Diagnosis and management of vitamin D deficiency
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5664 (Published 11 January 2010) Cite this as: BMJ 2010;340:b5664All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
In recent years there has been an intense interest in the role of
vitamin D (VitD) as more clarity emerges on its role in numerous
physiological functions. The recent review by Pearce and Cheetham, 2010
[1] has addressed the clinical and biochemical changes associated with
VitD deficiency as well as the population at risk of hypovitaminosis D.
The epidemic proportions of VitD insufficiency has encouraged public
health measures for supplementation, based on the preposition that
restoration of normal VitD status will be beneficial. Nonetheless, in
current clinical practice there is a wide variation in treatment targets
for VitD concentrations as well as VitD supplementation doses and
frequency.
VitD circulates mainly as the inactive 25-hydroxy-vitamin D (25OHD)
which is then converted to the active form 1, 25-dihydroxy-vitamin D
(1,25(OH)2D), by 1 alfa-hydroxylation predominantly in the kidney. It is
the latter that is the main regulator of calcium (Ca) homeostasis along
with parathyroid hormone (PTH) [1]. In routine practice serum total 25OHD
is measured to identify VitD insufficiency and monitor response to
treatment due to its relatively higher circulating concentration, ease of
measurement and longer half life compared to 1,25(OH)2D [1] and the
difficulty of relating concentrations with clinical status, except in rare
conditions of the VitD receptor defects [2]. An area of concern often
overlooked is the diagnoses of insufficiency being based on a biochemical
measurement commonly done by immunoassays, which themselves are subject to
analytical variability [3, 4]. Nonetheless, a concentration of 25OHD in
the range of 25-80 ug/L (63 - 200 nmol/L) is considered optimal for bone
health [5] and is a suitable target to achieve in clinical practice. At
the other end of the spectrum VitD toxicity is extremely rare with the
majority of patients with reported VitD toxicity having concentrations
>150ug/L (374nmol/L) [1].
Recommendations from the Institute of Medicine (IOM), for VitD
supplementation suggest 200 IU/d from birth-50 years, 400 IU/d for ages 51
-70 years, and 600 IU/d for those >70 years old [1]. Recent evidence
show that dietary VitD intake correlates poorly with 25OHD concentrations
and that concentrations can remain marginal deficient despite consumption
of the recommended amount of VitD [4]. In the British National Formulary
(BNF) although a variety of VitD preparations are listed high strength
oral preparations are not readily available in tablet form [1].
Importantly oral supplementation using colecalciferol has been shown to be
more effective compared ergocalciferol and intramuscular administration
[6, 7]. Pearce and Cheetham, 2010, have recommended different treatment
regimes in order to optimise VitD status [1]. To ensure that serum 25OHD
concentrations exceed 40ug/L (100nmol/L), a total VitD supply of 4000 IU
(100mg) /d is required. There have been a number of studies supplementing
different doses of oral VitD (400IU to 40000IU/d). In a majority of these
adequate VitD status was achieved in either those with baseline
concentrations >25ug/L or with long duration (12-36 m) of treatment at
lower doses [4] however, optimum VitD status was achieved in a short
period (9m) at doses >10000IU/d [4].
We assessed the biochemical effectiveness and tolerability of an easy
to work through high dose oral supplementation protocol for the treatment
of hypovitaminosis D, in a busy outpatient Metabolic Bone Clinic setting
at a tertiary referral hospital. Sixty patients with fragility fractures
referred with hypovitaminosis D [<15ug/L (37nmol/L)] were treated
according to the protocol; 40000 IU [two capsules of Dekristol (IDIS, UK)]
daily for the first week, followed by 40000 IU (two capsules) once a month
for the next six months. The 25OHD, corrected Ca, phosphate, bone alkaline
phosphates and PTH were measured before and after six-month
supplementation (Table 1).
Table 1: Biochemical results at baseline and at six-month post high
dose oral vitamin D supplementation. All results expressed as median
(IQR). P value was calculated by Mann-Whitney U Test and a p value
<0.05 was considered significant.
=======================================================
Investigation Baseline / 6 month follow-up [p value]
25-Hydroxy vitamin D (ug/L)
7.5 (5.7-10.8) / 27.4 (19.4-37.8) [<0.001]
Corrected Calcium (mmol/L)
2.22 (2.18-2.28) / 2.26 (2.21-2.31) [0.82]
Phosphate (mmol/L)
1.21 (1.10-1.31) / 1.22 (1.12-1.37) [0.82]
Bone Alkaline Phosphatase (IU/L)
75 (61-107) / 70 (51-89) [0.27]
Parathyroid Hormone (pg/L)
80 (56-107) / 64 (47-80) [0.05]
=======================================================
In total, 57% achieved a 25OHD of >25ug/L on our high dose
protocol and of those with severe VitD deficiency (<10ug/L), 53%
reached an optimal 25OHD of >25ug/L. Importantly all patients reported
good compliance with no side effects and the percentage of patients
achieving VitD >25ug/L was higher than previously reported. However the
Deskritol preparation used in our protocol is currently an unlicensed
import to UK, thus naming this preparation will incur 'private
prescription' costs and local pharmacies can levy additional importing
costs. Hence, we compared the over the counter colecalciferol preparations
in the UK as potential substitutes (Table 2).
