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D3 5000 TO 50000 INTERNATIONAL UNITS/d SEVEN YEARS EXPERIENCE DOSING REVIEW

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Related to the nCoV situation:
D:How much is enough,how much is too much?

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Contents lists available at ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology
journal homepage: www.elsevier.com/locate/jsbmb
Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a
day in long-term hospitalized patients: Insights from a seven year experience
Patrick J. McCullougha,b,⁎, Douglas S. Lehrera,b, Jeffrey Amendb
a Department of Psychiatry, Wright State University School of Medicine, Dayton, OH, 45435, United States
b Summit Behavioral Healthcare, Cincinnati, OH, 45237, United States
A R T I C L E I N F O
Keywords:
Intact parathyroid hormone
Long-term supplementation
Adverse events
A B S T R A C T
Vitamin D3 is a secosteroid hormone produced in the skin in amounts estimated up to 25,000 international units
(IUs) a day by the action of UVB radiation on 7-dehydrocholesterol. Vitamin D deficiency is common due to both
lack of adequate sun exposure to the skin, and because vitamin D is present in very few food sources. Deficiency
is strongly linked to increased risk for a multitude of diseases, several of which have historically been shown to
improve dramatically with either adequate UVB exposure to the skin, or to oral or topical supplementation with
vitamin D. These diseases include asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. All patients in
our hospital have been routinely screened on admission for vitamin D deficiency since July 2011, and offered
supplementation to either correct or prevent deficiency. During this time, we have admitted over 4700 patients,
the vast majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease
concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of
vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any
patient. Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000
IUs/day. Analysis of 777 recently tested patients (new and long-term) not on D3 revealed 28.7% with 25-
hydroxyvitaminD3 (25OHD3) blood levels<20 ng/ml, 64.1%<30 ng/ml, a mean 25OHD3 level of 27.1 ng/
ml, with a range from 4.9 to 74.8 ng/ml. Analysis of 418 inpatients on D3 long enough to develop 25OHD3 blood
levels>74.4 ng/ml showed a mean 25OHD3 level of 118.9 ng/ml, with a range from 74.4 to 384.8 ng/ml. The
average serum calcium level in these 2 groups was 9.5 (no D3) vs 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs
8.6 to 10.7 mg/dl (D3), after excluding patients with other causes of hypercalcemia. The average intact parathyroid
hormone levels were 24.2 pg/ml (D3) vs. 30.2 pg/ml (no D3). In summary, long-term supplementation
with vitamin D3 in doses ranging from 5000 to 50,000 IUs/day appears to be safe.
1. Introduction
Vitamin D was misnamed in 1922, when it was isolated from both
cod liver oil and the skin of laboratory animals subjected to UVB radiation
[1]. Its chemical structure was determined in the 1930s, and it
was discovered to be a secosteroid hormone made by the action of UVB
radiation present in sunshine on 7-dehydrocholesterol in the skin [2,3].
By the 1930′s, cod liver oil, sunshine and phototherapy were known
to be effective treatments for several diseases. Cod liver oil had been
used to cure both rickets and tuberculosis in the 1800′s [1,4,5]. Sunshine
and phototherapy were used to cure tuberculosis in the 1890′s
and 1930′s [1,6–10]. In fact, the Nobel prize in medicine was awarded
to Dr. Neils Ryberg Finsen in 1903 for curing hundreds of long-standing
cases of TB with refracted light rays from an electric arc lamp [6,7], and
this method of treatment became the standard of care for treating TB
until the discovery of antibiotics in the 1940′s [10–12]. In addition,
both rickets [5,13] and psoriasis [14] were also reported to improve
dramatically with sun exposure.
Because of the link between sunshine and vitamin D formation,
physicians in that era also began treating diseases with vitamin D alone,
and found much success. In the 1930s and 1940s reports were published
describing the successful use of vitamin D in treating psoriasis
[14], asthma [15], rheumatoid arthritis [16,17], rickets [1,5,18] and
tuberculosis [19–24]. Doses ranging from 60,000 to 300,000 IUs were
shown to control asthma [15], 150,000 to 600,000 IUs a day ameliorated
the signs and symptoms of rheumatoid arthritis [16,17], and
100,000 to 150,000 IU per day for 2 to 3 months completely cured
many long-standing cases of tuberculosis infections [19–24].
Redirecting
Received 2 October 2018; Received in revised form 23 December 2018; Accepted 31 December 2018
⁎ Corresponding author at: Summit Behavioral Healthcare, Cincinnati, OH, 45237, USA.
E-mail address: pmccullough1@cinci.rr.com (P.J. McCullough).
Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
Available online 04 January 2019
0960-0760/ © 2019 Elsevier Ltd. All rights reserved.
T
It is not clear why such high daily doses of vitamin D were chosen,
but the vitamin D doses used at that time were remarkably high based
on today’s standards. Estimates of the amount of vitamin D made in the
skin from sun exposure were unknown at that time, and would not be
made until the 1970s and 1980s.
