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Is High Dose Vitamin D Harmful – Dec 2012

Is High Dose Vitamin D Harmful?

Calcif Tissue Int Dec 2012 DOI 10.1007/s00223-012-9679-1
Kerrie M. Sanders • Geoffrey C. Nicholson • Peter R. Ebeling
K. M. Sanders (&) • G. C. Nicholson • P. R. Ebeling Department of Medicine, Western Health, NorthWest Academic Centre, University of Melbourne, PO Box 294, St Albans, VIC 3021, Australia e-mail: ksanders at unimelb.edu.au
G. C. Nicholson
Rural Clinical School, School of Medicine, University of Queensland, Toowoomba, QLD, Australia
Received: 7 February 2012/Accepted: 15 November 2012 © Springer Science+Business Media New York 2012

Comment by VitaminDWiki

  1. This paper seems to consider that it is OK to have an annual amount of something in a single day
    Imagine the problem of taking 300 liters of water in a single day, or 300 grams of Vitamin C, etc. etc.
  2. This paper ignores the documented problems of Vitamin D2, and treats D3 equal to D2
  3. This paper ignores the need for cofactors - a huge imbalance in the body is a big problem
  4. This paper ignores the need of Vitamin K2 to make sure that any excess Calcium does not cause problems
  5. This paper ignores the problem of too much Calcium and not enough Magnesium when increasing vitamin D

see wikipagehttp://www.vitamindwiki.com/tiki-index.php?page_id=1936

See also VitaminDWiki

see wikipage: http://www.vitamindwiki.com/tiki-index.php?page_id=2475
PDF attached to the bottom of this page
Just a portion of each of the tables are shown below


With the potential to minimize the risk of many chronic diseases and the apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than the current recommended intakes, recent research has focussed on supplementing individuals with intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures. This review summarises the results from studies that have used intermittent, high doses of vitamin D, with particular attention to those finding evidence of adverse effects. Results from observational, population-based studies with evidence of a U- or J-shaped curve are also presented as these findings suggest an increased risk in those with the highest serum 25D levels. Speculative mechanisms are discussed and biochemical results from studies using high-dose vitamin D are also presented. Emerging evidence from both observational studies and RCTs suggests there should be a degree of caution about recommending high serum 25D concentrations for the entire population. Furthermore, benefit of the higher doses commonly used in clinical practice on falls risk reduction needs to be demonstrated. The safety of loading doses of vitamin D should be demonstrated before these regimens become recommended as routine clinical practice. The current dilemma of defining vitamin D insufficiency and identifying safe and efficacious repletion regimens needs to be resolved.

The need for vitamin D supplementation has evolved because it is widely recognized that a significant proportion of many populations has inadequate vitamin D status [1]. Serum 25-hydroxyvitamin D (25[OH]D) levels of 25 nmol/L or less are considered "deficient," while the definition of "insufficiency" varies, with some experts regarding less than 50 nmol/L as the cut-off [2] and others considering less than 75 nmol/L as "insufficient" [3-5]. "Insufficient" in this review refers to 25(OH)D levels in the range 25-50 nmol/L, "intermittent" dosing refers to at least 1-week dosing intervals, and high dose refers to an intermittent bolus dose of at least 20,000 IU or a daily dose of 4,000 IU. Although the risk of many chronic disorders may be reduced by an upward shift in the community's vitamin D status, daily dosing has proven to be problematic, particularly for older people, the group most likely to directly benefit from an improvement in vitamin D status [6]. Many randomized trials have reported poor compliance with daily regimens [7]. Furthermore, some people require substantial doses of vitamin D to achieve serum 25(OH)D levels within the target range [8, 9]. An intermittent, larger dose of vitamin D reduces this compliance issue in a simple and cost-effective manner and reduces the likelihood that the target group will remain below the threshold of 25(OH)D regarded as insufficient, although significant controversy exists regarding what level of serum 25(OH)D is sufficient [3, 10-12]. Both the public and practitioners want to make informed decisions regarding both the target level of 25(OH)D to optimize health and the appropriate dosing regimen to achieve this target level.