Table 2: Comparison of Deskritol with some of the popular over the
counter oral colecalciferol supplements
=======================================================
Oral Vitamin D Preparation / Trade Name (Manufacturer) / Available
dose Quantity per pack) / Cost per pack (GBP) / Cost for 6-month
supplementation - dose (GBP)
1. Colecalciferol capsules / Deskritol (IDIS, UK) / 20000 IU (50) /
19.30 / 26 (10.03)
2. Colecalciferol liquid / Martindale Pharma / 3000 IU/mL (100 mL) /
71.14 / 173.29mL (123.27)
3. Colecalciferol tablets / SunVit-D3 (D3 Vitamin LLP) / 1000 IU
(180) / 8.16 / 520 (22.85)
4.Colecalciferol tablets / Ultra-D3 (Vitabiotics Ltd) / 1000 IU (96)
/ 5.00 / 520 (27.08)
5.Colecalciferol chewable / BioLife (Lifestyle Natural Health) / 1000
IU (90) / 9.95 / 520 (57.48)
6.Colecalciferol capsules / Vitamin D3 (Natures Remedy) / 1000 IU
(100) / 6.99 / 520 (36.35)
7.Colecalciferol capsules / Vitamin D3 (Softgels Solgar) / 1000 IU
(100) / 7.05 / 520 (36.66)
8.Colecalciferol capsules / Vitamin D (Higher Nature) / 500 IU (120)
/ 5.50 / 1040 (47.67)
=======================================================
As summarsied in Table 2, not only are Deskritol 20000 IU capsules
more cost effcetive but may also improve patient compliance as the lower
strength preparations will require on avearge >500 pills in order to
demonstrate comparable efficacy. Our protocol also fares better in terms
of cost than taking 20000 IU/d for 3m or longer [4].
Giving high dose oral colecalciferol as a priming dose followed by a
lower dose maintenance is preferable to low dose daily preparations and iv
routes. Combination with calcium supplements should be for those
intolerant to dairy produce or vegeterians with high phytate in their
diet. Concurrent calcium supplements has alerted the public to other non-
skeletal risk risks and therefore previous widespread prescriptions of
combined calcium and VitD should be reconsidered with a risk of non-
compliance.
Royce P Vincent: Specialist Registrar Chemical Pathology.
royce.vincent@nhs.net,
Sarah A Brannigan: Fracture Prevention Nurse Specialist, David Shipnaugh:
CAPA International Education Student, Mark Phillips: Orthopaedics
Consultant & Caje Moniz: Consultant Chemical Pathologist
Reference
1. Pearce SH, Cheetham TD. Diagnosis and management of vitamin D
deficiency. BMJ. 2010;340:b5664.
2. Cozzolino M, Brenna I, Volpi E et al. Restoring the physiology of
vitamin D receptor activation and the concept of selectivity. Contrib
Nephrol. 2011;171:151-6.
3. Carter GD. Accuracy of 25-hydroxyvitamin D assays: confronting the
issues. Curr Drug Targets. 2011;12:19-28.
4. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D
concentrations, and safety.
Am J Clin Nutr 1999;69:842-56.
5. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults:
when to test and how to treat. Mayo Clin Proc 2010;85:752-7.
6. Romagnoli E, Mascia ML, Cipriani C et al. Short and long-term
variations in serum calciotropic hormones after a single very large dose
of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the
elderly. J Clin Endocrinol Metab 2008;93:3015-20.
7. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2)
as a vitamin supplement. Am J Clin Nutr 2006; 84: 694-7.
Competing interests: No competing interests
Dear Editor
Vitamin D deficiency in children remains a significant healthcare problem.
Pearce and Cheetham, in their article on 'Diagnosis and management of
Vitamin D deficiency', quite clearly recommend the use of calciferol
(3,000-6,000 IU per day) in the treatment of Vitamin D deficiency in
children . Expert opinion from the British Society for Paediatric
Endocrinology and Diabetes also confirm this recommendation, yet
anecdotal evidence suggests that some children diagnosed with vitamin D
deficiency are being treated inappropriately.
We have recently completed a prospective 2 year survey of Vitamin D
deficiency in Wales where newly presenting cases (under the age of 16)
were notified through the Welsh Paediatric Surveillance Unit (WPSU), a
surveillance programme for rare disorders with participation from all
paediatricians in Wales.