When these estimates were made, which range from 10,000 to
25,000 IU per day [25–27], it became apparent that the daily doses of
vitamin D selected by clinicians during the 1930s and 1940s were about
an order of magnitude higher than what the body actually produces
from sun exposure. We now know that our bodies are designed to
produce vitamin D3 in the skin from the action of sunshine on the
precursor molecule 7-dehydrocholesterol, and very little is obtained
from the diet [28].
Unfortunately, reports soon surfaced in the 1930s and 1940s describing
complications from vitamin D induced hypercalcemia after
prolonged daily intake of these supra-physiologic daily doses of vitamin
D [17,29–32]. It was thought at the time that vitamin D induced hypercalcemia
led to several patient deaths, and as a result, the use of
vitamin D in these high doses for treating disease fell out of favor.
However, it is not clear from the literature how many people may
have actually died from vitamin D toxicity, as there were also remarkable
reports describing patients who recovered without long-term
complications after ingesting massive amounts of vitamin D for long
periods of time.
One such report was published in 1948, describing in detail patients
who recovered uneventfully after taking 150,000 to 600,000 IU a day
for 2 to 18 months for rheumatoid arthritis [17]. A more recent toxicity
report from 2011 confirms that this is still possible, as an individual
who inadvertently took 970,000 IUs daily for one month, and another
who took 1,864,000 IUs of vitamin D daily for 2 months, both recovered
uneventfully within a few months after stopping the vitamin D
and receiving supportive care [33]. Both individuals became symptomatic
from the hypercalcemia. The first had a serum 25OHD level of
645 ng/ml, and a calcium of 13.2 mg/dl, and the second had a serum
25OHD level of 1220 ng/ml, and a calcium of 15.0 mg/dl. However, the
hypercalcemia resolved in both patients over time after cessation of the
vitamin D supplement. Both the symptoms abated and the calcium levels
became normal after the 25OHD level dropped below 400 ng/ml.
In addition, with the relatively short course of treatment for tuberculosis,
many patients were able to safely ingest 100,000 to 150,000
IU/d for several months and achieve complete cures without developing
complications related to hypercalcemia or withdrawing from
therapy [19–24].
Unfortunately, instead of titrating down the dose of vitamin D to see
if a lower dose range might exist that would still be clinically effective
but without causing hypercalcemia in treating patients with these diseases,
vitamin D was labeled as toxic, and the use of these high doses for
treating disease stopped. The recommended daily dose of vitamin D was
then reduced to the amounts present in a teaspoon of cod liver oil, or
approximately 400 IU/day [18], and has remained there for several
decades. This is in spite of the fact we now know that the body will
make much more than this amount with exposure to sunshine or phototherapy.
It wasn’t until the late 1960′s that the active steroid hormone form
of vitamin D3, namely 1,25-dihydroxyvitamin D3, was discovered, and
the vitamin D receptor (VDR) was characterized [2]. It is now recognized
that vitamin D3 exerts significant control over normal cellular
metabolism in many different cells and tissues throughout the body [3].
Vitamin D3 has been found to control cellular metabolism in 2 distinct
ways: a) via rapid reactions which occur at the plasma membrane by
interacting with the VDR and opening or closing ion channels, and b) by
binding to the VDR in the nucleus of the cell, where it is then able to act
as a gene switch and turn on and off gene transcription [3].
The exact number of gene products controlled by vitamin D3 is
unknown, but the active hormone form of vitamin D3 was recently
found to bind via its receptor to 2776 distinct binding sites in a human
cell line, many of which were located near autoimmune and cancer
associated genes [34].
This may help to explain the strong association that has been found
between vitamin D deficiency and increased risk for a multitude of
diseases, including Alzheimer’s disease, asthma, several autoimmune
diseases such as Crohn’s disease, multiple sclerosis, psoriasis, rheumatoid
arthritis and ulcerative colitis, many cancers including breast,
colon, prostate, sarcomas and skin cancer, chronic pain, dementia,
depression, diabetes mellitus, epilepsy, fibromyalgia, falls, fractures
and muscle weakness, osteoporosis, osteomalacia, Parkinson’s disease,
pregnancy complications including premature birth and death, rickets,
schizophrenia and seasonal affective disorder [1,28,35].
We have also learned much more about toxicity and safety with oral
dosing of vitamin D3 over the past 20 years. In 1999, a comprehensive
review article on vitamin D supplementation, 25OHD blood levels, and
safety was published, and found that toxicity from hypercalcemia appeared
to involve intake of daily doses of vitamin D greater than 40,000
IU/day [36].
In 2003, a study was published evaluating the safety and dose response
of daily supplementation with three oral doses of vitamin D3.
This study compared placebo versus supplementation with 836 IU,
5500 IU or 11,000 IU a day in 67 healthy adult male volunteers over a
5-month period. Mean baseline 25OHD blood levels were 28.1 ng/ml,
rising to a mean level of 64 ng/ml in the 5500 IU/day group, and 88 ng/
ml in the 11,000 IU/day group after 5 months. No adverse events related
to vitamin D3 supplementation were reported [37].
