Haroon and Fitzgerald, J Arthritis 2012, 1:2

Arthritis http://dx.doi.org/10.4172/2167-7921.1000105

Review Article Open Access

Vitamin D Deficiency and its Repletion: A Review of Current Knowledge

and Consensus Recommendations
Haroon M* and Fitzgerald O
Department of Rheumatology, St. Vincent’s University Hospital, Ireland

Abstract
In last few years we have witnessed an explosion of research revealing the wide spread prevalence of vitamin
D deficiency among all ages, communities, and different disease spectrums. Clearly, vitamin D has been shown to
have effects beyond its traditional role in mineral metabolisms, which are mediated through the activation of vitamin
D receptors distributed in a variety of tissues. There are strong epidemiological links between vitamin D deficiency
and chronic diseases and will continue to be a focus of future research. However, this research information has
not yet been fully translated into clinical practice. The increased awareness of the level of vitamin D deficiency in
the general population and its potential impact on skeletal and extra skeletal health outcomes have highlighted
the important need to understand and follow the latest research knowledge in this area. There remains a poor
understanding among health professionals as regards the prescribing policy and the provision of appropriate vitamin
D supplements. This review will discuss the physiological role of vitamin D, and the available literature on vitamin
D deficiency with respect to its definition, associated factors, prevalence, and management recommendations, and
the safety of its repletion.

Key words: Vitamin D; Deficiency; Repletion effects [3]. Genomic effects of vitamin D are mediated by classical gene
transcription or protein synthesis route, which is initiated by binding
Introduction of 1,25(OH)2D to its nuclear high-affinity vitamin D receptor (VDR)
Our knowledge regarding the physiological role of vitamin D has [4,5], which results in changes in the gene transcription of mRNA
significantly advanced during last few decades. There have been strides and subsequent de novo protein synthesis [6]. However, non-genomic
in the development of strategies to prevent and treat the deficiency functions of vitamin D are generally rapid responses (minutes to hours).
of this natural hormone – vitamin D; however, vitamin D deficiency Many of these rapid responses are believed to be mediated by 1,25D
remains under recognised and untreated. Vitamin D is a seco-steroid binding to a plasma membrane-associated receptor [3,7], which in
hormone with one endocrine function – calcium regulation- but with turn, initiates a cascade leading to the formation of a second messenger
multiple autocrine functions. The principal function of vitamin D is to (cAMP, diacylglycerol, inositol triphosphate, arachidonic acid) or
control calcium metabolism, and its deficiency impacts the quality and phosphorylation of intracellular proteins. Such receptors are located
quantity of bone formation by affecting calcium absorption. Besides its in classical target organs involved in vital calcemic actions of vitamin
effects on musculoskeletal system, 1,25-dihydroxyvitamin D inhibits D, such as the intestine, bone, kidney and parathyroid, as well as in
cellular growth, stimulates insulin secretion, modulates immune many other tissues and cell types [2], including the immune system
function, and inhibits renin production. These findings most likely [8]. However, such non-genomic actions of vitamin D have not been
explain the observations that vitamin D deficient people are more prone demonstrated in vivo. The main biologic actions of 1,25-(OH)2 vitamin
to solid tumours, autoimmune diseases and hypertension [1]; however, D are: absorption of calcium from intestine leading to the mineralization
discussing such health consequences is beyond the scope of this paper. of bone matrix; osteoblast differentiation; and inhibition of parathyroid
hormone secretion. In calcium deficiency states, 1,25(OH)2D mobilizes
Basic Physiology and Molecular Biology calcium stores from the bone through stimulation of monocytic cells
to become mature osteoclasts, and thus, helps to maintain the serum
To understand the importance of vitamin D, we need to understand
its physiology. Vitamin D is a steroid hormone, and there are 2 forms calcium in the normal range [9]. Similarly, when vitamin D levels
of vitamin D - vitamin D2 (known as ergocalciferol) and vitamin are low, compensatory secondary hyperparathyroidism increases the
D3 (named as cholecalciferol). Vitamin D2 is a plant extract and renal conversion of 25OHD and thereby maintains normal or slightly
Vitamin D3 is synthesized by humans in the skin, when it is exposed increased plasma levels of 1,25(OH)2D. Moreover, this active form of
to ultraviolet-B (UVB) rays from sunlight. Vitamin D is further vitamin D is stored in the adipose tissue rather than remains in the
hydoxylated in the liver to 25 hydroxyvitamin D (25OH vitamin D), circulation and, therefore, is not a good measure of vitamin D status
which can accumulate in certain tissues. 25-OH vitamin D is the
predominant circulating form of vitamin D in the blood and because
*Corresponding author: Dr. Muhammad Haroon, Department of Rheumatology, St
of its close regulation by the availability of vitamin D, measurement of Vincent’s University Hospital, Elm Park, Dublin 4, Ireland, E-mail: [email protected]
25(OH) vitamin D is the most reliable indicator of vitamin D status.
Received March 28, 2012; Accepted July 19, 2012; Published July 21, 2012
The active form, 1,25 dihydroxyvitamin D, is formed by subsequent
hydroxylation in the kidney, and its half-life is very short (<4 hours). Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion:
The renal hydroxylation is very closely regulated: enhanced by PTH, A Review of Current Knowledge and Consensus Recommendations. J Arthritis
1:105. doi:10.4172/2167-7921.1000105
hypocalcaemia and hypophosphataemia and inhibited by 1,25(OH)2D
itself [2]. 1,25(OH)2D is the principal hormonal form of vitamin D, Copyright: © 2012 Haroon M, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
responsible for most of its biologic actions. Molecular mechanisms of use, distribution, and reproduction in any medium, provided the original author and
action of 1,25-dihydroxyvitamin D include genomic and non-genomic source are credited.

