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Effects of vitamin D in the elderly population: current status and perspectives
© Bruyère et al.; licensee BioMed Central Ltd. 2014
Received: 6 May 2014
Accepted: 29 June 2014
Published: 28 September 2014
Besides its well-known effect on bone metabolism, recent researches suggest that vitamin D may also play a role in the muscular, immune, endocrine, and central nervous systems. Double-blind RCTs support vitamin D supplementation at a dose of 800 IU per day for the prevention of falls and fractures in the senior population. Ecological, case–control and cohort studies have suggested that high vitamin D levels were associated with a reduced risk of autoimmune diseases, type 2 diabetes, cardio-vascular diseases and cancer but large clinical trials are lacking today to provide solid evidence of a vitamin D benefit beyond bone health. At last, the optimal dose, route of administration, dosing interval and duration of vitamin D supplementation at a specific target dose beyond the prevention of vitamin D deficiency need to be further investigated.
The role of vitamin D in bone health has been known for over a century. More recent researches suggest that vitamin D may also play a role in the muscular, immune, endocrine, and central nervous systems. The objective of the current paper is to critically review observational and interventional studies on the potential effect of vitamin D on health outcomes among the elderly population. The vitamin D assays and the optimal vitamin D level are also discussed.
Vitamin D assay and thresholds of vitamin D status
If all experts now agree that 25-hydroxy-vitamin D (25(OH)D) is the biomarker of choice to evaluate patients’ vitamin D status, the level of 25(OH)D that would be considered “normal” is more debated. Indeed, as the level of 25(OH)D fluctuates according to seasons, the reference ranges observed in “healthy” populations should be different in summer vs. winter, which does not make sense. Accordingly, all experts agree that a threshold defining vitamin D deficiency should be determined in relation to clinical outcomes, i.e. a value below which a detriment for health could be expected. This threshold is different whether we consider the general population or diseased patients. For the first ones, the Institute of Medicine recommends a target of 20 ng/mL and proposes Reference Dietary Intakes (RDI) that should help 97.5% of the population to reach this level . These RDIs are of 400 IU from birth to 1 year old, 600 IU from 1 to 70 years old and 800 IU above 70 years. It should be noted, however, that other references intake values have been suggested based on other methodologies . Anyway, in western populations, with a light sunshine exposure, no UVB synthesis from late fall to early spring and a diet containing limited amounts of vitamin D, a basic supplementation of 400–600 IU per day should thus be necessary to achieve these goals, at least in winter. It should be noted that this supplementation could be performed without preliminary 25(OH)D determination as the 20 ng/mL threshold is only a recommendation (no harm will happen if the subject presents a value slightly lower or higher than 20 ng/mL) and the doses proposed are totally safe.
For patients, and particularly for patients presenting kidney, bone or phosphocalcic disorders, many experts consider however that this 20 ng/mL threshold is too low . They thus suggest a target of 30 ng/mL, according to different levels of proof, like the relation between parathormone (PTH) and vitamin D (even if the results from the studies show a substantial heterogeneity in this relationship), the prevalence of signs of mineralization defects below 30 ng/mL  or, most importantly, the levels reached by patients in treated group of randomized controlled trials showing a positive effect of vitamin D vs placebo (mainly studies on fracture or risk or fall prevention [5, 6]). In this context, there is some evidence that a benefit is expected if the patient’s 25(OH)D level is higher than the cut-off and a monitoring of 25(OH)D levels is thus mandatory. Recently, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommended that 50 nmol/L (i.e. 20 ng/mL) should be the minimal serum 25-(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health . However, ESCEO also states that in fragile elderly subjects who are at elevated risk for falls and fracture, a minimal serum 25-(OH)D level of 75 nmol/L (i.e. 30 ng/mL) should be reached for the greatest impact on fracture. The doses necessary to reach the target of 30 ng/mL are definitively higher than the ones necessary to obtain 20 ng/mL. They can reach 800–2000 IU per day or 24000–60000 IU per month, and require a control 3 months after initiation of the treatment, when a plateau is reached. According to the 25(OH)D levels reached, the doses can be tailored to maintain the patient in the 30–50 ng/mL range. This range is totally safe as it is naturally obtained in populations exposed during all year to high UV radiation, like the Maasaï, who present a mean 25(OH)D concentration of 46 ng/mL with extreme values ranging from 25 to 75 ng/mL . Compliance of the patient with the treatment is however problematic and yearly controls should be performed. Daily, weekly or monthly doses are equivalent in rising and maintaining 25(OH)D levels and patients should choose which form they prefer. Large, yearly doses, should however be abandoned as totally non physiologic, and even potentially harmful .
In the nineties and early twenties, most laboratories were using the DiaSorin RIA to assess 25(OH)D levels. The cut-offs of 20 and 30 ng/mL are notably derived from studies that were using this assay device. However, the increasing number of requests has led most of the clinical laboratories to switch to methods presenting a larger throughput, i.e. automated immunoassays or liquid chromatographs coupled with two mass spectrometers in tandem (LC-MS/MS). The determination of 25(OH)D concentration is however far from an easy task and several important problems, among which the very high lipophilic nature of the molecule and its strong association with its carriers, vitamin D binding protein (VDBP) and albumin have to be overcome to correctly assess the parameter . VDBP can be present at different concentrations depending on some physiological or pathological conditions, like race , pregnancy or chronic kidney disease, which could influence the kinetic of the liberation of the molecule [12, 13]. Vitamin D can be found as vitamin D2 or D3 and the assay should measure both 25(OH)D2 and 25(OH)D3 . Different other metabolites of vitamin D can be present in the serum of the patients at different levels, possibly interfering with either immunoassays or LC-MS/MS methods . Just like any other immunoassays, vitamin D assays are prone to heterophilic antibodies interference, leading to potential spurious results . Last but not least, the lack of standardization of the different assays remains a major problem. A worldwide standardization program (Vitamin D Standardization Program, VDSP), coordinated by the Centers for Disease Control and Prevention (CDC), the National Institute of Standards and Technology (NIST) and the University of Ghent, Belgium, is ongoing to improve the standardization and will certainly reduce the variation observed between methods and laboratories in healthy individuals. Nevertheless, different problems will remain in special populations, like pregnant women or hemodialyzed patients, for whom standardization seems to be less efficient [12, 13]. Moreover, neither 25(OH)D2 standardization nor 25(OH)D2 recovery will be solved by the VDSP. Finally, re-standardization will impact the traditional “20” or “30” ng/mL values that are used as clinical cut-offs to define vitamin D sufficiency. Indeed, as already mentioned, these cut-offs derive from studies that generally used the DiaSorin RIA for 25(OH)D measurements. Using these cut-offs with immunoassays or LC-MS/MS methods that are differently calibrated is thus hazardous. Re-standardization will reduce method-to-method variations, but will consequently also impact the cut-off values, that will need to be updated according to the new standard.