14 new cases were notified (2007-08), with all except one case coming from
ethnic minority families. The mean (range) age at diagnosis was 14 months
(10 days-3 yrs) giving an incidence in Wales of 4.3/100,000 (0-4 years).
Ten were breastfed from birth with 8 still being breastfed at time of
diagnosis. None of the mothers received Vitamin D during pregnancy. Seven
had radiological evidence of rickets and non-skeletal findings varied from
pain (n=2) to failure to thrive (n=2) and developmental delay (n=3). All
had low Vitamin D levels (mean 4.1, range <4-14.5?g/l, [normal
>20?g/l]), raised PTH (mean 61, range12.1-260pmol/l, [normal 0.9-
5.4pmol/L]) with six having hypocalcaemia and five hypophosphataemia.
There was wide variation in treatment offered which included
Ergocalciferol (D2) and Cholecalciferol (D3) in adequate doses to nine
children, some with the addition of Calcium Sandoz. However five children
were being inappropriately treated with Calcit D3 (n=1), Calcichew D3
(n=1) and alfacalcidol (1 ? hydroxycholecalcidol) (n=3). Calcit D3 and
Calcichew D3 only contain 440 and 400 IU respectively of calciferol and
would be insufficient to treat Vitamin D deficiency. Alfacalcidol is
inappropriate as it does not replace Vitamin D stores. Furthermore,
alfacalcidol should only be used where there is an abnormality in renal
hydroxylation of Vitamin D or PTH deficiency/resistance such as
hypophosphataemic rickets, hypoparathyroidism or pseudohypoparathyroidism,
patients with 1-alpha hydroxylase deficiency and patients with chronic
renal disease who are hypocalcaemic and/or have raised PTH.
This small survey worryingly suggests that approximately one third of
children with Vitamin D deficiency are being inappropriately treated once
the diagnosis has been made. Since the incidence of Vitamin D deficiency
in children appears to be increasing3, healthcare professional dealing
with this disorder need to be better informed of treatment modalities.
Ref:
1 Pearce SHS, Cheetham TD. Diagnosis and management of vitamin D
deficiency. BMJ 2010;340:142-147
2 Algrove J. Vitamin D expert opinion.
http://www.bsped.org.uk/professional/guidelines/index.htm 2009;accessed
10th January 2011.
3 Misra M, et al on behalf of the Drug and Therapeutics Committee of the
Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in
children and its management: review of current knowledge and
recommendations. Pediatrics. 2008;122 (2):398 -417
Competing interests: No competing interests
Dear Sir,
vitamin D assays and calcium method standardisation
There is a fair amount of discussion relating to vitamin D both in
the medical and lay press and other media with scare stories of a shortage
of vitamin D in UK pharmacies and patients requiring huge doses ( Radio
4, "You and Yours", 26th August 2010). The basic assumption that all of
these reports make is that the 'number' generated by the vitamin D assay
actually correlates with clinical observations. It seems that the bulk of
this 'evidence' has been adduced from the NHANES1,2 and WHI3 studies which
both showed that the incidence of hip fractures is increased in the
lowest quintile of vitamin D concentrations. The NHANES study did not
correct data for age or other risk factors for fractures , in terms of
vitamin D, data were corrected for BMI, sun blockers and milk intake. The
outcome of the randomisation of postmenopausal women onto supplementation
or not was a slight increase in hip bone density, but no change in the
fracture rate. So although there was a higher relative risk of hip
fractures in the quartile with the lowest vitamin D, supplementation did
not materially alter outcome. A recent report from Sweden showed a much
lower incidence of vitamin D deficiency in that Northern population. As
anyone with an interest in this field can attest there are different cut-
offs for diagnosing so-called severe deficiency or deficiency varying from
25-70 ?g/l .
I have recently audited the results of calcium and vitamin D requests from
general practice as well as in-patients to our Chemical Pathology
laboratory. The initial purpose of the audit was to identify the
prevalence of hypocalcaemia which, anecdotally, seemed inordinately high
locally and also to establish a protocol for more targeted vitamin D
requesting. The initial audit reviewed 66860 results of requests for
calcium measurement (between 29.07.2009 and 30.04.2010) of whom 20128 had
hypocalcaemia, 46010 were normocalcaemic and 722 patients were
hypercalcaemic (prevalence of 30% for hypocalcaemia), confirming the
suspicion that our method was probably reporting with a negative bias. Of
these, 1154 patients also had a request for vitamin D analysis (referred
to another laboratory that uses tandem mass spectrometry to measure 25-
hydroxyl vitamin D - regarded as the 'gold-standard').
60% of the requests to measure vitamin D were on normocalcaemic patients
(table 1), 1% on hypercalcaemic patients and the rest on hypocalcaemic
patients. These were single measurements in almost all cases.