In 2005, a report defining “Circulating levels of vitamin D indicative
of sufficiency” was published [38]. Based on analysis of specific biomarkers
that appropriately increase or decrease with changes in
25(OH)D levels, it was determined that a 25OHD blood level of<32
ng/ml was indicative of insufficiency. A blood level>100 ng/ml was
set as the upper limit of normal, but the author noted that based on
evidence available at that time, that it may actually be higher. It was
also noted that “The current adult recommendations for vitamin D,
200–600 IU/d, are very inadequate when one considers that a
10–15 min whole-body exposure to peak summer sun will generate and
release up to 20,000 IU vitaminD-3 into the circulation. “
In 2007, a publication on Vitamin D Toxicity, Policy, and Science
noted that “hypercalcemia is the hazard criterion for vitamin D”, and
argued that “because sunshine can provide an adult with vitamin D in
an amount equivalent to daily oral consumption of 250ug (10,000 IU)/
d, this is intuitively a safe dose.” The point was also made that because
“clinical trial evidence shows that a prolonged intake of 250ug (10,000
IU)/d of vitamin D is likely to pose no risk of adverse events in almost
all individuals in the general population; this meets the risk for a tolerable
upper intake level [39].”
A comprehensive review also published in 2007 on the risk of daily
dosing with vitamin D also concluded that 10,000 IU/day should be the
safe tolerable upper intake level, and estimated that 25OHD blood levels
above 240 ng/ml were required to result in clinically significant
hypercalcemia [40]. It should be noted that 25OHD blood levels were
unable to be measured until the 1970′s [41], which explains why
25OHD blood levels associated with hypercalcemia in the 1930s and
1940s are unknown.
In 2008, a report on the pharmacokinetics of vitamin D toxicity was
published, in which the author concluded that “although current data
support the viewpoint that the biomarker plasma 25(OH)D concentration
must rise above 750 nmol/l (300 ng/ml) to produce vitamin D
toxicity, the more prudent upper limit of 250 nmol/L (100 ng/ml)
might be retained to ensure a wide safety margin” [42].
In 2010, a study from Ireland reported 25OHD blood levels measured
before and after using narrow band UVB phototherapy to treat 29
patients with psoriasis in the wintertime in Ireland, and were compared
to 29 age-matched untreated control patients with psoriasis [43].
The median baseline 25OHD level was 23 ng/ml, with a range of
9–46 ng/ml in the treatment group. All patients responded to treatment
P.J. McCullough, et al. Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
229
with phototherapy within 25–118 days with essentially complete
clearing of their skin, at which time 25OHD blood levels were again
measured. The median 25OHD blood level increased to 59 ng/ml in the
treated group, with a range of 32–112 ng/ml, while no change in either
disease severity or 25OHD blood levels were observed in the control
group. These 25OHD blood levels were remarkably similar to those
reported in 1977 in a dose response study in which healthy volunteers
received 10,000 IU of vitamin D a day for at least 4 months [25].
In 2011, a community-based cohort study involving 3667 subjects
also found daily dosing with 10,000 IU a day or lower to be safe, with
no reported adverse events or 25OHD blood levels above 200 ng/ml,
and concluded that “universal intake of up to 40,000 IU of vitamin D
per day is unlikely to result in vitamin D toxicity” [44].
In 2012, no adverse events were reported due to vitamin D supplementation
over the course of a year in two separate reports in which
oral vitamin D3 was given at a dose of 4000 IU a day. In these studies,
mean 25OHD blood levels after 12 months were 66 ng/ml and 67 ng/
ml, with a range of 35 ng/ml to 95 ng/ml [45,46].
At our institution, we have found the majority of patients admitted
for care to be vitamin D deficient at the time of admission (< 30 ng/ml
25OHD). They also receive little to no direct sun exposure during their
hospital stay, which often lasts for 12 months or longer. For these
reasons, as well as those discussed above, we offered daily supplementation
with oral vitamin D3 as a standard of care in July of 2011.
Our goal was to supplement our patients with an amount of vitamin
D3 at the low end of the range of amounts that the body has been shown
to make on a daily basis with adequate sun exposure to the skin, and
which have been shown in previous oral dosing studies and reviews to
be safe and effective at raising serum 25OHD levels. One of the authors
(PM) started this practice in April 2009 while working at a post-acute
care hospital for the same reasons, and found that long-term daily
supplementation with 5000 to 10,000 IU of vitamin D3 was safe in
several hundred patients (unpublished data). This practice was then
continued after changing hospitals in 2011.
In this report, we will present 4 sets of data. The first will be a
review of changes in 25OHD3, calcium and iPTH blood levels over time
in patients who were on daily supplementation with either 5000 IU/d
or 10,000 IU/d of vitamin D3 for at least 12–29 months. This is basically
an extension of the work previously discussed published by Dr.
Robert Heaney in 2003, who showed that this was safe over a period of
5 months [37].