Effects of vitamin D on falls
In a meta-analysis of 8 double-blind RCTs including a total of 2426 individuals aged 65 and older , anti-fall benefits of vitamin D supplementation were observed from a dose of 700 IU per day onwards. In a re-analysis requested by the Institute of Medicine , when treatment was the only predictor (regardless of dose level), there was a significant reduction in the odds of falling: OR = 0.73 [0.62, 0.87]; p = .0004. When the model was expanded to capture the impact of both high dose and low dose treatments, high dose vitamin D treatments (700 to 1000 IU vitamin D per day) reduced the odds of falling (OR = 0.66 [0.53, 0.82]; p = .0002), while low dose vitamin D treatments did not (OR = 1.14 [0.69, 1.87]; p = .61). In the Report on Vitamin D (FCN Report (2012), there was a 38% reduction in the risk of falling with a treatment duration of 2 to 5 months and a sustained significant effect of 17% fall reduction with a treatment duration of 12 to 36 months with vitamin D supplements/doses of 700 to 1000 IU. Thus, benefits of vitamin D supplementation of 700 to 1000 IU per day on fall prevention are rapid and sustained and concern all subgroups of the senior population .
Effects of vitamin D on bone
Results from double-blind randomized controlled trials
Vitamin D is essential for bone growth [18, 19] and bone health preservation . Higher 25(OH)D levels are associated with higher bone density in younger and older adults . Also, in various double-blind RCTs, vitamin D supplementation increased bone density and reduced bone loss [22, 23]. In a meta-analysis summarizing the evidence of 12 double-blind RCTs involving 42279 individuals aged 65 and older, oral vitamin D supplementation reduced the risk of hip fracture by 18% and the risk of any non-vertebral fracture by 20% . However, similarly to fall prevention, the benefit on fracture prevention depends on the dose of vitamin D. Fracture prevention required a received dose (treatment dose*adherence) of more than 482 IU vitamin D per day. The primary use of received dose (dose*adherence) as opposed to treatment dose from double-blind RCTs allowed for the assessment of anti-fracture efficacy by a dose that accounts for the low adherence in several recent large trials [24, 25]. Any lower received dose than 482 IU per day did not reduce fracture risk at either any non-vertebral site or the hip. Similarly to the data on fall prevention with vitamin D, at the highest received dose of vitamin D (>482 IU per day) the prevention of non-vertebral fractures was present in all subgroups of the older population independently of age and type of dwelling . Notably, there was a suggestion that vitamin D3 was superior to vitamin D2 for both fall and fracture prevention [5, 6].
A participant level meta-analysis from 11 double-blind RCTs (31022 individuals with mean age 76 years, 91% women sustaining 1111 incident hip and 3770 non-vertebral fractures) assessed the effect of actual dose of vitamin D on fracture reduction. Actual dose considered adherence to treatment and additional vitamin D intake outside the study medication. In this pooled analysis, fracture reduction was only present at the highest actual intake of 800 IU of vitamin D per day (range: 792 to 2000 IU/d) with a 30% reduction at the hip and 14% reduction at any non-vertebral site independently of vitamin D treatment, age group, gender, type of dwelling and study . This study further suggested that the typical intent-to-treat results for vitamin D, which was replicated by the authors with a non-significant 10% reduction at the hip and 7% reduction at any non-vertebral site, may underestimate the benefit of vitamin D supplementation and explain the conflicting results of other meta-analyses .
Results from meta-analyses on fracture prevention that also included open-design trials
A review and meta-analysis commissioned by the US Department of Health and Human Services (HHS) has addressed the effect of vitamin D supplementation on all fractures in postmenopausal women and men aged 50 and older . The pooled results for all fractures included 10 double-blinded and 3 open design trials (n = 58712). However, it did not support a significant reduction of fractures with vitamin D (pooled odds ratio = 0.90; 95% CI 0.81-1.02). The report suggested that the benefit of vitamin D may depend on additional calcium and may be primarily seen in institutionalized individuals, which is consistent with the meta-analysis of Boonen et al. .
The DIPART group conducted a patient-based meta-analysis including 7 large trials on vitamin D with 68500 individuals aged 47 and older  : two open design trials [30, 31], one trial with intra-muscular vitamin D, and 4 of the 10 double-blind RCTs included in the 2009 meta-analysis described above (one RCT using intermittent vitamin D2 doses without calcium , one RCT with 400 IU of vitamin D3 without calcium , one trial with 800 IU of vitamin D3 per day with and without calcium and less than 50% adherence , and one trial with 400 IU of vitamin D with calcium ). On the basis of the inclusion criteria, a reduced overall risk of fracture (hazard ratio = 0.92; 95% CI 0.86 to 0.99) and a non-significant reduction of hip fractures (hazard ratio = 0.84; 95% CI 0.70 to 1.01) was found for trials that used vitamin D plus calcium. Vitamin D supplementation alone, irrespective of dose, did not reduce fracture risk. It was concluded that vitamin D, even in a dose of 400 IU of vitamin D per day reduces the risk of fracture if combined with calcium. Notably, this regimen was tested in 36282 postmenopausal women in the Women’s Health Initiative Trial over a treatment period of 7 years and did not reduce the risk of fracture .
A most recent 2014 trial-level meta-analysis (76497 participants) was based on a mix of trials with blinded and open designs, follow-up periods that were as short as 1 month, administered doses and compliance that ranged widely, and endpoints that ranged from primary to secondary along with un-pre-specified, and consequently were adjudicated and non-adjudicated. However, despite the great variety and mixed quality of trials, the authors documented a significant 8% reduction for total fractures and a significant 16% reduction for hip fractures for vitamin D plus calcium supplementation .
Discussion on the meta-analyses that also included open-design trials
In all 3 meta-analyses reviewed above, dose heterogeneity may have been missed due to the inclusion of open design trials plus a dose evaluation that did not incorporate adherence to treatment. A dose–response relationship between vitamin D supplementation and fracture reduction as documented for the two 2009 meta-analyses of double-blind RCTs [5, 6], is supported by epidemiologic data showing a significant positive trend between serum 25(OH)D concentrations and hip bone density  and lower extremity strength [35, 36]. Factors that may obscure the benefit of vitamin D supplementation are low adherence to treatment , too low doses of vitamin D, or the use of the less potent vitamin D2 [37, 38]. Furthermore, open design trials  may bias results towards the null because vitamin D is available over the counter.