Of the hypocalcaemic patients 401 (48%) had low vitamin (assuming 70
nmol/l as cut-off) and of the normocalcaemic patients 432 (52%) had low
vitamin D. 17% had raised vitamin D. There was no correlation with PTH nor
ALP. In fact of 1154 patients only 17 patients had 'biochemical'
hypocalcaemia (low calcium with raised PTH) together with a raised ALP
with low or undetectable vitamin D. ROC analysis (figure 1) shows that
vitamin D had no ability to identify or classify patients with
hypocalcaemia. Subsequent to the initial audit , I carried out a second
audit on three months of identical data, subsequent to implementation of a
new calcium assay. These data show a prevalence of 17% of hypocalcaemia,
and the vitamin D assay performing slightly better (figure 2), but still
not fit for purpose. This illustrates two potential problems. The first
being that calcium assays may not be correctly reporting calcium
concentrations as our assay was not (although performing adequately on all
quality assurance schemes) and the vitamin D assay used may not reflect
active cellular vitamin D and therefore pathology.
Hypovitaminosis D may be a clinical problem and certainly have
consequences, but I question whether the current assays can correctly
identify 'true' vitamin D deficiency. Before this issue becomes
politicised and a potential target for policy change, the assays need
intensive scrutiny and development.
References:
1. Looker Anne C et al 2008 Serum 25-hydroxyvitamin D status of the US
population: 1988-1994 compared with 2000-2004 The American Journal of
Clinical Nutrition 88(6):1519, 2008
2. Looker Anne C et al 2008 Calcium plus vitamin D supplementation and
the risk of fractures. New England Journal of Medicine 354;7: 669-681.
3. Cauley Jane A et al 2008 Serum 25-Hydroxyvitamin D Concentrations and
Risk for Hip Fractures Annals of Internal Medicine August 19, 2008 vol.
149 no. 4 242-250
4. Gallagher, J Chris, and Sai, Adarsh 2010 J. Vitamin D insufficiency,
deficiency and bone health. J Clin Endocrinol Metab 95(6):2630-2633
5. Melhus H et al 2010 Plasma 25-hydroxyvitamin D levels and fracture risk
in a community-based cohort of elderly men in Sweden. J Clin Endocrinol
Metab 95:2637-2645.
6. Priemel M et al 2010 Bone mineralisation defects and vitamin D
deficiency: histomorphometric analysis of iliac bone crest biopsies and
circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 25:305-
312
Competing interests: No competing interests
We have a practice with a significant ethnic minority population in
Glasgow, latitude 55°N and not famed for its sunshine. We decided to look
at knowledge of pregnant women from ethnic minority backgrounds regarding
the need for vitamin D in pregnancy and whether vitamin D supplements were
actually being taken.
Of 20 women approached, 17 responded. Of those, 11 (65%) were aware
of the importance of adequate vitamin D intake in pregnancy. 10 (59%)were
taking a preparation containing vitamin D (of which 3 were a prescribed
calcium and vitamin D preparation and 7 were a leading brand multivitamin
marketed for pregnancy). The proportion of women buying over the counter
vitamins was similar to that noted by Zipitis, El Azabi and Samanta [1].
Interestingly 50% (3) of the women not aware of the need for vitamin D
were on supplements, while only 64% (7) of the women who seemed to be
aware of the need for vitamin D were actually taking them. There were 5
women previously known to be vitamin D deficient. Of those, 3 (60%)were
aware of the need for vitamin D in pregnancy and were taking supplements,
while 2 (40%) were not aware of this and not taking their supplements
(even though these had been prescribed).
There is clearly a need for better education in this area. The same
number of women recalled being told about vitamin D by a doctor or a
midwife. Only 7 (41%) of women had heard of the Healthy Start Scheme, and
we note that none of our patients were taking Healthy Start vitamins.
However, this may because the scheme has only been rolled out in our area
since the start of the year. The Healthy Start vitamins would certainly be
more economical than the leading brand which was widely used (albeit there
is a slight anomaly in that pregnant women are entitled to free
prescriptions but are asked to pay for this recommended supplement unless
on benefits). We will in future recommend Healthy Start vitamins to women
at their initial consultation when pregnant.
One reason given by women with know vitamin D deficiency for poor
compliance was the unpalatability of supplements. We therefore arranged a
blind tasting of calcium and vitamin D supplements on the NHS Greater
Glasgow and Clyde formulary at a practice meeting. The universal opinion
was that the generic calcium and ergocalciferol tablets were disgusting,
although the branded products (which all contained significantly more
calcium) were tolerable. Of note, the calcium and ergocalciferol tablets
were also the most expensive (£7.03 for 30 days on a BD dosage, compared
to £3.69 for the cheapest branded product with equivalent vitamin D but
more calcium). We agree that there is a need for a suitable economical
preparation available on prescription for treatment of vitamin D
deficiency and subsequent longterm supplementation. The Healthy Start
vitamin tablets are not prescribable, but contain only vitamin C and folic
acid in addition to vitamin D 400IU(although the drops contain vitamin A).