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ISSN: 2167-7921 JAHS, an open access journal Volume 1 • Issue 2 • 1000105
Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion: A Review of Current Knowledge and Consensus Recommendations.
J Arthritis :105. doi:10.4172/2167-7921.1000105

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in serum. Both 25OHD and 1,25(OH)2D undergo a 24-hydroxylation greater amounts of vitamin D gets sequestered in the adipose tissue,
[10], which represents the first step in the biodegradation which ends and the part of the upper small intestine where vitamin D is absorbed
with the formation of water-soluble calcitroic acid. is bypassed in such gastric surgery. Hence, people who are obese may
need larger than usual intakes of vitamin D to achieve the required
Factors Associated With Vitamin D Deficiency 25(OH)D levels comparable to those of normal weight [11].
Poor intake Minimal erythemal dose
There are multiple reasons for vitamin D deficiency. An important A minimal erythemal dose (MED) is the amount of sun exposure
cause of vitamin D deficiency can be insufficient intake of dietary required to produce a faint pinkness to the skin [31-32]. Previous
vitamin D. Extremely few foods naturally contain vitamin D, apart estimates suggest that a single MED of simulated sunlight will raise
from oily fish in the form of salmon, mackerel, and sardines which are circulating levels of 25(OH)D comparable to the ingestion of 10,000
relatively rich in vitamin D3. Similarly, only a small number of foods to 25,000 IU of vitamin D3 [33]. Thus, it is suggested that exposure of
are fortified with vitamin D such as milk, orange juice and some bread the face, arms, hands, and legs for 20% to 25% of that time (i.e., 6 to 8
and cereals. Such fortification is used in many developed countries [11]. minutes) 2 to 3 times a week is adequate to meet the body’s requirement
In Europe, margarine, vegetable oil and milk are commonly fortified, [34]. This time will vary depending on a number of external and
whereas in the USA, enrichment of flour, cornflakes, milk and juice individual factors such as latitude, season, time of day, amount of the
is common practice. It is important to note here that >90% of our clouds [35], age and especially the skin type, as people with dark skin
vitamin D requirements come from sunlight exposure [12]. The average require considerably longer (3-4 times) exposure time [36,37]. Hence,
increment in serum 25(OH) D concentrations has been estimated at some believe that it is impractical to prescribe a uniform message to the
1–2 nmol/L for every 40 IU (1 microgram) of vitamin D3 depending general population given the number of variables that need to be taken
on baseline 25(OH)D concentrations. Generally, the two forms of into consideration [38].
vitamin D, D2 (ergocalciferol) and D3 (cholecalciferol), are considered
equivalent [13-15]. However, using 25(OH) D as an objective measure Season and latitude
of response to vitamin D administration has shown that vitamin D3 is a
Seasonal and latitudinal variations of 25 hydroxyvitamin D levels
more potent form of vitamin D compared to vitamin D2. Hence, some
have long been described, with the highest levels reported during
experts suggest that vitamin D2 should not be used for supplementation
summer sun exposure and decreased levels in late winter season [39].
or fortification [16]. A recent systematic review examined the effects of
The likely explanation is that during winter season, more ultra violet B
food fortification on circulating 25(OH)D concentrations by reviewing
photons are absorbed by ozone layer, due to the fact that sunrays enter
13 randomised controlled trials. This showed a consistently positive
at more oblique angle. It has been noted that above the latitude of 37°,
response of dietary vitamin D supplementation among young adults,
there are even more marked decreases in the number of ultraviolet
postmenopausal women and elderly men [17]. There is also some
B photons reaching the earth surface during the winter months of
suggestion that this treatment effect is dependent on baseline 25 (OH)
November to February. Therefore, very little vitamin D3 is produced
vitamin D levels, as the trials with low baseline 25(OH)D levels (i.e.,
in the skin during the winter [32]. Not surprisingly, Webb et al. have
<50 nmol/L) [18-21] have consistently demonstrated a greater percent
already shown that in the USA, ineffective vitamin D synthesis extended
increase in 25(OH)D levels at the end of study compared to trials with
from October through March in Edmonton, where latitude is 52 degree
higher baseline 25(OH)D levels (i.e., >50 nmol/L) [22-25].
north [40]. Similarly, in Boston (42°N) no vitamin D is produced from
Poor production, malabsorption and obesity November through February [34]. Between 0 and 10 degrees latitude,
there is very intense sunlight for several hours before and after noon,
Factors that can prevent exposure to sunlight are crucial in causing year-round. People with pale or untanned skin will have plenty of
vitamin D deficiency. Such factors include: aging (which causes exposure in just a few minutes. Between 10 and 30 degrees latitude,
decreased dermal production through atrophic skin changes and there are several hours of very strong sunlight each day, especially
decreased renal production of 1,25(OH)2 vitamin D by diminishing during the summer, but the hours after dawn and before dusk can be
renal function), changes in latitude, time of the day, and life style milder. Between 30 and 50 degrees latitude, sunlight can be strong
factors, such as limited outdoor activity, can have a marked influence during the summer only, and spring is generally mild. Upwards of 50
on the cutaneous production of vitamin D. Similarly, any hindrance to degrees latitude, inhabitants are particularly at risk given the summers
ultraviolet sunlight exposure onto the skin in the form of either sunscreen are often short and they often have pale skin. Dark skin people living at
use or increased melanin pigmentation (dark skinned individuals) these latitudes are at a very high risk of vitamin D deficiency.
can potentially cause vitamin D deficiency. Vitamin D deficiency is
also more common in adults who cover their skin for cultural reasons A recent systematic review has evaluated the effect of UV exposure
[26-29]. A systematic review found that the risk factors for vitamin D on serum 25(OH)D concentrations by reviewing 8 randomised
inadequacy most often found in post-menopausal women include poor controlled trials, where four trials used solar exposure and the other
sun exposure, limited time spent outdoors, inadequate dietary vitamin four used artificial UV-B sources. [41-48]. This has concluded that 25
D intake, winter season and increased age [30]. Another important (OH)D levels increase with both solar and artificial UV-B exposure
factor for vitamin D deficiency is poor absorption of vitamin D, which [17].
generally occurs in people with fat malabsorption, given vitamin D is a The role of sunscreens
fat-soluble vitamin. Such fat malabsorption is associated with a variety
of medical conditions including some forms of liver disease, cystic It is important to recognize that sunscreens, while protecting from
fibrosis, and Crohn’s disease. skin cancers, absorb the ultraviolet radiations before entering the
skin and, hence, may block the most important source of vitamin D
Similarly, people who are obese or who have undergone gastric production leading to a theoretical risk of vitamin D deficient states.
bypass surgery may become vitamin D deficient overtime given the