The second data set will compare 25OHD3, calcium and iPTH blood
levels obtained in patients not on vitamin D3 supplementation (new
admissions and long-term patients declining supplementation) vs those
obtained in patients on D3 supplementation long enough to have
achieved a 25OHD3 blood level of at least 74.4 ng/ml.
The third data set will show changes in 25OHD3, calcium and iPTH
blood levels in 3 people who have been taking daily doses of vitamin D
ranging from 25,000 IU/d to 60,000 IU/d for 2 to 8 years.
The first is a patient who has been on 50,000 IU/d of vitamin D2 for
over 2 years for treatment of psoriasis. The second is a staff member
who has been on 25,000 IU/d for several years for treatment of asthma
(author JA), and the third is a staff member who has been on 60,000
IU/d of vitamin D3 for the past 4 years for the treatment of an ulcerated
skin lesion (author PM). All 3 individuals experienced marked clinical
improvement in their chronic medical problems on vitamin D supplementation
without complications.
The fourth data set will be a comparison of data set 1 with results
from reports in the literature previously discussed which published data
showing changes in 25OHD3 blood levels after either daily oral supplementation
with varying doses of vitamin D, or phototherapy
[25,37,43,45,46], after varying lengths of time. (The data tables from
this discussion are available in the supplemental data section).
2. Materials and methods
Summit Behavioral Healthcare (SBH) is a 291-bed state psychiatric
hospital in Cincinnati, Ohio. The patient population consists of male
and female adults age 18 and over. The majority of the patients have a
diagnosis of severe mental illness at the time of admission, usually
schizophrenia, schizoaffective disorder, or bipolar disorder. Many of
the patients also have coexisting substance abuse issues.
All patients at our facility have been offered supplementation with
either 5000 IU/d or 10,000 IU/d (attending doctor’s choice) of over-the
counter vitamin D3 as a standard of care since July 2011 for the
treatment and prevention of vitamin D deficiency. This is done due to
the many risks associated with vitamin D deficiency, and because the
majority of our patients are deficient in 25-hydroxyvitamin D3
(25OHD) at the time of admission, and receive minimal sun-exposure to
their skin during the course of their admission. The vendor used during
this entire time frame was Major Pharmaceuticals, and 5000 IU capsules
were used in all patients, with the exception of one patient with
psoriasis, who was treated daily with a 50,000 IU gel capsule of vitamin
D2.
After observing a number of patients on long-term supplementation
developing 25OHD blood levels>100 ng/ml, a research proposal requesting
permission to do a retrospective chart review of this data was
submitted to and approved by the Institutional Review Boards of the
Ohio Department of Mental Health and Addiction Services and Wright
State University.
Study material consisted of pharmacy and laboratory records of
patients at Summit Behavioral Healthcare who received oral vitamin D
supplements between July 2011 and July 2018. All clinical procedures
and laboratory assessments were done in the context of clinical care and
without intention to perform research.
The main risk related to excessive vitamin D supplementation is
hypercalcemia, which has only been shown to occur after ingestion of
supra-physiological doses of vitamin D for extended periods of time.
Over the counter supplements are not regulated by the Food and Drug
Administration (FDA), and therefore their quality cannot be assured.
Thus, monitoring of appropriate dose response to vitamin D3 supplementation
and signs and symptoms of possible toxicity related to hypercalcemia
is warranted.
All new admissions to the hospital are asked to consent to admission
blood work, and the majority comply. This will typically include a
complete blood count, complete metabolic profile, lipid profile, thyroid
profile, glycosylated hemoglobin, acute hepatitis panel, 25OHD, and
intact PTH. Follow-up blood levels are obtained periodically thereafter,
at the discretion of the unit primary care physician, but at least once a
year. All blood samples were sent to Laboratory Corporation of America
(LabCorp) for analysis during this time period.
None of the patients in this report were on calcium supplements,
and only a small percentage were on a daily multivitamin or fish oil
capsules. Depending on the patient’s legal status, lengths of stay may
last for greater than a year, thus permitting confident assessment of
clinical and laboratory parameters associated with vitamin D3 utilization
over long intervals.
Medication treatment for severe mental illness depends on the diagnosis
and typically includes an antipsychotic for psychosis, a mood
stabilizer, a benzodiazepine for agitation, anxiety, or extrapyramidal
side effects (eps), or an anticholinergic medication or a beta blocker for
the treatment of associated iatrogenic movement disorders.
Many of our patients are relatively young and healthy with few comorbid
conditions. Patients with other non-psychiatric medical problems
are maintained or started on medications appropriate for their
medical problems, with the most commonly encountered problems
being asthma, diabetes, dyslipidemia, heart disease, hypertension, hypothyroidism
and obesity.