According to current evidence from biochemical, observational, and randomized controlled trials (RCTs), serum 25(OH)D levels of at least 50 nmol/L are required for normalization of PTH levels, to minimize the risk of osteomalacia, and for optimal bone and muscle function [2, 13, 14], with many experts regarding 75 nmol/L as the threshold for optimal bone health [12, 15-17]. The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss, and increased risk of low-trauma fractures. From a skeletal perspective, evidence from RCTs suggests that vitamin D may be considered a threshold nutrient with little bone benefit observed at levels of 25(OH)D above that at which parathyroid hormone (PTH) is normalized [2]. However, molecular studies have demonstrated that vitamin D plays a role in cell differentiation, function, and survival [18, 19]. Adequate calcium intake is imperative to gain optimal benefit from improving vitamin D status in those with insufficient 25(OH)D levels. The relative contributions of vitamin D and calcium to reducing fracture risk remain unclear [20], and improving calcium intake is also associated with suppression of PTH levels [21, 22]. Observational studies have shown a decreased risk of many disorders, including certain types of cancer, mental disorders, cardiovascular disease, and skin and autoimmune disorders, associated with serum 25(OH)D levels greater than 70-80 nmol/L [9, 12, 16]. It has therefore been argued that 25(OH)D levels should be in the range of 70-100 nmol/L to maximize these nonskeletal benefits.

With the potential to minimize the risk of many chronic diseases and the apparent safety of ingesting doses of oral vitamin D severalfold higher than the current recommended intakes, recent research has focused on supplementing individuals with intermittent, high-dose vitamin D. There is an urgent need to determine the efficacy and safety of these regimens. Using biochemical parameters of safety, particularly plasma and urine calcium, there are numerous studies reporting that a single oral dose of 300,000-600,000 IU of D2/D3 rapidly enhances serum 25(OH)D and reduces PTH in people with deficiency [23-25]. Although dosing intervals of greater than 2-3 months and/or intermittent bolus doses ([200,000 IU) are not regarded as physiological [[26], such an approach offers a realistic and pragmatic public health measure to target at-risk populations and addresses the emerging public health issue of widespread vitamin D insufficiency [6, 27].

However, two recent RCTs, both using annual high-dose vitamin D, reported an increase, rather than a decrease, in the primary outcome of falls [27] and fractures [27, 28].

These findings highlight the need for a better understanding of different dosing regimens before pragmatic, population-based interventions are implemented. This review summarizes results from studies that have used intermittent, high doses of vitamin D, with particular attention to those finding evidence of adverse effects. Results from observational, population-based studies with evidence of a U-or /-shaped curve are also presented as these findings suggest an increased risk in those with the highest serum 25(OH)D levels. We do not attempt to present a comprehensive, systematic review of the extensive number of observational and intervention studies reporting the health benefits of improving vitamin D status in adults with insufficient status [7, 29-32] or to present a balanced view of the potential risk/benefit ratio of vitamin D supplementation.

Biochemical Outcomes of Single, Large Doses of Vitamin D

The immediate concern of hypervitaminosis D is hyper-calciuria and hypercalcemia [2]. However, a large therapeutic window exists for vitamin D-related hypercalcemia, which has not been reported at serum 25(OH)D levels below 220 nmol/L and generally not reported below 500 nmol/L [2]. Based on these biochemical parameters, Vieth and colleagues [17] conducted a 6-month safety and efficacy study and concluded that consumption of more than 4,000 IU/day causes no harm and effectively raises 25(OH)D levels to high-normal concentrations (<140 nmol/L) in practically all adults. The 2011 Institute of Medicine report on dietary intake of vitamin D recommended an upper limit of 4,000 IU/day, although it also stated that up to 10,000 IU/day is safe [33].