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ISSN: 2167-7921 JAHS, an open access journal Volume 1 • Issue 2 • 1000105
Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion: A Review of Current Knowledge and Consensus Recommendations.
J Arthritis 1:105. doi:10.4172/2167-7921.1000105

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Sunscreens give different level of protection against sunburn, ranging if untreated; levels of 25-50 nmol/l or 12-20 ng/ml represent a milder
from sun protection factor (SPF) of 6 to >50. Sunscreen controversy form, often termed insufficiency, which can potentially lead to
about vitamin D deficiency vs. the risk of skin cancer continues to hyperparathyroidism, accelerated bone turnover and osteoporosis [78].
persist. Earlier studies showed a significant drop in the cutaneous However, a growing number of researchers warn that the distinction
production of vitamin D with the use of sunscreens [49-51]. While, between deficiency and insufficiency is artificial and there is much
it has been shown that a sun protection factor of 8 can reduce the overlap between the two conditions. Studies have shown a significant
skin production of vitamin D by 95% (49), there are no randomized improvement in calcium absorption at serum 25OHD level of 67.5
controlled trials to confirm the same. On the other hand, many trials, nmol/L compared to 55.5 nmol/L [67]. Similarly, it has been observed
including a randomized controlled trial, have revealed that sunscreens that by increasing 25 (OH) vitamin D levels from an average of 50 to
do not prevent the production of sufficient vitamin D [43,52-56]. A 86 nmol/L increases calcium absorption by 45% to 65%, implying that
recent review on this topic has concluded that although sunscreens there is significant decrease in intestinal calcium absorption when the
can significantly reduce the production of vitamin D, their normal level is even 75 nmol/L or less [68]. In contrast to the findings of this
usage does not generally result in vitamin D insufficiency [57]. Non- study, dropping serum 25OHD from 122 to 74 nmol/L did not produce
melanoma skin cancers occur on the most sun exposed areas, such as a significant difference in calcium absorption [69]. This suggests that
the face and hands, whereas most melanomas occur on the areas least vitamin D levels should ideally exceed 75 nmol/L, and levels between
exposed to the sun [58]. Non-melanoma skin cancer is now the UK’s 50 to 75 nmol/L can be considered relative insufficiency. As new data
commonest malignancy, and malignant melanoma is the commonest becomes available, the threshold for diagnosis of vitamin D deficiency
cancer in the 15-34 year group [59]. To add to the confusion, apart from is likely to rise even higher. Different values of 25(OH)D have been
the well known benefits of sun avoidance in reducing skin cancers, used as cut-offs to define low vitamin D states, and this depends on the
intermittent and occupational sun exposure has been found to reduce distinct health outcome studied. The most commonly used functional
the risk of malignant melanoma [60,61]. measures to assess the adequacy of vitamin D status include: the level
Too much sun is the main risk factor for skin cancer; on the other of 25(OH) vitamin D needed to maximally suppress the circulating
hand, too little sun and wearing sunscreen continuously may lead to parathyroid hormone; and the level associated with highest bone
vitamin D deficiency [32]. Hence, the health promotion message of mineral density, greatest calcium absorption, reduced rates of bone
emphasizing the importance of UV protection against skin cancers loss, and reduced fracture rates. In this regard, for a long time the levels
and the issue of low vitamin D due to sunlight avoidance should not be of 50nmol/L were considered the cut-offs, given its association with
taken as opposing each other. We recommend the sensible exposure to suppression of parathyroid hormone [70]. However, the research has
sunlight, for example, a brief exposure to the sun before applying the revealed few important facts: serum levels of 25-hydroxyvitamin D are
sunblock. directly related to bone mineral density, and maximum bone density is
achieved when the 25-hydroxyvitamin D level reached 100 nmol/L or
Infants
more; when the level is 75 nmol/L or less, there is a significant decrease
Breast fed infants are among the many common groups which are in intestinal calcium absorption; similarly, when the level is 50 nmol/L,
considered at higher risk of developing vitamin D deficiency. Human calcium absorption drops by 35% [68,71]. This stimulates an interesting