P.J. McCullough, et al. Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
230
3. Results
3.1. Changes in 25OHD3, calcium and iPTH blood levels over time in
patients who have been on daily supplementation with either 5000 IU or
10,000 IU a day of vitamin D3 for at least 12–29 months
Between July 2011 and Feb 2014, a total of 36 patients were
identified who received 5000 IU of vitamin D3 once daily for 12 months
or longer (group 1), and 78 patients who received 5000 IU of vitamin
D3 twice daily for 12 months or longer (group 2). A total of 125 and
344 serum levels of 25OHD, 225 and 515 serum calcium levels, and 26
and 61 serum iPTH levels were obtained in groups 1 and 2, respectively.
While significant differences were observed over time in mean
25OHD blood levels between the 2 groups, no cases of vitamin D-induced
hypercalcemia or any other adverse events related to vitamin D
supplementation were noted in any patient.
There were 2 cases of non-vitamin D related hypercalcemia observed
during this time frame. One was due to previously undiagnosed
primary hyperparathyroidism. The second was found to be due to hydrochlorothiazide
treatment for hypertension, which resolved with
cessation of the hydrochlorothiazide.
3.1.1. 25OHD levels
Baseline mean 25OHD levels were 24 ng/ml and 25 ng/ml. At
12months these increased to 68 ng/ml (n=9) in the 5000 IU/d group,
and 96 ng/ml (n=49) in the 10,000 IU/d group. At 16months the
mean 25OHD levels were essentially unchanged, with values of 60 ng/
ml (n=11) in group 1 and 97 ng/ml (n=11) in group 2.
The range of 25OHD values at months 12 and 16 were also very
similar in the 2 groups. At 12months the ranges were 41–95 ng/ml in
group 1 and 53–148 ng/ml in group 2. At 16months the ranges were
43–86 ng/ml in group 1, and 81–139 ng/ml in group 2 at 16 months.
The changes in individual and mean monthly 25OHD blood levels
over time are depicted graphically in Fig. 1.
3.1.2. Calcium levels
The mean monthly serum calcium levels ranged from 9 to 10 mg/dl
in patients on 5000 IU/d (n=225 values), and from 9.4 to 10 mg/dl in
patients on 10,000 IU/d (n=515 values). The highest serum calcium
level observed in both groups was 10.9 mg/dl. The mean monthly
serum calcium values are plotted in Fig. 2.
3.1.3. Intact parathyroid hormone levels
Intact parathyroid hormone (iPTH) levels were measured in a much
smaller number of patients. A total of 26 and 61 serum iPTH levels were
obtained in groups 1 and 2, respectively, with very few levels obtained
in the first 9 months in either group.
Although there were relatively few measurements of iPTH, the
monthly mean and range of values was very similar between the 2
groups between months 10 to 29. In particular, the range of monthly
mean values from months 23 to 29 is very similar between the 2 groups.
In group 1 it was 16 to 24 pg/ml (n=10), and 15 to 26 pg/ml in group
2 (n=16) (normal range 15–60 pg/ml). Many more data points for
iPTH levels will be discussed in data set 2.
Plots of the mean monthly serum iPTH values (pg/ml) with standard
deviation bars for patients taking 5000 IU/d and 10,000 IU/d of oral
vitamin D3 are shown in Fig. 3.
3.2. Comparison of 25OHD3, calcium and iPTH blood levels in patients not
on vitamin D3 (n=777) vs patients on D3 with 25OHD3 blood levels of at
least 74.4 ng/ml in the past 2 years (n=418)
There were no cases of vitamin D-induced hypercalcemia or any
other adverse events related to vitamin D supplementation observed in
any patient.
There were 7 cases of non-vitamin D related hypercalcemia observed
during this time frame. Five were due to previously undiagnosed
primary hyperparathyroidism. One was found to be due to treatment
with lithium and hydrochlorothiazide, which resolved with change in
medications. The last case occurred in association with a bout of acute
pancreatitis, which resolved with resolution of the pancreatitis.
3.2.1. Demographics & Number of 25OHD measurements at each vitamin
D3 dose (Table 1)
A total of 777 measurements of 25OHD made in patients over the
past 2 years who were not on D3 supplementation are included in this
analysis. This includes new admissions, long term patients who declined
vitamin D supplementation, and baseline levels in patients who
were on D3 long enough to have a 25OHD level>74.4 ng/ml.
Of this total, 568 measurements (73%) were made in male patients,
and 210 measurements (27%) in female patients. This is reflective of
the male to female patient ratio in the hospital. The age range was from
18 to 90 years old, and by race, 49.9% were black, 47.3% were white,
and 2.8% were other races.
A total of 418 measurements of 25OHD greater than 74.4 ng/ml
were identified in the past 2 years in patients who were on daily vitamin
D supplementation.
This includes 377 measurements in male patients (90%) and 41
measurements (10%) in female patients. The age range was from 19 to
76 years old, and by race, 60.3% were black, 38.3% white, and 1.4%
Fig. 1. Panel A: Plot of individual monthly 25OHD3 values (o) and mean monthly 25OHD3 values (x) for 36 patients taking 5000 IU of vitamin D3 daily (n=125
values). Panel B: Plot of individual monthly 25OHD3 values (o) and mean monthly 25OHD3 values (x) for 78 patients taking 10,000 IU of vitamin D3 daily (n=344
values).