Of the studies included in this review, the cases of hypercalcemia and/or hypercalciuria are few and their incidence in the randomized trials is rarely different from that observed in the placebo group (Table 1). The study by Grimnes and colleagues [34], where one group was given 6,500 IU/day and another was given 400 IU/day, reported a significant difference between groups in serum ionized calcium at 12 months. In another trial, two of 33 patients receiving a single bolus dose of 300,000 IU vitamin D3 had mild hypercalcemia [35]. Participants in this study were older, recruited from a rheumatology clinic, and likely to have reduced kidney function compared with other trial participants who were, on average, younger (Table 1). However, some of the larger trials did not specifically investigate for hypercalcemia or hypercalciuria (Table 1).
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A 1995 review of the safety and effectiveness of different regimes of vitamin D supplementation in the elderly suggested that daily low-dose supplementation is the regimen of choice for prevention of hypovitaminosis D but that intermittent high-dose regimens would be a safe and be significant variation in the level of serum 25(OH)D effective alternative in patients with poor compliance [36]. reached when individuals are given the same dose and form As reported in individual trials [8, 9, 37], there appears to of the vitamin.

Table 2 Observational studies with evidence of harm at higher end of vitamin D status

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Vitamin D doses expressed in international units (IU). D2 vitamin D2 (ergocalciferol), D3 vitamin D3 (cholecalciferol), IM intramuscular injection, 25(OH)D serum 25-hydroxyvitamin D (nmol/L), 1,25(OH)D serum 1,25-dihydroxyvitamin D (levels quoted as mean and standard deviation unless stated otherwise), IQR interquartile range, N/A not available, RIA radioimmunoassay, HPLC high-pressure liquid chromatography, LC-MS/MS liquid chromatography coupled with tandem mass spectrometry, HR hazard ratio (95 % confidence interval), RR relative risk (95 % confidence interval), BTM bone turnover markers, CTX C-terminal-telopeptide (bone resorption marker), BAP bone-specific alkaline phosphatase, P1NP amino-terminal propeptide of type 1 procollagen (bone formation markers), F females, M males

There is a caveat that earlier studies were reliant on 25(OH)D assays that have shown considerable intra- and intersample variation in the assessment of serum 25(OH)D concentrations and were unreliable in measuring serum D2 levels [38]. Although the performance of radioimmunoassay and enzyme-linked assays is acceptable, the bias and imprecision of many automated methods may be problematic at the lower, clinically and analytically important range (<50 nmol/L) of the assay [2].

Evidence from Observational Studies

A majority of observational studies have reported that vitamin D is associated with a beneficial effect on risk of colon, breast, prostate, and ovarian cancers [39]. Since vitamin D synthesis and serum 25(OH)D levels are inversely correlated with latitude and positively correlated with sunlight, some studies have mapped disease incidence rates with latitude to investigate a possible protective effect of vitamin D status and risk of disease. Encouragingly, there is a consistency of findings between geographic studies and serum studies where samples of the population have had biochemistry assessments, ideally with the blood collection point several years prior to any diagnosis of cancer or other disease of interest [39]. Vitamin D and its metabolites are thought to reduce the incidence of many types of cancer by inhibiting tumor angiogenesis and hyperproliferation as well as stimulating cellular apoptosis [40]. Since vitamin D regulates a gamut of physiological processes, including immune modulation, resistance to oxidative stress, and modulation of other hormones, it is not surprising that low vitamin D has been associated with increased risk of several cancers and chronic diseases [41] as well as cancer mortality [42].