Could there be a role for wider use of these in the meantime as an
acceptable form of vitamin D supplementation for those at risk?
Reference:
1. Zipitis, El Azabi and Samanta. Vitamin D supplementation, guidelines,
and awareness of midwives and new mothers. Rapid Response BMJ 29 January
2010
Competing interests:
None declared
Competing interests: No competing interests
Vitamin D3: Is there an upper limit?
Pentti Tuohimaa1,2, Marianne Kuuslahti1 and Yan-Ru Lou3
1Department of Anatomy, Medical School, University of Tampere, Finland
2 Centre for Laboratory Medicine, Tampere University Hospital, Finland
3Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Finland
The review article entitled "Diagnosis and management of vitamin D deficiency" by Pearce [1] begun a vivid discussion in this journal. The general trend in those papers is that a significant vitamin D fortification is needed and serum concentrations of 25OHD3 should 75 nmol/L or more [2]. The comments cover several important aspects. However, two important aspects of vitamin D endocrinology were not covered:
1. The feedback systems in vitamin D endocrinology
2. The known risks of a slightly elevated serum concentrations of 25OHD3.
For more than two decades, a reciprocal feedback between 25OHD3 and 1,25(OH)2D3 has been known and the metabolic clearance rate seems to be the explanation, because 24-metabolites increase in the serum [3-5], but also the rate of synthesis of the respective metabolite might be affected. Since 25OHD3 is known as an inactive precursor metabolite, these findings were not understood before our recent study demonstrating the hormonal activity of 25OHD3 [6] and its synergistic action with 1,25(OH)2D3 [7]. Thus, 1,25(OH)2D3 and 25OHD3 act via the same nuclear receptor, VDR and synergistically at their physiological concentrations. Fig. 1 shows the induction of mRNA of 24-hydroxylase (CYP24A1) in a highly sensitive mouse kidney cells lacking 1α-hydroxylation. A strong synergism is seen at the concentration of 0,05 nM 1,25(OH)2D3 plus 100 nM 25OHD3, whereas at the "normal" physiological concentration of humans, 0,05 nM + 50 nM, respectively, there is a minimal induction. This result suggests that these cells begin to defend against too high dosage at a concentration of calcidiol within the range 50-100 nM. The results are in agreement with our earlier studies [7] that calcidiol has an inherent hormonal activity, but when it is acting alone, 250 nM concentration is needed. In vivo, the two hormones are acting in concert and they regulate negatively each other. Therefore, the serum concentration of 25OHD3 can be raised only moderately without decreasing intracellular concentration of 1,25(OH)2D3 and thereby the sum effect of the two calcipherol hormones. This suggests that there is an upper limit concentration for serum 25OHD3. In this respect, 25OHD3 does not differ from other hormones including retinoic acid. The upper limit concept is supported by some epidemiological data and aging studies summarized in a review [8]. The optimal 25OHD3 serum concentration based on the present knowledge seems to be 40-80 nmol/L, but the optimum might differ among different diseases and among different populations, therefore more studies are needed. An easy way to estimate maximal daily dose is to assaying serum 24OH metabolites. If 24OH metabolites increase, the dosage is too high.
The induction of 24-hydroxylation in vitamin D target cells suggests that the present way of oral administration of vitamin D3 may not be the most optimal. It is obvious that a single pill of vitamin D3 containing daily dose will cause a rapid increase of its serum concentration and consequently a peak concentration of 25OHD3. This activates, in turn, 24-hydroxylation reducing the efficiency of the treatment. Therefore, multiple small doses of vitamin D3 might be more optimal as used for many drugs. Alternatively, narrow band UV-B exposure should be considered. Sun exposure causes an even and moderate serum level of 25OHD3. The oral or topical treatment of psoriasis with highly active calcipotriol or –triene is the first phase cure for mild cases, but the more advanced diseases are treated with UV-B phototherapy. In these therapies vitamin D3 resistance should be taken into consideration..
REFERENCES
1. Pearce SH, Cheetham TD: Diagnosis and management of vitamin D deficiency. BMJ 2010; 340: b5664.
2. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al.: The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr 2007; 85(3): 649-50.
3. Clements MR, Davies M, Hayes ME, et al.: The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf) 1992; 37(1): 17-27.
4. Halloran BP, Bikle DD, Levens MJ, Castro ME, Globus RK, Holton E: Chronic 1,25-dihydroxyvitamin D3 administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate. J Clin Invest 1986; 78(3): 622-8.
5. Vieth R, McCarten K, Norwich KH: Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production. Am J Physiol 1990; 258(5 Pt 1): E780-9.