The curve (—) represents a rising exponential curve of the mean monthly values. The middle curves (—) represent the 95% confidence band, and the outer curves
(—) represent the 95% prediction band. Units are ng/ml. (Figs. 1 to 3 are courtesy of the late Dr. Robert P. Heaney, Creighton University.)
P.J. McCullough, et al. Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
231
other. This variance in more measurements in black males is likely a
reflection of differences in length of stay between the populations.
The majority of 25OHD3 values>74.4 ng/ml, i.e. 79%, were obtained
on patients taking 10,000 IU/d, with 17% in patients on 5000
IU/d, and 4% on doses higher than 10,000 IU/d. There was one patient
with psoriasis who was on 50,000 IU of vitamin D2 daily for more than
2 years. There were 2 other patients with psoriasis who were taking
doses ranging from 20,000 IU to 45,000 IU of vitamin D3 daily. All 3
patients showed marked improvement in their psoriasis within 3 to 4
months without developing any complications.
The breakdown of the actual numbers of 25OHD blood levels above
74.4 ng/ml obtained at varying doses of vitamin D3 is shown in Table 1.
3.2.2. Comparison of the mean and range of serum 25OHD, calcium and
iPTH levels in patients not on D3 vs on oral D3 long enough to achieve
25OHD blood levels>74.4 ng/ml
The mean 25OHD blood level in patients on D3 supplementation
was 118.9 ng/ml, vs. 27.1 ng/ml in patients not on D3 supplementation,
for a difference of 91.8 ng/ml between the groups, as shown in Table 2.
With the exception of one patient in the No D3 group, there was no
overlap in the range of 25OHD values between the 2 groups. The distribution
of serum 25OHD values is discussed in Section 3.2.3, and is
shown in Table 3.
In spite of the large difference between mean 25OHD values between
the 2 groups, the mean and range of calcium levels were almost
identical in the D3 group vs the no D3 group, also shown in Table 2.
The mean serum calcium level in the D3 group was 9.6 mg/dl, vs
9.5 mg/dl in the no D3 group. The range of serum calcium levels was
8.7–10.7 mg/dl in the D3 group, vs 8.4–10.7 mg/dl in the No D3 group.
A total of 7 patients with elevated calcium levels due to causes other
than vitamin D were excluded, as discussed in Section 3.2.
The distribution of serum calcium values was also very similar
Fig. 2. Panel A: Plot of mean monthly serum calcium values (mg/dl) with standard deviation bar in 36 patients on 5000 IUs of vitamin D3 daily. Panel B: Plot of
mean monthly serum calcium values (mg/dl) with standard deviation bar in 78 patients on 10,000 IUs of vitamin D3 daily. The red lines are weighted mean values.
Fig. 3. Panel A: Plot of mean monthly serum iPTH levels (pg/ml) with standard deviation bars in patients on 5000 IU of vitamin D3 daily. Panel B: Plot of mean
monthly serum iPTH levels (pg/ml) with standard deviation bars in patients on 10,000 IU of vitamin D3 daily. The red line is the weighted mean value.
Table 1
Number of 25OHD levels at each D3 dose.
D3 Dose No D3 D3 Total
0 777 0 777
5000 x 70 70
10,000 x 331 331
20,000 x 5 5
40,000 x 4 4
45,000 x 1 1
50,000 x 7 7
total 777 418 1195
Note: baseline labs for patients on D3 are included in the no D3 group, and were
not analyzed separately from patients who did not take D3.
Table 2
Summary of D3 vs No D3 Supplementation - Mean, Range, N.
Test D3 No D3 D3 No D3 D3 No D3
Mean Mean Range Range N N
25OHD 118.9 27.1 74.4 - 384.8 4.9 - 74.8 418 777
Calcium 9.6 9.5 8.7 - 10.7 8.4 - 10.7 381 728
iPTH 24.2 30.2 5 - 54 8.0 - 77.0 261 650
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between the 2 groups, and are discussed in Section 3.2.4, and shown in
Table 4.
The mean iPTH level in patients on D3 was 24.2 pg/ml, vs 30.2 pg/
ml in those not on D3. The range of values was also narrower in the D3
group, at 5–54 pg/ml, vs 8–77 pg/ml in the no D3 group, as shown in
Table 2.
The distribution of serum iPTH values is discussed in Section 3.2.5,
and is shown in Table 5.
Beginning in January 2017, intact PTH blood levels were routinely
obtained on all new admissions to the hospital, and with all follow-up
25OHD blood levels. For this reason, there are significantly more iPTH
blood levels in both groups of patients compared to those available in
Data Set 1.
This was done as an additional measure to monitor for toxicity from
vitamin D supplementation, as blood levels of iPTH have been shown to
be undetectable in cases of vitamin D toxicity secondary to hypercalcemia
[33]. There were no undetectable blood levels of iPTH in
any patient.