milk generally provides <25 IU/L to 78 IU/L, which is not enough to proposal that cut-offs should be based on determining an optimal level
meet vitamin D requirements [62,63]. Vitamin D content of breast for health as opposed to the minimum level to prevent severe deficiency.
milk is related to mother’s vitamin D status; in other words, vitamin Based on this concept, a number of world experts now believe that
D deficiency in a pregnant woman causes deficiency in the fetus [63]. hypovitaminosis D (i.e. vitamin D ‘deficiency’) should be defined as a
This can have direct impact on the baby’s health, not only during 25-hydroxy (25-OH) vitamin D level ≤ 75 nmol/L (i.e., ≤ 30 ng/ml in
their early life but also as an adult. For example, bone mineral accrual the U.S.) [72]. However, there are some experts who believe this may be
in early childhood and the risk of recurrent wheezing episodes in too low and they believe the vitamin D sufficiency should be defined
children have been linked to low vitamin D intake by women during as a plasma 25(OH)D concentration of >80 nmol/L [73] and >100
pregnancy [64,65]. Maternal deficiency can cause tetany in neonates, nmol/L [74]. Interestingly, IOM adopts a much conservative approach
which is caused by hypocalcemia and may accompany infantile or adult in defining vitamin D deficiency – serum 25(OH)D was considered as
vitamin D deficiency. Tetany may cause paresthesias, carpopedal and
adequate at a level of 20 ng/ml. This report has been discussed in detail
facial spasm; and, if very severe, seizures. A recent report from Canada
somewhere else in this paper.
has shown that 94% of infants diagnosed with rickets had been breast
fed [66]. Hence, American Association of Pediatrics recommends One major issue contributing to heterogeneous results and limiting
that infants, who are exclusively or partially breastfed, should be the pooling of data is the actual method of measurement of vitamin
supplemented with 400 IU of vitamin D per day [63]. D, where considerable variability exists. Among the several methods
available are the ones based on competitive protein binding assay
Issues in Defining Vitamin D Deficiency (CPBA), radioimmunoassay (RIA), enzyme-linked immunoassay,
25(OH) vitamin D is the major circulating form of vitamin D. In random access automated assay using chemiluminescence technology,
clinical practice, measurement of 25(OH) vitamin D is used to diagnose high performance liquid chromatography (HPLC) and liquid
intestinal malabsorption, vitamin D deficiency or intoxication, and to chromatography-mass spectrometry (LC-MS) [75]. These methods
monitor therapeutic response in patients being treated for vitamin have been shown to give discordant results [76]. For example, the
D-related disorders. Consensus has not been reached on exact cut- chemiluminescent assay usually provides higher 25(OH) vitamin
off points of 25(OH) vitamin D levels that can delineate vitamin D D results compared to other methodologies. In addition, some can
deficiency, but most studies and especially Institute of Medicine (IOM) underestimate the total 25(OH)D due to their inabilities in individually
agree on the following cut-offs: levels of <20-25 nmol/l or <12 ng/ml quantifying ergocalciferol [25(OH)D2] and cholecalciferol [25(OH)
represent vitamin D deficiency that inevitably results in osteomalacia, D3] [77]. To overcome these issues, a standard reference preparations

J Arthritis
ISSN: 2167-7921 JAHS, an open access journal Volume 1 • Issue 2 • 1000105
Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion: A Review of Current Knowledge and Consensus Recommendations.
J Arthritis 1:105. doi:10.4172/2167-7921.1000105

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were long awaited so that serum 25(OH)D can be accurately and reliably the sickest or who died during their ICU stay [100]. Similarly, very low
measured, and validated. In July 2009, a standard reference material has levels of vitamin D are reported in almost all different clinical settings,
been produced by the National Institute of Standards and Technology for example, in outpatient clinics, inpatients, and also in primary care
(NIST), in collaboration with the National Institutes of Health’s Office of settings [101-107]. Clearly, the risk of developing vitamin D deficiency
Dietary Supplements, and this is hoped to improve the standardisation extends well beyond the traditional risk categories of nursing home or
of operating procedures and reference intervals [78,79]. older housebound residents.

