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Vitamin D treatment
options in physician‘s
everday practice
Author: Höck Anna Dorothea MD
Internal Medicine and Psychotherapy
Sunlight is the natural source of
vitamin D
Why is
deficiency
of vitamin
D3 so
frequent:
• Preference of indoor works in
western life style
• Sun protectors
• Living in an area more than 40
degrees beyond equatorial
latitude
• Living in crowded cities with huge
buildings
Speech Dr. Hoeck. September 18th, 2011
2
Immune-, nervous-, endocrine-,
cardio-vascular system
Calcium-phosphate
metabolism by a
bowel-kidney-bonebrain-adipocyte axis
Tissue and cell-tissue
cross-talk
Cell cycle,
proliferation,
differentiation,
apoptosis
Energy metabolism
Cell signal
transduction
Speech Dr. Hoeck. September 18th, 2011
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Vitamin D is activated to 1,25(OH)2D3
by CYP27B1
This active vitamin D behaves like other steroid hormones
(e.g., cortisol, estrogen, thyroid hormone)
By binding to a special steroid receptor, named „vitamin D
binding receptor“ (VDR) it is able to act as a transcription
factor to induce, repress or modulate gene expression
However, non genomic actions are known as well (signal
transducing actions) which augment the transactivation
processes
Speech Dr. Hoeck. September 18th, 2011
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My first experiences in 1993:
A patient with severe unexplainable fatigue, progressive sleeping disorder, and
finally nearly complete hair loss
Initial diagnosis by 4 physicians: depression
However: psychotherapy did not work
Finally revised diagnosis:
severe vitamin D deficiency with secondary hyperparathyroidism
[25OHD3: 4 ng/ml (10nmol/L)]
Speech Dr. Hoeck. September 18th, 2011
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Therapy with 10,000 IU (250 mcg)/d
25-hydroxycholecalciferol
Clinically: initially striking recovery from fatigue and malaise
However: tríal to treat with 20,000 IU (500 mcg)/d resulted in bone pains
In spite of continuous vitamin D substitution, hair loss persisted
Muscle cramps, anxiety, and persisting difficulty concentrating developed.
Hence mineral therapy was initiated (potassium, magnesium, phosphate, citrate).
Result: hair loss turned out to be reversible!
Speech Dr. Hoeck. September 18th, 2011
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Why did I avoid calcium
supplementation?
My great fear:
to induce kidney stones in presence of elevated parathormone
My consideration:
sufficient vitamin D induces sufficient calcium resorption (when consuming milk
products)
My nightmare:
milk-alkali syndrome !
My knowledge now:
more than 4,000 mg calcium/d are able to induce milk-alkali syndrome
Speech Dr. Hoeck. September 18th, 2011
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However: the follow up of case
histories tought me some lessons
Applied doses:
This patient
developed a
fibromyalgia-like
syndrome
in spite of
efficient vitamin
D substitution
(25OHD3 about
60 ng/ml)
I learned to
view fatigue
as a
leading
symptom
and treated it
with vitamin D
Speech Dr. Hoeck. September 18th, 2011
slight to
moderate
fatigue:
5,000 IU (125
mcg)/d
severe fatigue:
10,000 IU (250
mcg)/d
8
Fatigue and functional symptoms were combined and
graded.
Treatment results dependent on grade.
Mild to
moderate:
All grades:
better results
when adding
base powder.
Higher doses,
better results!
mostly:
very successful
treatment results.
However, in some
cases:
worsened
sleeping disorder,
or
hyperexcitability
Speech Dr. Hoeck. September 18th, 2011
Severe:
mixed results!
Some patients:
No response!
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This introduced me into the calcium
problem
Calcium and phosphate are stored in bone as
hydroxyapatite
Serum calcium level is strictly controlled
Free calcium is in the cell a second messenger
Calcium binds to proteins altering structure and function
(channels, receptors, enzymes, adapters, storage proteins)
Speech Dr. Hoeck. September 18th, 2011
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The calcium replete and deplete state
hypothesis
• CaR active?
• FGF23/Klotho active
Replete
Deplete
• CaR inactive?
No PTH-suppression
• Bone resorption by PTH +
inflammatory cytokines
Speech Dr. Hoeck. September 18th, 2011
11
The controversy about calcium
Other
persuasions:
• No calcium, but high dose vitamin D
with rapid saturation to optimal
25OHD3-level.
Von Helden, Vitamin Delta Research Group, Germany
• 25OH more than 18 ng/ml (43nmol/L)
and 800 mg calcium/d: lowest PTH.