Nevertheless, there are now several observational studies reporting a U-orJ-shaped association between disease and serum 25(OH)D and latitude and/or ultraviolet B radiation levels, where those in the highest percentiles have an inverse risk compared with those in the lowest (Table 2)[43]. While cross-sectional data have many limitations, the findings are hypothesis-generating [44] and can be used to develop protocols for RCTs. The findings from prospective case-control cohort studies where blood collection occurred many years prior to diagnosis add another dimension to the evidence. The results from these studies generally support vitamin D supplementation in those with low vitamin D status. However, the findings argue for caution before increasing 25(OH)D levels and associated dosing regimens beyond evidence clearly supported by RCTs and meta-analyses

RCTs Demonstrating Harm

The evidence of harm relating to high-dose vitamin D centers on the findings of two RCTs that used annual high-dose vitamin D (Table 3), although results from RCTs using lower, more frequent dosing regimens have not been consistently clear. The different forms of the vitamin used in the studies and the different delivery modes demonstrate that the adverse outcomes are not restricted to one form of the vitamin. either study included calcium supplementation as part of the protocol. In the British Wessex study, 9,440 community-dwelling participants (4,354 men and 5,086 women) aged 75-100 years were randomly allocated to receive an annual injection of 300,000 IU vitamin D2 or matching placebo every autumn over 3 years [28]. In the entire cohort the risk of any first fracture was not different in the two treatment groups. However, the vitamin D group showed an increased risk of hip/femur fracture (hazard ratio [HR] = 1.49, 95 % confidence interval [CI] 1.02-2.18) and hip/femur/wrist fracture (HR = 1.40, 95 % CI 1.07-1.82). Analysis of the female subjects showed that vitamin D treatment was associated with a borderline increased risk of any nonvertebral fracture (HR = 1.21, 95 % CI 1.00-1.47) and increased risk of hip/femur (HR = 1.80, 95 % CI 1.12-2.90) and hip/femur/wrist fracture (HR = 1.59, 95 % CI 1.17-2.16). However, vitamin D treatment was not associated with increased risk of any fracture in males. o effect on falls was observed, although this was not a primary outcome and falls were ascertained by 6-monthly recall. The other study, of 2,256 community-dwelling Australian women aged 70-92 years randomly allocated to receive an annual oral dose of 500,000 IU vitamin D3, demonstrated a 15 % (95 % CI 1.02-1.30) increased rate of falls and a 26 % (95 % CI 1.00-1.59) increased rate of fractures [27]. A temporal pattern was observed, with the greatest increase occurring in the first 3 months after dosing (falls: p for homogeneity = 0.02). A temporal pattern of risk was not demonstrated in the Wessex study, although the 6-monthly ascertainment of fractures did not optimize this post hoc analysis (unpublished).

Serial biochemistry was performed only in a very small proportion of participants in both these RCTs (0.04 % and 6.1 % participants; Smith et al. [28] and Sanders et al. [27], respectively). either study recruited participants based on low 25(OH)D levels at screening. We are unable to infer that the adverse effects are confined to participants whose 25(OH)D levels were either deficient/insufficient or replete at baseline. It is well documented that the incremental increase in serum 25(OH)D is likely to be lower in those already replete prior to supplementation [24], and there is substantial variation in dose-response curves between individuals [8, 9]. There is therefore no evidence base to justify large annual loading doses of vitamin D to specific groups based on their baseline 25(OH)D level. Based on the reduction in fractures using 4-monthly dosing regimens in the Trivedi et al. [46] RCT and the biochemical results by Bacon et al. [24] and Ilahi et al. [47], it seems prudent to restrict intermittent higher doses to intervals not greater than 2-4 months. However, the reasoning is speculative, and RCT evidence with physical outcomes using a variety of dosing regimens is urgently needed. The fall characteristics from the Australian study do not suggest that the increased falls were attributable to one subgroup of participants experiencing the most falls. The proportion of participants falling multiple times did not vary between the vitamin D and placebo groups (unpublished data), and Kaplan-Meier plots of time to first fall show significant differences between the groups (p = 0.003). In another recent publication, a small group (n = 12) of older (mean age 73 years) subjects was treated with a single oral dose of 600,000 IU vitamin D3 [48]. Serum 25(OH)D increased from 54 ± 14 nmol/L at baseline to 168 ± 43 nmol/L at day 3 when the bone turnover markers C-terminal telopeptide (CTX) and N-terminal telopeptide (NTX) peaked at over 50 % above baseline. PTH decreased and 1,25-dihydroxyvitamin D (1,25[OH]D) increased by 25-50 % [48]. Rossini and colleagues [48] suggest that this transient increase in bone turnover markers may explain the negative clinical results obtained in studies using intermittent high-dose vitamin D. Sanders and colleagues [49] have also reported increased bone turnover among a sample of participants who underwent biochemistry assessments and had a very high incremental rise in serum 25(OH)D levels. While increased bone turnover may contribute to the demonstrated increase in fracture risk, this does not explain the clear evidence of increased falls in the Australian study

(Table 3).