Prevalence of Vitamin D Deficiency Treatment of Vitamin D Deficiency

The prevalence of vitamin D deficiency is very well documented Natural foods are very poor reservoirs of vitamin D, and their
across the globe, and no age, race or the disease spectrum seem to be fortification is generally not sufficient. The treatment options to achieve
free of this deficiency. The majority of such studies are focussed on optimal circulating level of 25(OH)D are sunlight, artificial ultraviolet
high-risk patients, for example, elderly patients living in institutions, light and vitamin D supplementation.
children and young adults, and pregnant females. People in the younger
age groups, who are otherwise healthy, are assumed not to require a Vitamin D3 vs. Vitamin D2
dietary source of vitamin D. There is accumulating evidence of the high Vitamin D is available in two different formulations: vitamin
prevalence of vitamin D deficiency in healthy young adults. Among D2, better known as ergocalciferol; and Vitamin D 3, also called
rheumatology outpatient attendees (the patient’s ages ranged from cholecalciferol. Most experts believe that vitamin D3 is more efficacious
19-91 years of age, the mean age was 53 ± 16 years), a recent study than vitamin D2 in raising serum 25(OH) vitamin D levels. Rather, the
has shown that the age of patients did not substantially influence differential efficacy of vitamin D2 and D3 in the treatment of rickets
the prevalence of vitamin D deficiency, as 78% of patients who were
has been reported since 1930 [108]. There are a multitude of reasons
aged ≤30 years were low in vitamin D [80]. A UK study, which was
to explain this. For example, vitamin D2 has a shorter half life and an
carried out in similar rheumatology outpatient settings, has shown that
increased rate of clearance from the circulation. There is possibly a
vitamin D deficiency is significantly more prevalent amongst general
rheumatology outpatients than osteoporotic or osteopaenic patients, higher affinity of hepatic 25-hydroxylase for vitaminD3 than for vitamin
irrespective of whether they were receiving vitamin D supplementation D2 [109], and 1,24(OH)2 D2 has less affinity for vitamin D receptor
at the time of measurement [81]. Cystic fibrosis patients are well than does 1,24(OH)2 D3 [110]. This has been confirmed in birds,
known to suffer from low vitamin D levels due to poor absorption monkeys and rats [111-113]. In humans, vitamin D3 supplementation
of fat-soluble vitamins, and accordingly there are recommendations has been shown to raise 25(OH) vitamin D levels more than vitamin
of its routine monitoring and supplementations in such patients [82- D2 supplementation. Using equal molar doses of vitamin D2 and D3,
84]. Research has shown that the level of vitamin D deficiency and a study has shown a much greater increase of 25(OH) D levels with
secondary hyperparathyroidism among general rheumatology patients vitamin D3 [114]. Similarly another study reported that to obtain the
is comparable to the patients suffering from cystic fibrosis (87% vs. 90% same effect, the dose of vitamin D2 was 2.5 times the dose of vitamin
patients had vitamin D levels <30 ng/ml and 21% vs. 25% patients had D3 [115]. In another study, a single dose of 50,000 IU of vitamin D2 or
secondary hyperparathyroidism, respectively [80]. This makes one to D3 revealed that serum 25(OH)D returned to baseline levels by day 14
suggest that rheumatology patients are at a higher risk of suffering from with vitamin D2; however, with vitamin D3, the serum 25(OH)D levels
vitamin D deficiency; however, more research is needed to prove this peaked at day 14 and remained above the baseline levels up to day 28
hypothesis [116]. In intervention trials, the average increment in serum 25(OH)
D has been estimated at 1.2 nmol/l for every mcg (40 IU) of vitamin
The likely explanation for vitamin D deficiency in young adults is
D3 [117], and a much smaller increment of only 0.3nmol/L for every
the low consumption of vitamin D containing foods, lack of exposure
to sunlight and limited outdoor activities. The fact that there are very microgram of vitamin D2 supplementation [118]. Another very recent
few foods, which are fortified with vitamin D in Europe, complicates trial, using vitamin D doses of 50,000 IU/week for 12 weeks, has revealed
this issue. The problem is not confined to the residents of temperate that D3 was not only about 87% more potent in raising and maintaining
climates; there are also reports of a high prevalence of low vitamin serum 25(OH)D concentrations, but also produced 2- to 3-fold greater
D status among people living in Qatar, Middle East, India, Pakistan, storage of vitamin D than does equal doses of D2 [119]. Conversely, it
and Ethiopia [85-89]. Moreover, it is alarming to note that in recent has been shown in some studies that vitamin D2 and vitamin D3 are
years, a resurgence of rickets has been observed among ethnic and equally effective in humans to raise circulating 25(OH)D levels [120-
cultural minority groups in the United Kingdom, Netherlands, 122]. We believe that vitamin D3 is a more potent form of vitamin D
Denmark and in Australasia [90-97]. Similarly, another report, where compared to vitamin D2, and should preferable be used. However, it is
25-hydroxyvitamin D were assessed in 8532 European postmenopausal important to emphasise that the increase in serum vitamin D levels is
women with osteoporosis or osteopenia, has shown a high prevalence inversely related to the starting level of 25(OH)D [123].
of vitamin D inadequacy in European postmeno¬pausal women (79.6% Available guidelines
and 32.1% when considering cut-offs of 80 and 50 nmol/L, respectively)
[98]. Among HIV-infected patients, a recent study has reported a high There are a number of recommendations from different clinical
prevalence of low vitamin D levels (70%). It has also been observed organisations for addressing the epidemic of vitamin D deficiency.
that some HIV therapies effect vitamin D metabolism and contribute These clinical practice guidelines are based on expert opinions and a
to its deficiency [99]. Very low levels of vitamin D have been described review of the available evidence.
in critically ill patients. Australian researchers have noted that almost • A position statement from the working group of the Australian and
half of people in an intensive care unit (ICU) were deficient in vitamin New Zealand Bone and Mineral Society, Endocrine Society of Australia
D, with the lowest levels of vitamin D noted among those who were and Osteoporosis Australia outline the people at risk of developing

J Arthritis
ISSN: 2167-7921 JAHS, an open access journal Volume 1 • Issue 2 • 1000105
Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion: A Review of Current Knowledge and Consensus Recommendations.
J Arthritis 1:105. doi:10.4172/2167-7921.1000105