Note: The mean and range of serum 25OHD, calcium and iPTH
levels was also evaluated separately for patients on 5000 IU, 10,000 IU
or>10,000 IU per day (see table in the supplementary data section).
The mean serum 25OHD levels were 102.9, 115.8, and 234.6 ng/ml
in the 3 groups, while the mean serum calcium values were 9.5, 9.6,
and 9.6, and the mean serum iPTH levels were 25.6, 24.2, and 21.5. The
distribution and range of serum calcium and iPTH values was also very
similar in all 3 groups
Hypercalcemia is the main risk from excessive vitamin D intake.
Because there was no difference in the mean and range of serum calcium
levels between the 3 groups, and because there were relatively
few data points in the>10,000 IU/d group, the data was reported with
the results of all 3 vitamin D doses combined when compared to patients
not taking vitamin D.
3.2.3. Distribution of serum 25OHD Concentrations (ng/ml)
The distribution of serum 25OHD levels in each group is shown in
Table 3.
Vitamin D deficiency was present in a significant percentage of the
patients not on vitamin D3 supplementation, depending on the reference
range used. A total of 28.5% had 25OHD levels<20 ng/ml,
while 64.3% were<30 ng/ml (Table 3).
A 25OHD level<20 ng/ml is currently considered deficient by the
Institute of Medicine [47,48], while a level<30 ng/ml is considered
insufficient by the Endocrine Society [27]. A 25OHD level of 100 ng/ml
is currently considered the upper limit of normal [27,38], while the
IOM warns of caution with 25OHD levels>50 ng/ml.
A majority of the patients (67.8%) on vitamin D supplementation
had 25OHD blood levels above 100 ng/ml. There were 9 blood levels
above 200 ng/ml, and 4 above 300 ng/ml.
A total of 6 of these thirteen 25OHD levels>200 ng/ml were in the
patient with psoriasis who was taking 50,000 IU/day of vitamin D2. His
serum calcium has been measured 13 times, and has ranged from 9.4 to
9.8 mg/dl. His iPTH levels were 40, 38, 29, and 32 pg/ml. His data is
presented in Table 6, and his case is discussed in more detail in Section
3.3.
A total of 4 of these levels above 200 ng/ml, 263, 384, 316 and 347
ng/ml, were observed in a second psoriasis patient taking 40,000 IU/d
on 3 occasions, and 45,000 IU/d on the fourth. Corresponding calcium
levels were 8.9, 9.5, 9.1, and 10.2 mg/dl, while iPTH levels were 6, 5, 9,
and 5 pg/ml.
There was one patient on 50,000 IU/d who had a 25OHD level of
263 ng/ml. Her calcium was 9.0 mg/dl, and iPTH was 24 pg/ml.
There were 2 patients on 10,000 IU/d with 25OHD levels over
200 ng/ml. Both had levels of 202 ng/ml, and these were the highest
25OHD levels observed in patients taking 10,000 IU/d. The serum
calcium was 9.8 mg/dl in one, not measured in the other, and the iPTH
levels were 18 and 24 pg/ml.
3.2.4. Distribution of serum calcium concentrations (mg/dl)
The distribution of serum calcium levels is shown in Table 4.
The distribution of serum calcium levels was very similar between
the 2 groups.
A total of 59.8% of the values were<9.7 mg/dl in the D3 group,
and 58.5% were<9.7 mg/dl in the No D3 group.
A total of 12.8% of the values were above 10.0 in both groups, and
there were no patients with a calcium level above 10.7 in either group.
The normal range in our reference laboratory is 8.7–10.2 mg/dl.
In the group of patients with calcium levels above 10.2 mg/dl, there
were no patients who exhibited any signs or symptoms associated with
hypercalcemia in either group. There was also a lack of persistence of
elevation of calcium levels above 10.2 in these patients on repeat
testing.
Because of the lack of signs or symptoms of hypercalcemia, the lack
of persistence of elevation of the calcium levels on repeat resting, and
the same rate of occurrence in both groups of patients, no one was
classified as having developed hypercalcemia who had calcium levels
above 10.2 in these 2 groups of patients.
3.2.5. Distribution of serum intact parathyroid hormone concentrations
(pg/ml)
The distribution of serum iPTH levels is shown in Table 5.
The distribution of serum intact PTH values is distinctly different
between the two groups. There is a shift to lower values in the D3 group
compared to the no D3 group. The percentage of iPTH values<30 pg/
ml is 79.7% in the D3 group, vs. 55.5% in the no D3 group. There were
no undetectable blood levels of iPTH in any patient. The lowest level in
the D3 group was 5, and in the No D3 group was 8.
3.3. Changes in 25OHD3, calcium and iPTH blood levels in 3 individuals
who have been taking daily doses of vitamin D ranging from 25,000 IU to
60,000 IU a day for 2 to 8 years
Three patients with psoriasis agreed to take vitamin D in doses
Table 3
Distribution of Serum 25OHD Concentrations (ng/ml) - D3 vs. No D3.