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Speculative Mechanisms

The mechanism by which high-dose vitamin D might increase falls and fracture is uncertain. The opposing outcomes of two studies [28, 46] that used the same total annual dose (300,000 IU intramuscularly) suggest that the dosing regimen (i.e., 4-monthly vs. annually) rather than the total dose might determine the outcome. While a dosing interval of 12 months is equivalent to four biological half-lives of vitamin D, at the time these two studies were conducted there was biochemical evidence of safety and preliminary evidence that these intermittent bolus doses may be efficacious at decreasing fracture risk in older women [36, 46, 50]. In addition, the Australian study team was specifically addressing the drop in vitamin D and increased fractures that occurs during winter [51]. The line of reasoning regarding the dosing interval is supported by the temporal risk pattern observed in the study of Sanders et al. [27] and the fact that harm has not been reported in the numerous studies that have used more frequent dosing [52]. However, the lower-level evidence of a U-shaped dose-response curve reported in some observational studies [53-55] is not consistent with a temporal pattern since it is unlikely that those in the highest quintile of vitamin D status in the community use high intermittent doses of supplemental vitamin D. However, it is possible that seasonal fluctuations in 25(OH)D levels may contribute to this apparent phenomenon. Vieth [26] contends that a U-or J-shaped curve of risk is observed only in populations residing farther away from the equator and who, therefore, have greater seasonal fluctuations. It is argued that the annual downward phase in seasonal cycles almost definitely creates a non-steady-state situation for the paracrine production of 1,25(OH)D responsible for the noncalcemic effects of vitamin D. It is also possible the adverse mechanism may be associated with gender since Smith and colleagues [28] did not demonstrate an increased fracture risk among men and the majority of participants in the Trivedi et al. [46] study demonstrating a reduced fracture risk using 100,000 IU every 4 months were men (76 %). A Welsh RCT using the same dosing regimen as Trivedi et al. [46] but with 76 % women reported no difference in fracture outcome [56] (Tables 1, 3). In addition, the Australian RCT recruited only women [27]. There is also weak evidence from RCTs using more frequent dosing regimens that the mechanism is not a single aspect but may be more complex (Table 4).

Table 4


It has been hypothesized that the increased numbers of falls and fractures may have, ironically, resulted from the benefits of vitamin D in that the older women randomized to vitamin D felt better and consequentially engaged in more at-risk falls behavior [52]. However, the Australian authors subsequently published mental well-being outcomes of this study. No significant differences were detected in any of the measured outcomes of mental health [57], making this explanation less likely. No differences between the groups relating to the circumstances or activity of the fall events has been identified (unpublished).

In their editorial, Dawson-Hughes and Harris [52] also hypothesized that the 500,000 IU dose may have triggered a short-term protective reaction in which CYP24 (25-hydroxyvitamin D-24-hydroxylase), the enzyme that catabolizes 1,25(OH)D, was upregulated, resulting in decreased blood and tissue levels of 1,25(OH)D. Although this hypothesis is consistent with results from an animal study [58], both the Wessex [28] and Rossini et al. [48]