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vitamin D deficiency, and the recommendations for managing vitamin September 2010 [130], and supported recommendations aiming
D deficiency [124]. This states that a significant number of people for serum 25-hydroxyvitamin D levels above 75 nmol/L. These
residing in Australia are deficient in vitamin D. The general population recommendations were directed for general population and not
should ensure the exposure of hands, face and arms to one-third confined to osteoporotic population. Vitamin D supplementation was
of a minimal erythemal dose of sunlight, or should take vitamin D considered indicated given that most Canadian adults have insufficient
supplement of 400 IU/day. Patients with vitamin D deficiency should exposure to sunlight and dietary intake to maintain this level
take supplementation of 3000–5000 IU ergocalciferol per day for 6–12
throughout the year. Recommended intake for low-risk and younger
weeks, and in those with moderate to severe deficiency, larger-dose
preparations of vitamin D should be considered. adults was suggested at 400–1000 IU daily and for high-risk and older
adults, to 800–2000 IU daily.
• An international public health project was initiated and named as
Daction in an attempt to better address vitamin D deficiency [125]. This • In late 2010, new Canadian guidelines for the management of
particularly emphasises the importance of maintaining vitamin D levels osteoporosis were published, which recommend higher intakes, with
at 100-150nmol/L, and this was considered as safe. routine supplementation at 400 to 1000 IU daily for those at low risk
and up to 2000 IU daily for high-risk individuals [131]. It is important
• In 2007, the Canadian cancer society announced recommendations
to note here that such higher intake of vitamin D are suggested for
of vitamin D supplementations, based on the mounting evidence linking
osteoporotic patients only.
vitamin D to reduced risk of different cancers [126]. It was suggested
that during the autumn and the winter, all adult Canadians should • In November 2010, Institute of Medicine (IOM) updated their
consider taking 1000 IU/day of vitamin D, however, people at high- original 1997 set of recommendations. They concluded that the
risk of developing vitamin D deficiency should consider supplementing majority of Americans and Canadians are receiving adequate amounts
1000 IU/day of vitamin D throughout the year. of both calcium and vita¬min D, and also warned regarding the
We believe that a word of caution is needed, given the lack of well- toxicity of vitamin D with bigger doses [78]. Although, they reviewed
designed randomised-controlled trials to prove or disprove the notion a range of health outcome measures, inconclusive and unreliable
of a causal role of vitamin D in cancer prevention. However, since there evidence of vitamin D and calcium supplementation was noted in all
is very low risk of harm in enhancing vitamin D levels, we strongly of these outcomes, apart from its role in bone health. Therefore, these
support the need for vitamin D repletion recommendations are based on the role of vitamin D and calcium in
• Guidelines from Poland also recommend that those adults with bone health only. These recommendations suggest: the adequate level
inadequate sun exposure or those aged >65 years, require a minimum of serum 25(OH)D is 45nmol/L (20 ng/ml), with a range of 45-75
supplementation of 800-1000 IU/day of vitamin D [127]. nmol/L (20-50 ng/ml); there is no improvement in bone growth and
• A round table discussion at the 5th International Symposium maintenance with vitamin D levels above 75 nmol/L (50 ng/ml); the
on the Nutritional Aspects of Osteoporosis was held in 2003, and the upper limit of daily intake is now doubled to 4,000 IU of D3 per day;
consensus among the experts was that a daily intake of 600 IU of vitamin and recommended dietary allowance (RDA) has been set at 600 IU/
D is required to reach a mean serum 25(OH)D level of 50 nmol/l, and day for everyone apart from those aged >70 years of age, where RDA
an intake of at least 800–1,000 IU is needed to attain a mean level of 75 was suggested to be at 800 IU/day. It should be emphasised that IOM
nmol/l. Moreover, it was suggested that a level between 50-80 nmol/L was given the task of assessing the current data on health outcomes
is required for optimal bone health, with a consensus median threshold associated with calcium and vitamin D, and to update dietary reference
of 75 nmol/L [128]. intakes. Hence, this IOM report is a guide to food manufactures, and
• International Osteoporosis Foundation (IOF) published its it was not the mission of that report to offer medical guidance for
position statement on optimal vitamin D status in early 2010 [129]. physicians, rather this should be left to the various societies issuing
These guidelines were specifically designed for elderly women and men their own medical recommendations. These recommendations have
aged over the age of 60 to 65 years, since most of the available evidence is been controversial [132], but one good outcome is the undoubted
based on this particular subset of population. These recommendations recognition of the key role of calcium and vitamin D in skeletal health,
are: consistent with a cause-and-effect relationship. Hence, rheumatologists
■ The dose of vitamin D required for optimal vitamin D status should routinely consider identifying and treating this extremely
depends on an individual’s baseline level of 25(OH) D, their BMI, and common condition – low vitamin D state - which has got excellent
their level of sun exposure. potential for both prevention and treatment.
■ For fall and fracture prevention, a serum 25(OH) D threshold of Effects of intermittent high-dose of vitamin D regimens
75 nmol/L is considered optimal.
It is also important to discuss recent concerns regarding very high
■ Serum 25(OH)D increases by about 1 ng/mL (2.5 nmol/L) for doses of vitamin D regimens. A double blind placebo-controlled trial
every 100 IU of additional vitamin D each day
has shown that a single annual 500 000-IU oral dose of cholecalciferol
■ The estimated average vitamin D requirement to acquire the (vitamin D3) increased risk of falls and fractures, with the greatest
serum level of 75 nmol/L is 800 to 1,000 IU per day. This might need increase occurring during the first 3 months after dosing [133].
to be adjusted depending on the associated risk factors, such as, the Similarly, another randomized, double-blind, placebo-controlled
starting level of 25(OH)D, obesity, associated osteoporosis, poor sun trial has evaluated the efficacy of annual 300,000 IU intramuscular
exposure, malabsorption and residents or immigrants from South Asia vitamin D2 (ergocalciferol) injection over 3 years. This particular study
and Middle East. has reported that annual high doses of vitamin D were ineffective in
■ To measure serum vitamin D levels for such at risk populations, preventing non-vertebral fractures [134]. It seems that rather than
as this not only helps to estimate the repletion dose, but also serves as a very high doses of intermittent vitamin D replacements, more frequent
baseline for future retesting. lower-doses regimens should be opted. Clearly, further research is
needed to better understand these findings.
• Osteoporosis Canada published its guidelines statement in