Conclusion on falls and fractures
Based on evidence from RCTs, oral vitamin D supplementation reduces both falls and non-vertebral fractures, including those at the hip. However, these benefits are dose-dependent and a dose of 700–1000 IU of vitamin D per day is required to assure both fall and fracture prevention in older adults.
Effects of vitamin D on muscle
Proximal muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency . Muscle manifestations such as proximal muscle weakness, diffuse muscle pain and gait impairments are well-known clinical symptoms of vitamin D deficiency . The activation of vitamin D receptors (VDRs), which is expressed in human muscle tissue [41, 42] appears to stimulate protein synthesis in muscle . Smaller and variable muscle fibres and persistence of immature muscle gene expression during adult life are found in mice lacking VDR . These abnormalities persist after correction of systemic calcium metabolism by a rescue diet, whereas the bone phenotype is normalized after correction of calcium and phosphate plasma concentrations .
Most observational studies show a positive association between higher 25(OH)D status and better lower extremity function in older adults, a lower risk of functional decline [35, 46], a lower risk of future falls and a lower risk of nursing care admission , including two population-based studies from the US  and Europe .
Consistently, in several trials of older individuals at risk for vitamin D deficiency, vitamin D supplementation improved strength, function, and balance [48–50]. Most importantly, these benefits translated in a reduction in falls in some of the same trials [48–50]. In three recent double-blind RCTs supplementation with 800 IU vitamin D3 resulted in a 4-11% gain in lower extremity strength or function [48, 50], and an up to 28% improvement in body sway [48, 49] in older adults aged 65 and older within 2 to 12 months of treatment. Extending to trials among individuals with a lower risk of vitamin D deficiency and including open design trials, a recent meta-analysis by Stockton identified 17 RCTs that tested any form of vitamin D treatment and documented a muscle strength related endpoint. The authors suggested that based on their pooled findings, vitamin D may not improve grip strength, but a benefit of vitamin D treatment on lower extremity strength could not be excluded (p = 0.07) among individuals with 25(OH)D starting levels of > 25 nmol/l and the authors report a significant benefit among two studies with participants that started with 25(OH)D levels < 25 nmol/l . In a more recent meta-analysis of Muir and Montero-Odasso, 13 randomized controlled trials were identified in seniors aged 60 years and older. In the pooled analysis, vitamin D supplementation had a significant benefit on postural sway and lower extremity mobility measured with the timed up and go and lower extremity strength .
Mechanistically, it has been suggested that 1,25-dihydroxyvitamin D binds to the nuclear VDR in muscle resulting in de novo protein synthesis [53, 54]. At a clinical level, this is supported by findings of three small trials in older adults, which documented an increase in type II muscle fibres after treatment with 1-alpha-calcidiol  or vitamin D2  or vitamin D3 .
Consequently, evidence supports the use of vitamin D supplementation to improve muscle strength and function but additional studies may be needed to define the optimal treatment dose.
Other potential effects of vitamin D in the elderly population
Many tissues without any obvious relationship with the calcium/phosphorus and/or bone metabolism are able to express the VDR, 1-alpha-hydroxylase, and 24-hydroxylase molecules. 25(OH)D enters these tissues and is locally hydroxylated into calcitriol which binds to the VDRs present in these cells. This “peripheral” production of calcitriol is not regulated by calciotropic hormones (PTH, FGF23, …), but seems dependent on the 25(OH)D concentration in the extra-cellular fluid of these tissues. This is the basis for the “non-classical” genomic effects of vitamin D that could be considered as “intracrine” by contrast with the classical endocrine effects of calcitriol. We also know that plasma calcitriol can exert rapid non genomic effects in some tissues such as muscle fibres or pancreatic beta-cells where it binds to membrane proteins resembling the VDR .
In addition to its effects on calcium/phosphorus metabolism, non vertebral fractures and falls, vitamin D may exert various other effects as suggested by numerous observational studies that reported positive associations between vitamin D deficiency (i.e. low circulating levels of 25(OH)D) and an increased risk for many diseases that remained significant after adjustment for confounders. Among these potential non classical effects, some may be highly relevant to the elderly.
Globally, many experimental studies support the suppression of acquired immunity and the stimulation of innate immunity by vitamin D. VDRs and 1-alpha hydroxylase are present in T and B lymphocytes, macrophages and antigen-presenting cells. Calcitriol reduces the proliferation of the T-lymphocytes, especially T-helper 1 (Th1) and Th17 lymphocytes and the production of certain cytokines with inflammatory properties. On the other hand calcitriol stimulates the production of other cytokines with anti-inflammatory actions such as IL10 and favours Th2 and regulatory T lymphocytes phenotypes. This modulation of acquired immunity is believed to be beneficial in a number of auto-immune diseases as suggested by studies showing that vitamin D deficiency is associated with higher incidence and poorer outcomes of some auto-immune diseases , and to have global anti-inflammatory effects  that could be of help in many diseases as an adjunct to usual therapy . As regards innate immunity, it is now known that macrophages or monocytes exposed to an infectious agent such as bacillus tuberculosis overexpress Toll-like receptors, VDRs, and 1-alpha hydroxylase. Provided that the 25(OH)D concentration in the cell’s extracellular liquid is sufficient, they produce 1,25(OH)2D which binds to the VDRs inducing the production of antimicrobial peptides such as cathelicidin which contributes to the destruction of the infectious agent . This mechanism may explain partly the relationship between the frequency of some infectious diseases and low 25(OH)D concentrations found in epidemiological studies .
Vitamin D deficiency has not only been found to be associated with an increased risk of major cardio-vascular events but also with cardio-vascular mortality in several studies . Potential mechanisms are complex and involve both direct effects of vitamin D on vascular endothelial cells, and indirect effects through the control of the renin-angiotensin system and thus blood pressure, on the PTH secretion, insulin secretion and sensitivity, and inflammation .
In non-dialyzed patients with chronic kidney disease, vitamin D deficiency is associated with albuminuria and a more rapid deterioration of renal function .
Finally, vitamin D sufficiency is associated with a delayed mortality not only in prospective observational studies , but also in interventional studies, especially when associated with calcium .