studies demonstrated increases (25-50 %) in serum 1,25(OH)D in those who had serial biochemistry assessments. From an evolutionary approach, Vieth [59] presents theargumentthatoralsupplementationofvitaminD is needed to improve health outcomes by lessening the destabilizing effect of annual fluctuations in serum 25(OH)D. He argues that the paracrine regulation of 1,25(OH)D in many tissues is disrupted by unstable 25(OH)D levels and that this adversely affects bone mineral density, mental well-being, infection, and cancer risk. The profile of 25(OH)D levels from the two studies showing harm does not appear distinctly different from a range of high-dose biochemical studies (Table 1). Although there is no uniformity in the time points of 25(OH)D assessment, peak 25(OH)D levels from these studies tend to be around 120-140 nmol/L. Ilahi and colleagues [47] suggest that the dosing interval of intermittent dosing regimens be not greater than 70 days to ensure that 25(OH)D levels do not decline below a target of 70 nmol/L.

The increased risk of falls in the Australian study demonstrates that the adverse mechanism is not confined to the skeleton. Post hoc analysis of changes in muscle strength in a nested substudy of these older women who underwent annual physical functioning assessments suggests a decline in muscle strength in those whose 25(OH)D level showed the greatest fluctuation from baseline [60]. Since there are vitamin D receptors in muscle, a sudden increase in vitamin D receptor occupancy could have an adverse effect on muscle function [61]. Vitamin D receptors are also present in the central nervous system [62], so an adverse effect on balance or coordination is also possible. Another recent Australian RCT of 686 ambulant women aged at least 70 years reported neither a beneficial nor an adverse effect on falls or physical function using a 3-monthly dosing of 150,000 IU cholecalciferol compared to placebo [63]. The study intervention period was 9 months, and the baseline 25(OH)D level measured in a subgroup of 40 participants was 66 ± 23 nmol/L. A review by Stockton and colleagues [64] concluded that vitamin D supplementation does not have a significant effect on muscle strength in vitamin D-replete adults.

Concluding Summary

While epidemiological studies provide evidence that vitamin deficiencies are associated with an increased risk of chronic disorders and/or cancer, the consequent philosophy that higher doses of the vitamin are protective and confer a reduced risk of these diseases is flawed [65, 66]. Two recent editorials on high-dose vitamin D have drawn analogies from the hard lessons learned from RCTs on high-dose vitamins A, B, C, and E [65, 66]. Supraphysio-logical levels of the vitamin taken as supplements do not emulate the apparent benefits of diets high in food that contain those vitamins and other lifestyle factors [67]. The findings from two recent high-dose RCTs [27, 28] identify a potential harm associated with high-dose vitamin D and support the notion that vitamin D could be now added to this list. Thus, in addition to evidence from enzyme kinetics relating to vitamin D metabolism [44], there is now high-level RCT evidence that vitamin D supplementation has potential toxicities other than simply hypercal-cemia/-uria. As our understanding of the pharmacokinetics of vitamin D metabolism becomes more sophisticated, clinical trials with novel dosing regimens should apply the principles of conventional pharmacology and vitamin D metabolism to the study design.

Interpretation of findings from many large RCTs has been limited by the lack of assessment of 25(OH)D status in the majority of participants. Future studies of supplementation should be adequately funded to allow comprehensive or universal measurement of serum 25(OH)D and related biochemical parameters [65, 68], with particular attention to large and rapid fluctuations in vitamin D status. Future studies should not base toxicity solely on the risk of hypercalcemia/-uria. There is an urgent need for dose-ranging studies with physical function outcomes [61, 64]. Emerging evidence from both observational studies and RCTs suggests that there should be a degree of caution about recommending high serum 25(OH)D concentrations for the entire population. Furthermore, a benefit of the higher doses commonly used in clinical practice on falls risk reduction needs to be demonstrated [69]. While it is recognized that intramuscular high-dose vitamin D preparations may be the only way of ensuring adequate vitamin D status in specific at-risk groups of patients, such as those suffering fat malabsorption, the safety of loading doses of vitamin D administered to the general population should be demonstrated before these regimens become recommended as routine clinical practice [65]. The current dilemma of defining vitamin D insufficiency and identifying safe and efficacious repletion regimens needs to be resolved.


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