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Controversy over Calcium and Vitamin D: Calcium or all post-menopausal women and men over 65 years take daily calcium
No Calcium supplementation of 1200 mg/day, and it is imperative to assess dietary
calcium consumption and adjust the total calcium intake accordingly.
An acceptable threshold for calcium intake has not been defined so . This is worth highlighting that presumed normal range of calcium
far. Most studies have used a daily calcium dose of 1,000-1,200 mg [135- levels differ in many countries, and it is vital to use reference local
138]. There had been some controversy as regards the additional benefit population otherwise, there is a potential risk of labelling erroneously
of adding calcium to vitamin D for fracture prevention. The arguments hypercalcaemia/hypocalcaemia. Clearly, further work needs to be done.
against achieving any significant benefit of adding calcium to vitamin
D comes from two studies, which showed that non-vertebral fracture Safety of Repleting Vitamin D Stores
prevention is calcium-independent provided the vitamin D dose is Vitamin D therapy is generally considered safe in most individuals.
greater than 400 IU per day [139,140]. Moreover, a 2007 meta-analysis There is no evidence of adverse effects with serum 25(OH)D ≤ 70
has revealed that calcium supplementation, whether in lower or higher ng/ml, i.e. 175 nmol/L. In addition, published reports of vitamin D
doses, had no effect on hip fracture risk reduction [141]. Likewise, a toxicity have nearly all involved intake ≥ 40,000-50,000 IU per day
2009 meta-analysis revealed no additional benefit of adding calcium for prolonged period of times [153]. It has been shown that healthy
therapy to higher doses of vitamin D supplementation (482-770 IU/ humans produce about 4,000 units of vitamin D a day, from all sources
day) for non-vertebral fracture risk reduction [142]. On the contrary, [154]. Moreover, studies using 10,000 IU of vitamin D/day for up to
Tang et al. has shown in 2007, through an extensive meta-analysis, that 5 months did not cause toxicity [155]. Currently, the upper tolerable
combination of calcium and vitamin D is more effective than calcium level for vitamin D supplementation is 2,000 IU/day for both males and
or vitamin D alone. More importantly, it showed that most papers females (1 year and older) including pregnant and nursing females, and
reporting a negative effect of the calcium-vitamin D association were 1,000 IU for infants (0-12 months). Some experts raise the upper limit
of vitamin D supplementation to 10,000 IU as per many safety trials
linked to a poor adherence to treatment [143], and minimum doses of
[156]. The issue of toxicity was especially highlighted when accidental
1200 mg of calcium and 800 IU of vitamin D were recommended for overfortification of milk from 1985 to 1991 led to a suspected outbreak
best therapeutic effect. of hypervitaminosis D associated with severe illness and death in the
Similarly, three recent systematic reviews, including a Cochrane USA [157]. It is unfortunate that most trials have excluded subjects with
review, have concluded that vitamin D supplementation without renal insufficiency or hypercalcemia, and included short durations of
exposure to vitamin D. The WHI trial was the largest trial (seven years
additional calcium intake was ineffective in preventing fractures [144-
follow up of 36,282 subjects) showing a significant increase in kidney
146]. A consensus statement from leading osteoporosis societies has
stones among postmenopausal women taking only 400 IU vitamin D3
suggested the combination of vitamin D with calcium, both for their plus calcium 1,000 mg a day [138]. However, it is difficult to make firm
better efficacy and, perhaps, for optimising adherence [147]. conclusions from this study due to the following: documentation was
Extraskeletal adverse events of calcium intake are quite made of only patient reported renal stones rather than the review of
complicated. Recent meta-analysis of randomised placebo controlled medical records or confirmed by physicians, and very poor compliance
rate of only 50-55%. A systematic review has found inadequate
trials showed that calcium supplementation at doses of ≥500 mg/day
reporting quality of vitamin D toxicity and inadequate power to detect
without additional vitamin D was associated with a 30% increase in adverse events in most of the reported trials; however, good tolerability
the incidence of myocardial infarction and an insignificant increase of vitamin D supplementation above current reference intakes was
in the risk of stroke and mortality [148]. Similarly, a 2008 randomised observed [17].
controlled trial of 1,000 mg/day of calcium revealed a 47% increase in
relative risk of combined cardiovascular endpoints [149]. Furthermore, One plausible explanation for vitamin D toxicity is the
the association of calcium intake with renal stones is well established. combination of heavy sun exposure with excessive supplementation
of vitamin D. There are a number of contraindications to vitamin
A randomized controlled trial in 36,282 postmenopausal women
D therapy. Hypersensitivity to vitamin D can occur, and primary
reported that a combination of supplemental calcium (1,000 mg/ hyperparathyroidism is the most common example where vitamin
day) and vitamin D (400 IU/day) was associated with a 17% increase D may exaggerate hypercalcemia. Occasionally, hypercalcemia due
in the incidence of renal stones or renal insufficiency [138]. On the to vitamin D therapy can occur when large groups of elderly people
contrary, a recent analysis of calcium supplementation and the risk of are given vitamin D supplements, but this is likely due to the fact that
atherosclerotic vascular disease in older women has shown calcium vitamin D deficiency can mask primary hyperparathyroidism in this
supplementation of 1200 mg daily does not significantly increase the group. In addition, patients with chronic granulomatous diseases, such
risk of atherosclerotic vascular disease in elderly women. This analysis as sarcoidosis, tuberculosis and lymphoma can become hypercalcemic
was based on the results of a 5-year randomized controlled trial with with vitamin D supplementation as there is additional production
a further 4.5-year follow-up observation [150]. Similarly, long-term of 1,25-dihydroxyvitamin D from macrophages [158,159]. These
follow up of RECORD study patients has shown that daily vitamin D or conditions are preferably labelled as “vitamin D hypersensitivity
calcium supplementation did not affect vascular disease mortality [151]. syndromes”.
Studies to date do not permit definitive conclusions since no randomised Vitamin D toxicity remains undetected for a considerable period of
controlled trials have been conducted primarily to assess the effect of time, and usually presents initially with elevated urine calcium excretion
calcium supplementation on vascular events. Rather the information and later on, an elevated serum calcium levels. Early symptoms of
is based on secondary analysis and reviewing the unpublished data hypercalcemia may include nausea, vomiting, and anorexia, followed
on cardiovascular events from the previous studies. Due to these by polyuria, polydipsia, weakness, fatigue, somnolence, headache, dry
concerns, it seems reasonable to recommend supplementing vitamin mouth, metallic taste, vertigo, tinnitus, and ataxia. Renal impairment
and metastatic calcifications may occur, particularly affecting the
D and calcium only to those who are at increased risk of osteoporosis,
kidneys. Elevated serum calcium levels are a constant finding when
and very reassuringly, calcium and vitamin D supplementation does toxic symptoms occur. Serum 25(OH)D levels are usually elevated
not influence coronary or cerebrovascular risk in generally healthy >150 ng/mL (>375 nmol/L). For the diagnosis of vitamin D toxicity,
postmenopausal women [146,152]. We recommend that at the very least levels of 1,25(OH)2D need not to be measured, as they may be normal.