6. Lou YR, Laaksi I, Syvälä H, et al.: 25-hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells. The FASEB Journal 2004; 18(2): 332-334.
7. Lou YR, Molnar F, Perakyla M, et al.: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. J Steroid Biochem Mol Biol 2010; 118(3): 162-70.
8. Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A: Vitamin D, nervous system and aging. Psychoneuroendocrinology 2009; 34 Suppl 1: S278-86.
TABLE 1. Synergistic action of 25OHD3 and 1α,25(OH)2 on 24-hydroxylase (CYP24A1) mRNA expression measured by real-time quantitative PCR in the primary kidney cells isolated from CYP27B1-/- (1α-hydroxylase deficient) mice (kindly provided by Dr René St-Arnoud). The results are normalized to the control gene Tbp. For material and methods see [7].
Treatment (nM) fold induction of CYP24A1
25OHD3 1,25(OH)2D3
0 0 1
50 0 1,6
100 0 0,9
250 0 89
0 0,05 1,4
0 0,1 32
0 1 66
50 0,05 9
50 0,1 3,3
50 1 133
100 0,05 475
100 0,1 16
100 1 132
250 0,05 232
250 0,1 190
250 1 268
Competing interests:
None declared
Competing interests: No competing interests
Vitamin D deficiency has re-emerged as a major public health concern
in
recent years. We read with great interest the elegant review by Pearce et
al,
highlighting the presentation, investigation and treatment of vitamin D
deficiency (1).
Given the association of vitamin D insufficiency with cardiovascular
diseases
and obesity, many vitamin D insufficient/deficient patients receive statin
therapy. We reported the first case series of vitamin D insufficiency in
statin-
users and identified vitamin D insufficiency as a risk factor for, and an
easily
treatable mimic of, statin-induced myalgia (2). Regrettably, the
therapeutic
role of vitamin D in the treatment of statin-induced myalgia is neglected
in
recent clinical reviews in vitamin D deficiency. In addition, some
patients with
statin-induced myalgia undergo invasive and expensive investigative
procedures, such as electromyography and muscle biopsy, before assessing
for vitamin D sufficiency (3).
In an updated series, we have found that 65 of 84 statin-users were
vitamin D
insufficient (serum 25-hydroxyvitamin D [25-D] <_60 nmol="nmol" l="l" of="of" whom="whom" _20="_20" were="were" frankly="frankly" deficient="deficient" _25-d="_25-d" _30="_30" l.="l." statin="statin" was="was" withdrawn="withdrawn" in="in" _15="_15" vitamin="vitamin" d="d" insufficient="insufficient" myalgic="myalgic" patients.="patients." all="all" treated="treated" with="with" oral="oral" d3.="d3." re-challenge="re-challenge" successful="successful" without="without" recurrence="recurrence" myalgia="myalgia" _10="_10" patients="patients" figure="figure" _1.="_1." lower="lower" pre-treatment="pre-treatment" and="and" older="older" age="age" associated="associated" re-challenge.="re-challenge." p="p"/> Vitamin D replacement allowed successful statin treatment in all
deficient
patients, previously intolerant. With vitamin D insufficiency common among
obese (4), we recommend patients with statin-induced myalgia be screened
(and treated) for vitamin D deficiency, before more expensive/invasive
investigations, eg electromyography/muscle biopsy, are considered.
Paul Lee MBBS FRACP p.lee@garvan.org.au
Jerry R Greenfield MBBS FRACP PhD
Lesley V Campbell MBBS FRACP PhD
References:
1. Pearce SH, Cheetham TD. Diagnosis and management of vitamin D
deficiency. BMJ;340:b5664.
2. Lee P, Greenfield JR, Campbell LV. Vitamin D insufficiency--a
novel
mechanism of statin-induced myalgia? Clin Endocrinol (Oxf) 2009;71(1):154-
5.
3. Echaniz-Laguna A, Mohr M, Tranchant C. Neuromuscular symptoms and
elevated creatine kinase after statin withdrawal. N Engl J Med;362(6):564-
5.
4. Lee P, Greenfield JR, Seibel MJ, Eisman JA, Center JR. Adequacy of
vitamin D
replacement in severe deficiency is dependent on body mass index. Am J Med
2009;122(11):1056-60.
Figure 1 Comparison between patients (N=11) who remained symptom free
following statin re-challenge, following vitamin D repletion (initial dose
1000-10,000 units/day, aim serum 25-D >60nmol/L), to those who did not
(N=5). Successful re-challenges were significantly older and more vitamin
D
deficient. Initial serum creatine kinase (CK) levels and final vitamin D
status
were not predictors.
Competing interests:
None declared
Competing interests: No competing interests
Nagaraj and Howe, consultants in public health medicine in Harrow mislead as to increasing vitamin D levels in the U.S. which an earlier respondent corrected with rock solid NHANES data that show a significant decrease over the years.