Parameters and conditions that should be controlled for an optimal evaluation of the effects of vitamin D in future RCTs
Conditions allowing an optimisation of the statistical power of the study (common conditions for trials of drugs and nutrients)
Sample size (number of participants) and trial duration must be appropriately calculated according to the frequency of the studied event in the recruited population. These points depend on the basal clinical status of the patients (larger sample and/or longer duration if the studied disease is not very active in the recruited patients)
Adherence/observance must be optimized (for example, new technologies such as SMS that are sent the day just before the treatment must be taken, in case of intermittent dosage, allow an easy reminding for the patients)
Conditions specific to a vitamin D trial
Choose to administrate vitamin D3 instead of D2, specially in case of intermittent dosage
Ensure that dietary calcium intakes of the participants are sufficient
Treat with daily doses or, in case of intermittent dosage, choose doses that are not too high (<or = 100000 IU) and not too spaced out (ideally < or = 1 month)
Choosing the dose will depend on the disease to be studied (search in the literature) but must be above 800 IU/day (often more)
Possible vitamin D supplements that were taken by the patients before the study must be stopped (paradoxically, it was found in some studies with a poor observance that some patients in the placebo group received in fact more vitamin D during the trial than some patients in the vitamin D group)
It will be important to recruit patients with low 25OHD serum levels (or at least much lower than the 25OHD levels that are targeted in the study) so that a frank increase of the 25OHD concentration may be observed on the one hand, and so that the placebo group is really insufficient/deficient on the other hand.
Three elements deserve further discussion.
In 2010, a large double-blind RCT by Sanders et al., included 2256 community-dwelling women aged 70 years and older, to test the benefit of 500000 IU of vitamin D3 given orally once a year, on fall and fracture prevention . In those women, mean age 76, considered to be at risk of fracture, 500000 IU of vitamin D once a year did not reduce, but instead increased the risk of falls by 15% and the risk of fractures by 26% compared to placebo, with the greatest increase in falls occurring during the first 3 months after dosing. These findings are consistent with another trial that tested 300000 IU of vitamin D2 as an intra-muscular injection once a year . The temporal pattern of events may suggest that the high dose of vitamin D may have induced a “protective” reaction resulting in an acute decrease in 1,25-dihydroxyvitamin D . Alternatively, the undocumented potential effect of vitamin D on muscle strength  and overall health (i.e. less infections and less hospital admissions ) in the Sanders trial, may have been an improvement in mobility which has ironically, led to increase opportunities to fall and fracture. As a result of the Sanders trial and given that the half-life of vitamin D is 3 to 6 weeks, a daily, weekly, or monthly dosing interval may be more advantageous and safer [84, 85].
How to promote optimal vitamin D status
Studies suggest that supplementation of 700 to 1000 IU of vitamin D per day may bring the concentration in 25(OH)D of 50% of younger and older adults up to 75–100 nmol/L [86–88] Individuals with a lower starting level may need a higher dose of vitamin D to achieve desirable levels, while relatively lower doses may be sufficient in individuals who start at higher baseline levels. Due to seasonal fluctuations of 25(OH)D levels , some individuals may be in the desirable range during summer months, but their levels will not sustain during the winter months, even in sunny latitudes [90, 91]. Furthermore, several studies suggest that many older persons will not achieve optimal serum 25(OH)D levels during summer months suggesting that, among this population, vitamin D supplementation should be independent of season [91–93]. Even among younger persons, the use of sunscreen or sun-protective clothing may prevent a significant production of 25(OH)D . Most vulnerable to low vitamin D levels are older individuals [91, 94], individuals living in northern latitudes with prolonged winters [89, 95], obese individuals , and individuals of all ages with dark skin pigmentation living in northern latitudes [21, 97, 98]. Naturally high 25(OH)D levels observed in healthy outdoor workers are 135 nmol/L  in farmers and 163 nmol/L  in lifeguards. As a first sign of toxicity, only serum 25(OH)D levels of above 220 nmol/L have been associated with hypercalcemia [101, 102].
Reverse causality and confounding factors in observational studies
When analysing results of observational studies, it is important to consider potential reverse causality or residual confounding factors. For example, lifestyle factors, not always adequately recorded in observational studies, could influence circulating levels of vitamin D and, as such, could confound the association between 25(OH)D levels and incidence of diseases. On the other hand, 25(OH)D levels might not be responsible for the changes in outcomes of the diseases but disability in itself might influence the vitamin D status of the individual. In other words, serum 25(OH)D levels could just be a biomarker of severity of the diseases. In principle, these issues with reverse causality and confounding factors could be ruled out with RCTs.
Results from ecological, case–control and cohort studies have shown that high vitamin D levels were associated with a reduced risk of bone fracture, falls, autoimmune diseases, type 2 diabetes, cardio-vascular diseases and cancer. Since the prevalence of vitamin D inadequacy is high, supplementation with vitamin D has then been recommended, especially in high risk and elderly population. Notably, evidence from double-blind RCTs support vitamin D supplementation at a dose of 800 IU per day for the prevention of falls and fractures in the senior population. Further, several studies reviewed in this paper suggest a potential effect of vitamin D in human health but large clinical trials are lacking today to provide solid evidence of a vitamin D benefit beyond bone health at all ages and fall prevention in the senior population. Additionally, the optimal dose, route of administration, dosing interval and duration of vitamin D supplementation at a specific target dose beyond the prevention of vitamin D deficiency needs to be further investigated. It is possible that the optimal level of vitamin D should be individualized, based on clinical and demographic characteristics of the subject and outcome.
- Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011, 96 (1): 53-58. Epub 2010/12/02. doi:10.1210/jc.2010-2704. PubMed PMID: 21118827; PubMed Central PMCID: PMC3046611PubMedView ArticleGoogle Scholar
- Cashman KD, Fitzgerald AP, Kiely M, Seamans KM: A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations. Br J Nutr. 2011, 106 (11): 1638-1648. doi:10.1017/S0007114511005058. PubMed PMID: 22000709. Epub 2011/10/18PubMedView ArticleGoogle Scholar
- Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011, 96 (7): 1911-1930. Epub 2011/06/08. doi:10.1210/jc.2011-0385. PubMed PMID: 21646368PubMedView ArticleGoogle Scholar
- Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T, Püschel K, Amling M: Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010, 25 (2): 305-312. Epub 2009/07/15. doi:10.1359/jbmr.090728. PubMed PMID: 19594303PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP, Henschkowski J: Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009, 169 (6): 551-561. Epub 2009/03/25. doi:10.1001/archinternmed.2008.600. PubMed PMID: 19307517PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J: Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009, 339: b3692-Epub 2009/10/03. doi:10.1136/bmj.b3692. PubMed PMID: 19797342; PubMed Central PMCID: PMC2755728.PubMedPubMed CentralView ArticleGoogle Scholar
- Rizzoli R, Boonen S, Brandi ML, Bruyère O, Cooper C, Kanis JA, Kaufman JM, Ringe JD, Weryha G, Reginster JY: Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin. 2013, 29 (4): 305-313. Epub 2013/01/17. doi:10.1185/03007995.2013.766162. PubMed PMID: 23320612PubMedView ArticleGoogle Scholar
- Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA: Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012, 108 (9): 1557-1561. doi:10.1017/S0007114511007161. PubMed PMID: 22264449. Epub 2012/01/24PubMedView ArticleGoogle Scholar
- Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC: Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010, 303 (18): 1815-1822. doi:10.1001/jama.2010.594. PubMed PMID: 20460620. Epub 2010/05/13PubMedView ArticleGoogle Scholar
- Wallace AM, Gibson S, de la Hunty A, Lamberg-Allardt C, Ashwell M: Measurement of 25-hydroxyvitamin D in the clinical laboratory: current procedures, performance characteristics and limitations. Steroids. 2010, 75 (7): 477-488. doi:10.1016/j.steroids.2010.02.012. PubMed PMID: 20188118. Epub 2010/03/02PubMedView ArticleGoogle Scholar
- Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, Powe NR, Thadhani R: Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013, 369 (21): 1991-2000. Epub 2013/11/22. doi:10.1056/NEJMoa1306357. PubMed PMID: 24256378PubMedPubMed CentralView ArticleGoogle Scholar
- Heijboer AC, Blankenstein MA, Kema IP, Buijs MM: Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein concentration. Clin Chem. 2012, 58 (3): 543-548. doi:10.1373/clinchem.2011.176545. PubMed PMID: 22247500. Epub 2012/01/17PubMedView ArticleGoogle Scholar
- Depreter B, Heijboer AC, Langlois MR: Accuracy of three automated 25-hydroxyvitamin D assays in hemodialysis patients. Clin Chim Acta. 2013, 415: 255-260. Epub 2012/11/20. doi:10.1016/j.cca.2012.10.056. PubMed PMID: 23159781PubMedView ArticleGoogle Scholar
- Cavalier E, Wallace AM, Carlisi A, Chapelle JP, Delanaye P, Souberbielle JC: Cross-reactivity of 25-hydroxy vitamin D2 from different commercial immunoassays for 25-hydroxy vitamin D: an evaluation without spiked samples. Clin Chem Lab Med. 2011, 49 (3): 555-558. doi:10.1515/CCLM.2011.072. PubMed PMID: 21288179. Epub 2011/02/04PubMedView ArticleGoogle Scholar
- Kobold U: Approaches to measurement of vitamin D concentrations - mass spectrometry. Scand J Clin Lab Invest Suppl. 2012, 243: 54-59. doi:10.3109/00365513.2012.681956. PubMed PMID: 22536763. Epub 2012/05/02PubMedGoogle Scholar
- Cavalier E, Carlisi A, Bekaert AC, Rousselle O, Chapelle JP: Human anti-animal interference in DiaSorin Liaison total 25(OH)-vitamin D assay: towards the end of a strange story?. Clin Chim Acta. 2012, 413 (3–4): 527-528. Epub 2011/11/30. doi:10.1016/j.cca.2011.11.014. PubMed PMID: 22122994PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Willett W, Orav JE, Kiel DP, Dawson-Hughes B: Fall prevention with vitamin D: clarifications needed. BMJ. 2011, 342: d2608-View ArticleGoogle Scholar
- Specker BL, Ho ML, Oestreich A, Yin TA, Shui QM, Chen XC, Tsang RC: Prospective study of vitamin D supplementation and rickets in China. J Pediatr. 1992, 120 (5): 733-739. PubMed PMID: 1578308. Epub 1992/05/01PubMedView ArticleGoogle Scholar
- Aksnes L, Aarskog D: Plasma concentrations of vitamin D metabolites in puberty: effect of sexual maturation and implications for growth. J Clin Endocrinol Metab. 1982, 55 (1): 94-101. doi:10.1210/jcem-55-1-94. PubMed PMID: 6978890. Epub 1982/07/01PubMedView ArticleGoogle Scholar
- Smith R, Dent CE: Vitamin D requirements in adults. Clinical and metabolic studies on seven patients with nutritional osteomalacia. Bibliotheca nutritio et dieta. 1969, 13: 44-45. PubMed PMID: 5344713. Epub 1969/01/01PubMedGoogle Scholar
- Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B: Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004, 116 (9): 634-639. doi:10.1016/j.amjmed.2003.12.029. PubMed PMID: 15093761. Epub 2004/04/20PubMedView ArticleGoogle Scholar
- Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, Falconer G: Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med. 1991, 115 (7): 505-512. PubMed PMID: 1883119. Epub 1991/10/01PubMedView ArticleGoogle Scholar
- Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P: Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab. 1995, 80 (4): 1052-1058. doi:10.1210/jcem.80.4.7714065. PubMed PMID: 7714065. Epub 1995/04/01PubMedGoogle Scholar
- Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, et al: Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006, 354 (7): 669-683. PubMed PMID: 16481635PubMedView ArticleGoogle Scholar
- Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, Anderson FH, Cooper C, Francis RM, Donaldson C, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA, RECORD Trial Group: Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005, 365 (9471): 1621-1628. Epub 2005/05/12. doi:10.1016/S0140-6736(05)63013-9. PubMed PMIDPubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, Meyer HE, Pfeifer M, Sanders KM, Stähelin HB, Theiler R, Dawson-Hughes B: A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012, 367 (1): 40-49. Epub 2012/07/06. doi:10.1056/NEJMoa1109617. PubMed PMID: 22762317PubMedView ArticleGoogle Scholar