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Citation: Haroon M, Fitzgerald O (2012) Vitamin D Deficiency and its Repletion: A Review of Current Knowledge and Consensus Recommendations.
J Arthritis 1:105. doi:10.4172/2167-7921.1000105

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Treatment consists of stopping vitamin D, restricting dietary calcium, • The cut-offs to define vitamin D deficiency should ideally be based
restoring intravascular volume deficits, and, if toxicity is severe, giving on determining an optimal level for health as opposed to the minimum
corticosteroids or bisphosphonates. However, it is quite reassuring that level to prevent severe deficiency
toxicity stemming from pharmacological doses of vitamin D is very
uncommon, and majority of such reports of toxicities are caused by • It is hoped that the standardisation of operating procedures and
accidental overdose. Vigilance is imperative as the response to vitamin reference intervals will improve with the production of a standard
D supplementation or sun exposure widely varies; however, there reference material by the National Institute of Standards and Technology
are no consensus regarding how to best monitor those using regular (NIST), in collaboration with the National Institutes of Health’s Office
of Dietary Supplements.
supplementations.
• The prevalence of vitamin D deficiency is very well documented
Conclusion across the globe, and no age, race or the disease spectrum seem to be
free of its presence.
In summary, vitamin D deficiency is now well recognised as a
growing health concern. There is enough evidence to support its role • There is some evidence to support that vitamin D3 is more
in bone health; however, there is insufficient evidence to prove its role efficacious than vitamin D2 in raising and maintaining serum 25(OH)
beyond musculoskeletal health. Given the extreme rarity of vitamin D vitamin D levels
toxicity, it seems reasonable to advise general public (at the very least in • There is no evidence of adverse effects with serum 25(OH)D ≤
all post-menopausal women and men >65 years of age) regarding the 70 ng/ml, i.e. 175 nmol/L. However, most trials have excluded subjects
use of such foods, which contain higher contents of vitamin D, or to use with renal insufficiency or hypercalcemia, and included short durations
fortified food products. A clear public health strategy and guidance on of exposure to vitamin D. Continuous monitoring is essential as the
vitamin D supplementation is warranted. We hope that with growing response to vitamin D supplementation or sun exposure widely varies.
interest and research in the role of vitamin D, effective management
• Varied results of calcium-vitamin D association for bone health
strategies will emerge. . have been reported, however, based on the current evidence, we
recommend (at the very least in all post-menopausal women and men
Future Perspective > 65 years) the combination of minimum doses of 1200 mg of calcium
Firstly, standardization of vitamin D deficiency and repletion and 800 IU of vitamin D for best therapeutic effect.
protocols are required to better frame future studies of vitamin D
supplementation. Secondly, studies should also aim for genotype References
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