This is regarding their statement that "..the risk of chronic toxicity has also been documented (Leake CD. Vitamin D Toxicity. Cal West Med. 1936 Mar;44(3):149–150.).
In this 74 year old single page "editorial comment" the author proposes that 0.1 mg/d [4000 IU] is "an effective daily dose".
The author in fact mentions "massive" doses without defining massive and short-term toxicity and he then elaborates on the phenomenon of excess radiation used in (plant based) "preparations of ergosterol" that may simultaneously generate a substance named "toxisterol".
Clearly, this reference has nothing to do with the utilization or supplementation of/with c(h)olecalciferol, D3, the mammalian storage form of vitamin D and controlled hormone precursor.
If this is the best argument over the last 3/4 century against mass supplementation, I guess we can rest assured about safety. Here is that reference:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760419/?page=1
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760419/?page=2
It would be nice if authors actually checked their references and statements before making arguments that may affect people's health.
Competing interests:
None declared
Competing interests: No competing interests
The review by Professor Pearce and Dr Cheetham on vitamin D
deficiency is timely. The substantial public health problem imposed by
chronic vitamin D deficiency in our society has been known for some time
(1). Our diagnostic immunology service receives approximately 400 test
requests each week to measure serum vitamin D. Strikingly, over 70% of
these tests yield results that are below the normal range.
In addition to its well-known activity in bone metabolism, we write
to emphasize the importance of vitamin D in the normal functioning of the
immune system. Deficiency of vitamin D has been linked to a variety of
autoimmune disorders, cancers and chronic infections, notably tuberculosis
(2-4). Long-standing deficient immune function may contribute importantly
to all of these associations.
The receptor for vitamin D is expressed by virtually all cells of the
immune system. In keeping with this, vitamin D exerts several important
actions upon the innate immune system. For example, experimental models
show that vitamin D can enhance the anti-microbial activity of macrophages
and may boost their ability to kill tumour cells (4). As mentioned by
Moser et al above, vitamin D promotes the synthesis in phagocytes of
bactericidal proteins known as cathelicidins. Equally importantly, vitamin
D plays a critical role in the adaptive immune response. The heightened
sensitivity of T-cells to respond to antigen upon secondary encounter
depends critically upon vitamin D-mediated calcium signalling (5). Vitamin
D also influences the precise balance of cytokines that are produced
following T-cell activation, which may have important implications for the
type and appropriateness of inflammatory response that ensues (4).
As a clinical immunologist (JM), I commonly see patients with
recurrent or unexplained infection in whom routine immunological testing
reveals no clear-cut abnormalities. The role of vitamin D deficiency in
this clinical scenario is worthy of study. Furthermore, it would be of
interest to examine the immunological consequences of vitamin D status in
the general population and whether this impacts upon effectiveness of
immunomodulatory therapies, such as monoclonal antibodies and vaccines.
1. Iqbal SJ, Kaddam I, Wassif W, Nichol F, Walls J. (1994) Continuing
clinically severe vitamin D deficiency in Asians in the UK (Leicester).
Postgrad Med J 70: 708-14.
2. Williams B, Williams AJ, Anderson ST. (2008) Vitamin D deficiency
and insufficiency in children with tuberculosis. Pediatr Infect Dis J. 27:
941-2.
3. Nnoaham KE, Clarke A. (2008) Low serum vitamin D levels and
tuberculosis: a systematic review and meta-analysis. Int J Epidemiol. 37:
113-9.
4. Baeke F, Gysemans C, Korf H, Mathieu C. (2010) Vitamin D
insufficiency: implications for the immune system. Pediatr Nephrol. 2010
In press.
5. von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler
C. (2010) Vitamin D controls T cell antigen receptor signaling and
activation of human T cells. Nat Immunol. 11: 344-9.
Competing interests:
None declared
Competing interests: No competing interests
Sir
In my last one decade of my practice, I have seen more than ten
thousand patients and have prescribed NSAIDS to less than a 1000 people.
The rest went home and off course got better with either calcium, vitamin
D, alfacalcidol, calcitriol, cod liver oil, methylcobalamine, vitamin k
and c, evening primrose oil, strontium, raloxifene, tibolone, isoflavones,
bisphosphonates, calcitonin prescribed in various combinations or alone.
Such is the menace of osteoporosis and that too in the tropics!!
As rightly pointed out by Dr Peter J Lewis, vitamin D deficiency can
disguise itself as so many local problems and here are some more that I
would like to add to the list-plantar fasciitis, Metatarsalgia,thigh pain,
Periarthritis shoulder, tennis elbow, De’Quervains wrist and carpal tunnel
syndrome too!!!
Is evidence required all the time for treatment? Well, evidence
requires money and what if the “now dying intelligent clinician” makes the
patient spend the same money for treatment rather than for evidence, with
his experience as evidence!