• 25OH more than 18 ng/ml (43nmol/L)
and 1200 mg calcium: PTH higher
Steingrimsdottir L, et al, JAMA 2005;294(18):2336-41
Speech Dr. Hoeck. September 18th, 2011
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However: There is a daily calcium loss
Bowel:
300 - 1000 mg
Kidney:
150 - 300 mg
Sweat:
up to 1500 mg
Daily bone exchange:
250-500 mg
Speech Dr. Hoeck. September 18th, 2011
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What I learned as well:
These
depletions
all look
very much
the same
•Calcium
•Phosphate
•Vitamin D3
•Other minerals
Speech Dr. Hoeck. September 18th, 2011
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The essentials of disease progression
Chronic
(idiopathic)
fatigue
Chronic
fatigue
syndrome
Fibromyalgia
Speech Dr. Hoeck. September 18th, 2011
Clear-cut
and well
defined
diseases
15
My fibromyalgia hypothesis
Resulting from long-standing vitamin Ddeficiency?
„rickets“ of the adults?
Very often:
severe life events since youth
Speech Dr. Hoeck. September 18th, 2011
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My hypothesis about MCS
Severe
calcium loss
essential
for disease?
Speech Dr. Hoeck. September 18th, 2011
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My hypothesis about chronic fatigue
syndrome
Often no vitamin
D/calcium
deficiency in
childhood,
therefore in the
beginning of life
excellent
performance
Most people
disclose a
very tough
personality
By excessive
strain and sun
deprivation:
very severe,
though more
acute vitamin D
and calcium
deficiency
Speech Dr. Hoeck. September 18th, 2011
Severe immune
dysfunction:
persistent
(opportunistic?)
infection?
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Why opportunistic infections?
Vitamin D
is an
important
immune
regulator
Enforces
innate
immunity
(pathogens
become
killed)
Speech Dr. Hoeck. September 18th, 2011
Modulates
adaptive
immunity
towards
immune
tolerance
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Is vitamin D useful in practice?
Nearly everyone complains about fatigue
Inexpensive
Combination possible with nearly all „state of the art“-therapies
Expensive „block buster-therapy“ evitable or better dose/response?
Patients are highly motivated not to be fatigued
Patients get their self esteem back
Psychotherapy is often no longer necessary
Speech Dr. Hoeck. September 18th, 2011
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These patients need vitamin D
The everyday
patient:
Prevention
Those with
remitting
infectious
disorders
Those with
fatigue and
functional
disorders
Speech Dr. Hoeck. September 18th, 2011
Those with
mild, moderate
or severe
chronic disease
conditions
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Of interest:
Horizontal and vertical disease history
Horizontal:
the almost fixed combination between fatigue and
functional disorders.
Vertical:
The age-specific picture of vitamin D deficiency.
The slow progression from dysfunction to somatic
disease.
Speech Dr. Hoeck. September 18th, 2011
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The three columns of disease
Energy deficit
• Best seen in nervous
system or in muscle force
Dysfunction
• Headache
• Sleep disorder
• Organ (heart, bowel,
bladder, muscles;)
and system dysfunction
(autonomous nervous-,
immune-, endocrine-,
cardiovascular-,
gastroenteral- ,
reproductive-)
• Lowered detoxification
• Pains
• Very typical: sweats,
thirst, hunger intolerance
Speech Dr. Hoeck. September 18th, 2011
Defined diseases
• Behaviour abnormalities
• Chronic infections
• Thyroid and ovary
disease
• Muskuloskeletal disease
and osteopenia
• Cardiovascular
• Cancer
• Metabolic disease
• Immune or connective
tissue disease
• Organ failure
• Osteoporosis and frailty
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Treatment options
What is the optimal 25 OHD3 level?
How to find the optimal vitamin D treatment dose?
Which compound?
Calcium Yes or No?
Basic compounds?
Speech Dr. Hoeck. September 18th, 2011
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The optimal 25OHD3 levels (1)
30 ng/ml = 80 nMol/L
40 ng/ml = 100 nMol/L
(Vieth R, Lips P, Heaney RP, Grant
WB, Giovannucci E, Hollis BW,
Hollick MF, Norman AW, many
others)
60 – 80 ng/ml = 150 – 200 nMol/L
(Gominak S, Garland CF)
(Grant WB, Pro Biophy Mol Biol
2009)
Groups (IARC and IOM) not wishing
that 95% of the population believe
that they are in health risk.