- Cranny A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, Atkinson S, Ward L, Moher D, Hanley D, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V: Effectiveness and safety of vitamin D in relation to bone health. 2007, http://archive.ahrq.gov/downloads/pub/evidence/pdf/vitamind/vitad.pdf. 2007Google Scholar
- Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P: Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab. 2007, 92 (4): 1415-1423. doi:10.1210/jc.2006-1404. PubMed PMID: 17264183. Epub 2007/02/01PubMedView ArticleGoogle Scholar
- Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010, 340: b5463-Epub 2010/01/14. doi:10.1136/bmj.b5463. PubMed PMID: 20068257; PubMed Central PMCID: PMC2806633Google Scholar
- Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, Baverstock M, Birks Y, Dumville J, Francis R, Iglesias C, Puffer S, Sutcliffe A, Watt I, Torgerson DJ: Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ. 2005, 330 (7498): 1003-Epub 2005/04/30. doi:10.1136/bmj.330.7498.1003. PubMed PMID: 15860827; PubMed Central PMCID: PMC557150PubMedPubMed CentralView ArticleGoogle Scholar
- Larsen ER, Mosekilde L, Foldspang A: Vitamin D and calcium supplementation prevents severe falls in elderly community-dwelling women: a pragmatic population-based 3-year intervention study. Aging Clin Exp Res. 2005, 17 (2): 125-132. PubMed PMID: 15977461. Epub 2005/06/28PubMedView ArticleGoogle Scholar
- Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, Evans R, Wareham K, Stone MD: Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int. 2007, 18 (6): 811-818. Epub 2007/05/03. doi:10.1007/s00198-006-0309-5. PubMed PMID: 17473911PubMedView ArticleGoogle Scholar
- Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI: Can vitamin D supplementation reduce the risk of fracture in the elderly? a randomized controlled trial. J Bone Miner Res. 2002, 17 (4): 709-715. doi:10.1359/jbmr.2002.17.4.709. PubMed PMID: 11918228. Epub 2002/03/29PubMedView ArticleGoogle Scholar
- Bolland MJ, Grey A, Gamble GD, Reid IR: The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diab Endocrinol. 2014, 2 (4): 307-320. doi:10.1016/S2213-8587(13)70212-2. Epub 2014 Jan 24View ArticleGoogle Scholar
- Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Deeg DJ, Smit J, Knol DL, Lips P: Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007, 92 (6): 2058-2065. PubMed PMID: 17341569PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, Dawson-Hughes B: Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. Am J Clin Nutr. 2004, 80 (3): 752-758. PubMed PMID: 15321818. Epub 2004/08/24PubMedGoogle Scholar
- Armas LA, Hollis BW, Heaney RP: Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004, 89 (11): 5387-5391. doi:10.1210/jc.2004-0360. PubMed PMID: 15531486. Epub 2004/11/09PubMedView ArticleGoogle Scholar
- Houghton LA, Vieth R: The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006, 84 (4): 694-697. PubMed PMID: 17023693. Epub 2006/10/07PubMedGoogle Scholar
- Al-Shoha A, Qiu S, Palnitkar S, Rao DS: Osteomalacia with bone marrow fibrosis due to severe vitamin D deficiency after a gastrointestinal bypass operation for severe obesity. Endocr Pract. 2009, 15 (6): 528-533. doi:10.4158/EP09050.ORR. PubMed PMID: 19491072. Epub 2009/06/06PubMedView ArticleGoogle Scholar
- Schott GD, Wills MR: Muscle weakness in osteomalacia. Lancet. 1976, 1 (7960): 626-629. PubMed PMID: 55903. Epub 1976/03/20PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Borchers M, Gudat F, Durmuller U, Stahelin HB, Dick W: Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res. 2004, 19 (2): 265-269. doi:10.1359/jbmr.2004.19.2.265. PubMed PMID: 14969396. Epub 2004/02/19PubMedView ArticleGoogle Scholar
- Ceglia L, da Silva Morais M, Park LK, Morris E, Harris SS, Bischoff-Ferrari HA, Fielding RA, Dawson-Hughes B: Multi-step immunofluorescent analysis of vitamin D receptor loci and myosin heavy chain isoforms in human skeletal muscle. J Mol Histol. 2010, 41 (2–3): 137-142. Epub 2010/06/16. doi:10.1007/s10735-010-9270-x. PubMed PMID: 20549314; PubMed Central PMCID: PMC2958104PubMedPubMed CentralView ArticleGoogle Scholar
- Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE: The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013, 34 (1): 33-83. doi:10.1210/er.2012-1012. Epub 2012 Nov 20PubMedView ArticleGoogle Scholar
- Bouillon R, Bischoff-Ferrari H, Willett W: Vitamin D and health: perspectives from mice and man. J Bone Miner Res. 2008, 23 (7): 974-979. doi:10.1359/jbmr.080420. PubMed PMID: 18442312. Epub 2008/04/30PubMedView ArticleGoogle Scholar
- Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T, Kato S, Matsumoto T: Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology. 2003, 144 (12): 5138-5144. doi:10.1210/en.2003-0502. PubMed PMID: 12959989. Epub 2003/09/10PubMedView ArticleGoogle Scholar
- LeBoff MS, Hawkes WG, Glowacki J, Yu-Yahiro J, Hurwitz S, Magaziner J: Vitamin D-deficiency and post-fracture changes in lower extremity function and falls in women with hip fractures. Osteoporos Int. 2008, 19 (9): 1283-1290. Epub 2008/04/01. doi:10.1007/s00198-008-0582-6 [doi]. PubMed PMID: 18373057PubMedPubMed CentralView ArticleGoogle Scholar
- Visser M, Deeg DJ, Puts MT, Seidell JC, Lips P: Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission. Am J Clin Nutr. 2006, 84 (3): 616-622. quiz 71–2. Epub 2006/09/09PubMedGoogle Scholar
- Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H: Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2008, 16: 16-Google Scholar
- Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C: Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000, 15 (6): 1113-1118. Epub 2000/06/07. doi:10.1359/jbmr.2000.15.6.1113 [doi]. PubMed PMID: 10841179PubMedView ArticleGoogle Scholar
- Bischoff HA, Stahelin HB, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew RA, Conzelmann M: Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003, 18 (2): 343-351. Epub 2003/02/06. doi:10.1359/jbmr.2003.18.2.343 [doi]. PubMed PMID: 12568412PubMedView ArticleGoogle Scholar
- Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL: Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int. 2011, 22 (3): 859-871. doi:10.1007/s00198-010-1407-y. PubMed PMID: 20924748. Epub 2010/10/07PubMedGoogle Scholar
