1.44-12.68, p = 0.009, respectively), compared with non-users with low vitamin D. ROC curve analysis showed the three groups significantly predicted frailty (area under the curve = 0.73), with sensitivity of 64.4% and specificity of 76.7%, while 25 (OH) D did not predict frailty. CONCLUSIONS: In these nursing home veterans, vitamin D supplement users were the most frail but with high 25 (OH) D. This can potentially be a cause of U-shaped associations between vitamin D levels and negative health outcomes.

The predicted lifetime costs and health consequences of calcium and vitamin D supplementation for fracture prevention-the impact of cardiovascular effects.

UNLABELLED: Some studies indicate that calcium supplementation increases cardiovascular risk. We assessed whether such effects could counterbalance the fracture benefits from supplementation. Accounting for cardiovascular outcomes, calcium may cause net harm and would not be cost-effective. Clinicians may do well considering cardiovascular effects when prescribing calcium supplementation. INTRODUCTION: Accounting for possible cardiovascular effect of calcium and vitamin D supplementation (CaD), the aims of this study were to assess whether CaD on balance would improve population health and to evaluate the cost-effectiveness of such supplementation. METHODS: We created a probabilistic Markov simulation model that was analysed at the individual patient level. We analysed 65-year-old Norwegian women with a 2.3 % 10-year risk of hip fracture and a 9.3 % risk of any major fracture according to the WHO fracture risk assessment tool (FRAX®). Consistent with a recent Cochrane review, we assumed that CaD reduces the risk of hip, vertebral, and wrist fractures by 16, 11, and 5 %, respectively. We included the increased risk of acute myocardial infarction (AMI) and stroke under a no-, medium-, and high-risk scenario. RESULTS: Assuming no cardiovascular effects, CaD supplementation produces improved health outcomes resulting in an incremental gain of 0.0223 quality-adjusted life years (QALYs) and increases costs by €322 compared with no treatment (cost-effectiveness ratio €14,453 per QALY gained). Assuming a Norwegian cost-effectiveness threshold of €60,000 per QALY, CaD is likely to be considered a cost-effective treatment alternative. In a scenario with a medium or high increased risk of cardiovascular events, CaD produces net health losses, respectively, -0.0572 and -0.0784 QALY at additional costs of €481 and €1033. CONCLUSIONS: We conclude that the magnitude of potential cardiovascular side effects is crucial for the effectiveness and cost-effectiveness of CaD supplementation in elderly women.

Vitamin D requirements of children: "all my life's a circle".

The importance of vitamin D for ensuring the health of children has long been understood. Over time, however, dietary recommendations for vitamin D intake have varied, with some eras seeing higher levels recommended and some lower. Remarkably, the current recommendations from the Institute of Medicine are not much different from those released with the first edition of the recommended dietary allowances in 1941. The present review examines the evolution of vitamin D recommendations over time and considers the differences and potential consequences related to the various recommendations in effect today. In considering strategies to evaluate the vitamin D status of children and efforts to assure its adequacy, individual caregivers and policy makers need to consider carefully the costs and potential risks of different screening strategies involving blood testing in children and of supplementation. More data on the long-term risks and benefits are needed before widespread screening or supplementation can be advocated.

Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand?

Epidemiological studies have reported associations between lower vitamin D levels and a great variety of diseases, prompting calls for widespread treatment of individuals with low vitamin D levels. Most of New Zealand's population have vitamin D levels for at least part of the year that are considered insufficient (25-hydroxyvitamin D <50-80 nmol/L). However, evidence for benefits of vitamin D supplementation in such populations is controversial and there is some evidence of harmful effects. Until adequately powered, randomised, controlled trials of vitamin D supplementation demonstrate safe improvements in health, clinicians should not focus on detecting/treating individuals with vitamin D insufficiency, instead treating those at high risk of vitamin D deficiency (25-hydroxyvitamin D <25 nmol/L), such as the frail elderly, and those with specific clinical indications. Treatment for such individuals does not require vitamin D measurements. Requests for vitamin D measurements in Auckland have nearly quadrupled in the past decade, from 8500 in the year 2000 to 32,800 in 2010, with substantial increases in cost. Vitamin D measurement is often inaccurate and imprecise, and the vast majority of tests performed currently do not reveal vitamin D deficiency. Therefore, a move away from routine vitamin D measurements seems sensible, though they are still indicated when investigating suspected metabolic bone disease or hypocalcaemia.