Therefore:
Correction of the desired 25OHD3
level down to
20 ng/ml (50 nMol/L)
Speech Dr. Hoeck. September 18th, 2011
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The optimal vitamin D dose (2)
4,000 IU = 100 mcg/day
2000 IU = 50 mcg/day (upper limit
of daily allowance: NHI)
Patients reached a steady state
(over 3 months)
Vieth R, 2006
Own clinical observations in severe
cases:
10,000 IU = 250 mcg/day 1-3 years.
When reaching 100 ng/ml = 250
nMol/L,
maintainance dose of 5,000 IU =
125 mcg/day (lifelong?)
Later own experience
(even better working):
3000 - 5000 IU = 75 - 125 mcg/day
and high dose calcium (1000 – 1800
mg elementary calcium/day
Speech Dr. Hoeck. September 18th, 2011
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However, there seem to exist pitfalls in therapy
effectiveness:
Chronic NFkB
activation is
able to
induce
compromised
vitamin D
actions
• Pathogens
• Chronic inflammatory stress
• Chronic stress of variant
origin
Farmer PK, et al. Am J Physiol Endocrinol Metab
2000; 279(1):E213-20.
Speech Dr. Hoeck. September 18th, 2011
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Possible way out: ultra-high dose cholecalciferol may
overcome treatment resistance
Raimund
von
Helden,
Delta
Research
Group:
• 40,000 IU (1,000 mcg)/d) or
100,000 IU (2,500 mcg/d)
• His arguments:
100,000 IU raise 25OHD3
about 10 ng/ml
Each 10 kg body weight need
additional 100,000 IU
Speech Dr. Hoeck. September 18th, 2011
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Which compound?
Alfacalcidol is usually
used in renal
insufficiency
In cancer vitamin D
analogs with noncalcemic actions might
become a key
treatment option
Speech Dr. Hoeck. September 18th, 2011
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Calcium Yes or No?
„Yes“ in most cases:
Aim:
Stop of proinflammation
„No“ (or with great caution):
Hypercalciuria
Granulomatous disease
Speech Dr. Hoeck. September 18th, 2011
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The safe range of calcium/creatinine
ratio 25OHD3 level
Up to 25OHD3 levels of 100
ng/ml or 250 nmol/L
ratio of urine calcium/creatinine
(mmol/L: mmol/L) remains
about 0.4.
Beyond 100 ng/ml: slow rise!
Toxic ratio:
1 or higher
Speech Dr. Hoeck. September 18th, 2011
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Two possible causes of hypercalciuria:
Severe calcium
deficiency with
paradoxical
hypercalciuria
(Altered set point
of CaR?)
Severe phosphate
deficiency with
hypercalciuria
(Renal tubular
acidosis?)
Speech Dr. Hoeck. September 18th, 2011
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Possible solutions against aquired forms of
hypercalciuria?
Fractionated low
single dose
calcium without
reducing the daily
supplementation
Calcium
supplementation
by basic powders
Speech Dr. Hoeck. September 18th, 2011
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An important absolute
contraindication!
Mutations in CYP24A1 leading to
idiopathic infantile Hypercalcemia
Schlingmann KP, et al. N Engl J Med 2011;365(5):410-21.
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Why basic powders:
Important observation:
Reduction of pains
Some patients reported
positive effects by
addional magnesium
ingestion
In particular, in MCS and
CFS additional phosphate
supplementation seemed
to be effective
Untreated people
showed variable
reductions of potassium,
calcium or magnesium
serum levels
Speech Dr. Hoeck. September 18th, 2011
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Contraindications
Absolute: Basic powder in case of terminal
renal insufficiency
Relative: Granulomatous disease
(hypercalcemia possible, reversible by cortisol)
CaR hyperactivating mutations?
(hypercalciuria)
Speech Dr. Hoeck. September 18th, 2011
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Your take-home messages (1)
Vitamin D, in combination with calcium/base powders, is indicated in most
patient you treat
Minor illness will fully disappear
However: Recurrence is the rule when stopping supplementation
Severe disease with organic manifestations mostly need classical drug therapy,
but by combining this with vitamin D and minerals renders therapy more effective
Speech Dr. Hoeck. September 18th, 2011
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Your take-home message (3)
Remember: vitamin D deficiency itself can induce renal functional impairment
with increased loss of calcium and phosphate
By treating with vitamin D, renal impairment can resolve
Believe your patients. Why should they lie?
Be open to find a connection between life events, working load and disease by
knowledge about the impact of concurring vitamin D deficiency and the resulting
calcium deficits
Speech Dr. Hoeck. September 18th, 2011
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