- Muir SW, Montero-Odasso M: Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc. 2011, 59 (12): 2291-2300. doi:10.1111/j.1532-5415.2011.03733.x. PubMed PMID: 22188076. Epub 2011/12/23PubMedView ArticleGoogle Scholar
- Sorensen OH, Lund B, Saltin B, Andersen RB, Hjorth L, Melsen F, Mosekilde L: Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Colch). 1979, 56 (2): 157-161.View ArticleGoogle Scholar
- Freedman LP: Transcriptional targets of the vitamin D3 receptor-mediating cell cycle arrest and differentiation. J Nutr. 1999, 129 (2S Suppl): 581S-586S. PubMed PMID: 10064337. Epub 1999/03/04PubMedGoogle Scholar
- Sato Y, Iwamoto J, Kanoko T, Satoh K: Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005, 20 (3): 187-192. Epub 2005/08/10. doi:10.1159/000087203 [doi]. PubMed PMID: 16088114PubMedView ArticleGoogle Scholar
- Ceglia L, Niramitmahapanya S, da Silva Morais M, Rivas DA, Harris SS, Bischoff-Ferrari H, Fielding RA, Dawson-Hughes B: A randomized study on the effect of vitamin D3 supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab. 2013, 98 (12): E1927-E1935. Epub 2013/10/11. doi:10.1210/jc.2013-2820. PubMed PMID: 24108316; PubMed Central PMCID: PMC3849671PubMedPubMed CentralView ArticleGoogle Scholar
- Nemere I, Schwartz Z, Pedrozo H, Sylvia VL, Dean DD, Boyan BD: Identification of a membrane receptor for 1,25-dihydroxyvitamin D3 which mediates rapid activation of protein kinase C. J Bone Miner Res. 1998, 13 (9): 1353-1359. doi:10.1359/jbmr.1922.214.171.1243. PubMed PMID: 9738506. Epub 1998/09/17PubMedView ArticleGoogle Scholar
- Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H: Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. J Bone Miner Res. 2011, 29 (28): 3775-3782. doi:10.1200/JCO.2011.35.7566. PubMed PMID: 21876081. Epub 2011/08/31Google Scholar
- Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, Newmark H, Holick MF, Garland FC: Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007, 103 (3–5): 708-711. Epub 2007/03/21. doi:10.1016/j.jsbmb.2006.12.007. PubMed PMID: 17368188PubMedView ArticleGoogle Scholar
- Arnson Y, Amital H, Shoenfeld Y: Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007, 66 (9): 1137-1142. doi:10.1136/ard.2007.069831. PubMed PMID: 17557889. PubMed Central PMCID: PMC1955167. Epub 2007/06/15PubMedPubMed CentralView ArticleGoogle Scholar
- Zanetti M, Harris SS, Dawson-Hughes B: Ability of vitamin D to reduce inflammation in adults without acute illness. Nutr Rev. 2014, 72 (2): 95-98. doi:10.1111/nure.12095. PubMed PMID: 24330160. Epub 2013/12/18PubMedView ArticleGoogle Scholar
- Soilu-Hanninen M, Aivo J, Lindstrom BM, Elovaara I, Sumelahti ML, Farkkila M, Tienari P, Atula S, Sarasoja T, Herrala L, Keskinarkaus I, Kruger J, Kallio T, Rocca MA, Filippi M: A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012, 83 (5): 565-571. Epub 2012/03/01. doi:10.1136/jnnp-2011-301876. PubMed PMID: 22362918PubMedView ArticleGoogle Scholar
- Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006, 311 (5768): 1770-1773. Epub 2006/02/25. doi:10.1126/science.1123933. PubMed PMID: 16497887PubMedView ArticleGoogle Scholar
- Jolliffe DA, Griffiths CJ, Martineau AR: Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol. 2013, 136: 321-329. doi:10.1016/j.jsbmb.2012.11.017. PubMed PMID: 23220552. Epub 2012/12/12PubMedView ArticleGoogle Scholar
- Leu M, Giovannucci E: Vitamin D: epidemiology of cardiovascular risks and events. Best Pract Res Clin Endocrinol Metab. 2011, 25 (4): 633-646. doi:10.1016/j.beem.2011.04.001. PubMed PMID: 21872804. Epub 2011/08/30PubMedView ArticleGoogle Scholar
- Pilz S, Tomaschitz A, Ritz E, Pieber TR: Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol. 2009, 6 (10): 621-630. doi:10.1038/nrcardio.2009.135. PubMed PMID: 19687790. Epub 2009/08/19PubMedView ArticleGoogle Scholar
- de Boer IH, Katz R, Chonchol M, Ix JH, Sarnak MJ, Shlipak MG, Siscovick DS, Kestenbaum B: Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. Clin J Am Soc Nephrol. 2011, 6 (9): 2141-2149. Epub 2011/08/13. doi:10.2215/CJN.02640311. PubMed PMID: 21836148; PubMed Central PMCID: PMC3359004PubMedPubMed CentralView ArticleGoogle Scholar
- Annweiler C, Llewellyn DJ, Beauchet O: Low serum vitamin D concentrations in Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2013, 33 (3): 659-674. doi:10.3233/JAD-2012-121432. PubMed PMID: 23042216. Epub 2012/10/09PubMedGoogle Scholar
- Annweiler C, Montero-Odasso M, Llewellyn DJ, Richard-Devantoy S, Duque G, Beauchet O: Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis. 2013, 37 (1): 147-171. doi:10.3233/JAD-130452. PubMed PMID: 23948884. Epub 2013/08/21PubMedGoogle Scholar
- Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S: Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012, 95 (1): 91-100. doi:10.3945/ajcn.111.014779. PubMed PMID: 22170374. Epub 2011/12/16PubMedView ArticleGoogle Scholar
- Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM, Salovaara K, Cooper C, Smith HE, Jacobs ET, Torgerson D, Jackson RD, Manson JE, Brixen K, Mosekilde L, Robbins JA, Francis RM, Abrahamsen B: Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab. 2012, 97 (8): 2670-2681. Epub 2012/05/19. doi:10.1210/jc.2011-3328. PubMed PMID: 22605432; PubMed Central PMCID: PMC3410276PubMedPubMed CentralView ArticleGoogle Scholar
- Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP: Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007, 85 (6): 1586-1591. PubMed PMID: 17556697. Epub 2007/06/09PubMedGoogle Scholar
- Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R: Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006, 83 (4): 754-759. PubMed PMID: 16600924. Epub 2006/04/08PubMedGoogle Scholar
- Mitri J, Dawson-Hughes B, Hu FB, Pittas AG: Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011, 94 (2): 486-494. doi:10.3945/ajcn.111.011684. PubMed PMID: 21715514. PubMed Central PMCID: PMC3142723. Epub 2011/07/01PubMedPubMed CentralView ArticleGoogle Scholar
- Witham MD, Nadir MA, Struthers AD: Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009, 27 (10): 1948-1954. doi:10.1097/HJH.0b013e32832f075b. PubMed PMID: 19587609. Epub 2009/07/10PubMedView ArticleGoogle Scholar
- Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, Li K, Bassali R, Guo DH, Thomas J, Pierce GL, White J, Holick MF, Zhu H: A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness. J Clin Endocrinol Metab. 2010, 95 (10): 4584-4591. Epub 2010/07/28. doi:10.1210/jc.2010-0606. PubMed PMID: 20660028PubMedView ArticleGoogle Scholar
- Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H: Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010, 91 (5): 1255-1260. doi:10.3945/ajcn.2009.29094. PubMed PMID: 20219962. Epub 2010/03/12PubMedView ArticleGoogle Scholar
- Camargo CA, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW: Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012, 130 (3): e561-e567. Epub 2012/08/22. doi:10.1542/peds.2011-3029. PubMed PMID: 22908115PubMedView ArticleGoogle Scholar
- Nimer A, Mouch A: Vitamin D improves viral response in hepatitis C genotype 2–3 naive patients. World J Gastroenterol. 2012, 18 (8): 800-805. doi:10.3748/wjg.v18.i8.800. PubMed PMID: 22371640. PubMed Central PMCID: PMC3286143. Epub 2012/03/01PubMedPubMed CentralView ArticleGoogle Scholar
- Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C: Effect of annual intramuscular vitamin D on fracture risk in elderly men and women–a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford). 2007, 46 (12): 1852-1857. doi:10.1093/rheumatology/kem240. PubMed PMID: 17998225. Epub 2007/11/14View ArticleGoogle Scholar
- Autier P, Boniol M, Pizot C, Mullie P: Vitamin D status and ill health: a systematic review. Lancet Diab Endocrino. 2014, 2 (1): 76-89.View ArticleGoogle Scholar
- Beckman MJ, Johnson JA, Goff JP, Reinhardt TA, Beitz DC, Horst RL: The role of dietary calcium in the physiology of vitamin D toxicity: excess dietary vitamin D3 blunts parathyroid hormone induction of kidney 1-hydroxylase. Arch Biochem Biophys. 1995, 319 (2): 535-539. doi:10.1006/abbi.1995.1328. PubMed PMID: 7786039. Epub 1995/06/01PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, Orav EJ, Stahelin HB, Willett WC, Can U, Egli A, Mueller NJ, Looser S, Bretscher B, Minder E, Vergopoulos A, Theiler R: Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med. 2010, 170 (9): 813-820. Epub 2010/05/12. doi:10.1001/archinternmed.2010.67. PubMed PMID: 20458090PubMedView ArticleGoogle Scholar
- Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC: Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2010, 21 (7): 1121-1132. doi:10.1007/s00198-009-1119-3. PubMed PMID: 19957164. PubMed Central PMCID: PMC3062161. Epub 2009/12/04PubMedView ArticleGoogle Scholar
- Chel V, Wijnhoven HA, Smit JH, Ooms M, Lips P: Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporos Int. 2008, 19 (5): 663-671. PubMed PMID: 17874029PubMedView ArticleGoogle Scholar
- Tangpricha V, Pearce EN, Chen TC, Holick MF: Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002, 112 (8): 659-662. PubMed PMID: 12034416. PubMed Central PMCID: PMC3091001. Epub 2002/05/30PubMedPubMed CentralView ArticleGoogle Scholar
- Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF: Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998, 8 (3): 222-230. PubMed PMID: 9797906. Epub 1998/11/03PubMedView ArticleGoogle Scholar
- Dawson-Hughes B: Impact of Vitamin D and Calcium on Bone and Mineral Metabolism in Older Adults. Biologic Effects of Light 2001. Edited by: Holick M. 2002, Springer US, 175-183.View ArticleGoogle Scholar
- Dawson-Hughes B, Harris SS, Dallal GE: Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr. 1997, 65 (1): 67-71. PubMed PMID: 8988915. Epub 1997/01/01PubMedGoogle Scholar
- Grant WB, Holick MF: Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005, 10 (2): 94-111. PubMed PMID: 15989379. Epub 2005/07/02PubMedGoogle Scholar
- McKenna MJ: Differences in vitamin D status between countries in young adults and the elderly. Am J Med. 1992, 93 (1): 69-77. PubMed PMID: 1385673. Epub 1992/07/01PubMedView ArticleGoogle Scholar
- Theiler R, Stahelin HB, Kranzlin M, Somorjai G, Singer-Lindpaintner L, Conzelmann M, Geusens P, Bischoff HA: Influence of physical mobility and season on 25-hydroxyvitamin D-parathyroid hormone interaction and bone remodelling in the elderly. Eur J Endocrinol. 2000, 143 (5): 673-679. Epub 2000/11/18. PubMed PMID: 11078992PubMedView ArticleGoogle Scholar
- Holick MF: Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr. 1995, 61 (3 Suppl): 638S-645S. PubMed PMID: 7879731. Epub 1995/03/01PubMedGoogle Scholar
- Theiler R, Stahelin HB, Tyndall A, Binder K, Somorjai G, Bischoff HA: Calcidiol, calcitriol and parathyroid hormone serum concentrations in institutionalized and ambulatory elderly in Switzerland. Int J Vitam Nutr Res. 1999, 69 (2): 96-105. PubMed PMID: 10218146. Epub 1999/04/28PubMedView ArticleGoogle Scholar
- Webb AR, Kline L, Holick MF: Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988, 67 (2): 373-378. doi:10.1210/jcem-67-2-373. PubMed PMID: 2839537. Epub 1988/08/01PubMedView ArticleGoogle Scholar
- Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA: The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004, 89 (3): 1196-1199. doi:10.1210/jc.2003-031398. PubMed PMID: 15001609. Epub 2004/03/06PubMedView ArticleGoogle Scholar
- Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR: Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002, 30 (5): 771-777. PubMed PMID: 11996918. Epub 2002/05/09PubMedView ArticleGoogle Scholar
- Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA: Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr. 2002, 76 (1): 187-192. Epub 2002/06/26. PubMed PMID: 12081833PubMedGoogle Scholar
- Haddock L, Corcino J, Vazquez M: 25(OH)D serum levels in the normal Puero Rican population and in subjects with tropical sprue and paratyroid disease. Puerto Rico Health Sci. 1982, 1: 85-91.Google Scholar
- Haddad JG, Chyu KJ: Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab. 1971, 33 (6): 992-995. doi:10.1210/jcem-33-6-992. PubMed PMID: 4332615. Epub 1971/12/01PubMedView ArticleGoogle Scholar
- Gertner JM, Domenech M: 25-Hydroxyvitamin D levels in patients treated with high-dosage ergo- and cholecalciferol. J Clin Pathol. 1977, 30 (2): 144-150. PubMed PMID: 191473. PubMed Central PMCID: PMC476338. Epub 1977/02/01PubMedPubMed CentralView ArticleGoogle Scholar
- Vieth R: Vitamin D, supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999, 69 (5): 842-856. PubMed PMID: 10232622. Epub 1999/05/08PubMedGoogle Scholar
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