I have never asked for serum vitamin D levels ever in my practice and
may have asked for serum alkaline phosphatase, calcium in less than a 100
patients.
An extremely cheap and reliable test that I have relied upon umpteen
number of times, whenever I have suspected secondary osteoporosis, is ESR!
Wake up clinicians {Ref.1} and start using your experience as
evidence!!!!
Regards
Milind.
Ref.1
Systematic Review: Comparative Effectiveness and Harms of
Combinations of Lipid-Modifying Agents and High-Dose Statin Monotherapy
· Mukul Sharma, et al
Ann Intern Med published ahead of print August 31, 2009
Competing interests:
None declared
Competing interests: No competing interests
Re: Diagnosis and management of vitamin D deficiency
Mega dose vitamin D supplementation in children in developing countries.
Sir,
Vitamin D deficiency has now been accepted as one of the major nutrition problems among children and is of paramount importance. The estimate that 70 – 100% children in the Indian subcontinent have vitamin D deficiency is not an exaggeration.( 1,2,3) In India alone the numbers would be overwhelming.There are three major approaches to the control of this problem: 1) improvement in sun exposure to ensure adequate intake of vitamin D; 2) fortification of foods with vitamin D; and 3) periodic administration of large doses of the vitamin D. No significant research has been carried out in developing countries on developing these intervention programmes and evaluating their impact on the large scale. Although the goal of controlling the forms of malnutrition may be difficult to attain, it is not unrealistic as far as vitamin D deficiency is concerned, provided that the knowledge now in hand is applied. Of the various measures available, the massive dose vitamin D programme could be regarded as a safe and potentially effective intervention to prevent vitamin D deficiency.
Studies to see the effect of vitamin D supplementation starting at two years of age, six monthly, by giving mega dose of 1,80000 International units each time (equivalent to 1000 iu / day) Assessing vitamin D levels at 5 years of age in this population of children and compared to those children who never received any supplement of vitamin D could potentially be a starting point to suggest to policy makers that mega vitamin D supplementation is a safe and effective method to counteract the menace of vitamin D deficiency which is endemic in countries like India. The effectiveness of periodic large dosing of the vitamin needs to be demonstrated. Such a study would lay to rest any scepticism about the efficacy of this method, and demonstrate for the first time that proper distribution of massive doses of vitamin D (1,80000 I U) can bring about a significant reduction in the incidence of vitamin D deficiency, and that periodic large dosing of vitamin D is conceptually simple. However, the operational aspects of a programme should receive much attention as otherwise any programme will be marred. For the delivery of vitamin D to the community: medical approach which offers treatment for children with rickets and, targeted approach which covers high risk groups are already in place. However, a universal system in which all preschool children are given the doses could be the most appropriate for a developing country like ours - ie covering all children and the first two components can be incorporated into the universal system.
Targeted delivery can reach only a minority of the “at risk” population. But a universal approach may be more successful. It is true that the absorption of vitamin D is incomplete in cases of giardiasis, which is very much prevalent in children. Although the most rational method to control this problem would be to treat giardiasis and consequent fat malabsorption, this does not mean that those infected with giardia do not benefit from therapeutic doses of vitamin D. Though the absorption may be lower, a child would still benefit from the amount absorbed. Vitamin D deficiency is a disease with a primary nutritional solution. Women play a crucial role in maintaining vitamin D nutrition of their children through breastfeeding. No concerted education campaigns seem to have been taken up to control vitamin D deficiency. For the prophylaxis programme to be effective, it should be aimed at the widest coverage of population which is at risk, and this should be done at minimum cost and with maximum community participation. We have an estimated 120 million preschool children in India as per the statistics published in Dec 2013 on the link www.unicef.org/infobycountry/india_statistics.html. Hence, local coverage cannot be expected to make a significant dent in the problem. It is here, perhaps, that the international agencies like WHO and UNICEF can contribute significantly by meeting the supply requirements.
References
1. Van Schoor, N.M.; Lips, P. Worldwide Vitamin D Status. Best Pract. Res. Clin. Endocrinol. Metab.2011, 25, 671–680, doi:10.1016/j.beem.2011.06.007.
2. Mithal, A.; Wahl, D.A.; Bonjour, J.P.; Burckhardt, P.; Dawson-Hughes, B.; Eisman, J.A.; El-Hajj Fuleihan, G.; Josse, R.G.; Lips, P.; Morales-Torres, J.; et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009, 20, 1807–1820, doi:10.1007/s00198-009-0954-6.
3. Van der Meer, I.M.; Middelkoop, B.J.; Boeke, A.J.; Lips, P. Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: An overview. Osteoporos. Int. 2011, 22, 1009–1021, doi:10.1007/s00198-010-1279-1.
Competing interests: No competing interests