High-dose vitamin D supplements are not associated with linear growth in a large Finnish cohort.

High vitamin D intake in childhood has been suggested to have an adverse influence on linear growth. In Finland, in the mid-1960s the official recommendation for infant vitamin D supplementation was 2000 IU/d (50 µg/d). We investigated whether high-dose vitamin D supplementation in infancy was associated with subsequent growth in height. We used data from a prospective population-based birth cohort study including all children due to be born in the 2 northernmost provinces in Finland in 1966 (12,058 live-births, coverage 96%). Information on each participant's height was collected at birth and ages 1, 14, and 31 y, as were possible confounding factors (data for analyses available from 10,060 singletons). Information on the frequency and dose of vitamin D supplementation was collected in 1967 when participants were 1 y of age. A weak association was found between frequency of vitamin D supplementation with greater height at age 1 y (P = 0.005), which was explained by birth characteristics and maternal and social factors (adjusted P = 0.34). Neither frequency nor dose of vitamin D supplementation was associated with height at 14 or 31 y (P > 0.13). To conclude, contrary to proposed evidence suggesting that vitamin D has a negative influence on growth rate at a dosage of ~2000 IU/d, supplementation at this level in the Northern Finland Birth Cohort was not associated with reduced height at any age studied.

Benefit-risk assessment of vitamin D supplementation.

UNLABELLED: Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D. INTRODUCTION: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk. METHODS AND RESULTS: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk. CONCLUSION: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.

Risk assessment for vitamin D.

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 microg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.

Primary vitamin D deficiency in children.

In recent years, the prevalence of vitamin D (calciferol) deficiency has increased and rickets has re-emerged in the UK and other developed countries as a public health problem. Infants, toddlers and adolescents in 'at risk' ethnic minorities (e.g. Asian, African Caribbean and Middle Eastern) are particularly likely to be vitamin D-deficient or to have rickets. Also at particular risk are babies and toddlers who have been exclusively breast-fed during infancy without receiving vitamin supplements, or whose mothers did not have vitamin D supplements during pregnancy. Here we discuss the management of children with primary vitamin D deficiency (i.e. that due to nutrient deficiency).

Assessment of dietary vitamin D requirements during pregnancy and lactation.

Concerns about vitamin D have resurfaced in medical and scientific literature because the prevalence of vitamin D deficiency in the United States, particularly among darkly pigmented persons, has increased. The primary goals of this review were to discuss past and current literature and to reassess the dietary reference intake for vitamin D in adults, with particular focus on women during pregnancy and lactation. The appropriate dose of vitamin D during pregnancy and lactation is unknown, although it appears to be greater than the current dietary reference intake of 200-400 IU/d (5-10 microg/d). Doses of < or =10 000 IU vitamin D/d (250 microg/d) for up to 5 mo do not elevate circulating 25-hydroxyvitamin D to concentrations > 90 ng/mL, whereas doses < 1000 IU/d appear, in many cases, to be inadequate for maintaining normal circulating 25-hydroxyvitamin D concentrations of between 15 and 80 ng/mL. Vitamin D plays no etiologic role in cardiac valvular disease, such as that observed in Williams syndrome, and, as such, animal models involving vitamin D intoxication that show an effect on cardiac disease are flawed and offer no insight into normal human physiology. Higher doses of vitamin D are necessary for a large segment of Americans to achieve concentrations equivalent to those in persons who live and work in sun-rich environments. Further studies are necessary to determine optimal vitamin D intakes for pregnant and lactating women as a function of latitude and race.

Assessment of Hypervitaminosis D during the first trimester of pregnancy on the mouse embryo. Preliminary report.

The effect of hypervitaminosis were studied in pregnant mice during 0-3 and 4-7 days of gestation. After pregnancy was determined, mothers received 50 000 I.U. of vitamin D2 during the first gestational period. During the first half of the first trimester, the vitamin D treatment did not significantly influence maternal weight, fetal weight, implantation rate and survival of the embryo. The number of mothers with malformed fetuses significantly increased during critical treatment periods (from 4-7 days of pregnancy.