N 74 to 79 80 to 89 90 to 99 100 to 199 200 to
299
> 300
D3 418 29 52 54 270 9 4
% 6.9% 12.4% 12.9% 64.6% 2.2% 1.0%
N 0 to 9 10 to 19 20 to 29 30 to 39 40 to 49 >50
No D3 777 26 196 278 177 74 26
% 3.3% 25.2% 35.8% 22.8% 9.5% 3.3%
Table 4
Distribution of Serum Calcium Concentrations (mg/dl) - D3 vs. No D3.
N <9 9 to 9.3 9.4 to 9.6 9.7 to 9.9 10 to 10.3 10.4 to 10.7 >10.7
D3 381 24 84 120 104 39 10 0
NoD3 728 34 196 219 186 83 10 0
D3 % 6.3% 22.0% 31.5% 27.3% 10.2% 2.6% 0.0%
NoD3 % 4.7% 26.9% 26.9% 25.5% 11.4% 1.4% 0.0%
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ranging from 20,000 IU/d to 50,000 IU/d while hospitalized, and each
showed marked clinical improvement in their skin within 3 to 4 months
without the development of hypercalcemia or any other adverse events
related to supplementation with vitamin D. The data from 2 of these
patients was discussed earlier in data set 2, and one will be reviewed in
more detail in this section.
One of the psoriasis patients was a 29-year-old obese black male
who started on 50,000 IU of vitamin D2 po daily on the day of admission,
and has now been taking this dose for 29 consecutive months
without complication.
On admission, his psoriasis was poorly controlled, in spite of being
followed in the dermatology clinic at the local medical school. He had
extensive plaques on his scalp, forehead, and ears, and scattered plaques
on his chest, abdomen, elbows and thighs. He was being treated
with topical steroid creams and medicated shampoos at the time of
admission. He was not on a vitamin D supplement. PASI scores were not
routinely calculated, but it was approximately 7 at the time of admission.
His skin began improving shortly after starting on vitamin D2, was
markedly improved within a few months, eventually cleared completely,
and has remained clear for many months. He is no longer using
topical steroids or medicated shampoos, and is no longer being seen in
the dermatology clinic.
The patient chose to leave the dose of vitamin D2 at 50,000 IU/d,
which is provided in a single capsule, rather than titrate the dose down
using multiple 5000 IU vitamin D3 capsules. His serum calcium and
iPTH levels have been checked numerous times, and have remained
normal. His 25OHD blood level has been ranging from 250 ng/ml to
308 ng/ml, 13 calcium levels have ranged from 9.4 mg/dl to 9.8 mg/dl,
and four iPTH levels have ranged from 29 pg/ml to 40 pg/ml.
He has never developed any adverse reactions to the vitamin D2. A
24-hour urine calcium and creatinine was obtained in July 2017, which
was unremarkable.
His data is shown in Table 6.
The other 2 cases to be discussed involve two of the authors, who
previously reported in 2017 on their experience in taking
20,000–60,000 IU of vitamin D3 daily for 2–6 years without complication
[49].
One (JA) has experienced marked clinical improvement in his
asthma since starting on vitamin D3 in 2011. His asthma was previously
poorly controlled on usual medical care. Prior to taking vitamin D3, he
would have 5 to 6 severe asthma exacerbations a year, requiring
bedrest, time off from work, and treatment with antibiotics and oral
steroids. He was on usual care for asthma during this time, and saw a
pulmonologist and primary care physician on a regular basis.
Since starting on the vitamin D3 in 2011, he has only had one
serious exacerbation, which occurred when he inadvertently lowered
his dose from 10,000 IU/d to 5000 IU/d early in the course of therapy
with vitamin D. He originally started on 10,000 IU/d, and has since
titrated the dose to 30,000 IU/d. He has discontinued most of his other
asthma medications. During this time period his labs were measured
several times. He has had 25OHD levels 96.6, 161.1, and 106.9 ng/ml,
calcium levels of 9.2, 10.0, 9.9, and 9.9 mg/dl, and iPTH of 25 pg/ml
(most recent calcium and iPTH from May 2018). All lab results were
obtained through his primary care office.
The second (PM) experienced marked clinical improvement in an
ulcerated skin lesion on his hand after titrating his daily vitamin D3
dose from 20,000 IU/d to 60,000 IU/d over the course of 4 years. The
ulceration was dime-sized, developed while taking 20,000 IU/d, and
slowly shrank in size as the dose of vitamin D3 was increased.
The ulceration was presumed to be a non-melanoma skin cancer. It
was eventually excised, and showed no cancer cells after reviewed by
pathology. It has never recurred since excision approximately 2 years
ago. His 25OHD levels have been measured every 6 months since
Table 5
Distribution of Serum intact Parathyroid Hormone Concentrations (pg/ml) - D3 vs No D3.
N 0 to 10 10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 >59
D3 261 4 72 132 37 12 4 0
No D3 650 1 79 282 192 57 29 10
D3 % 1.5% 27.6% 50.6% 14.2% 4.6% 1.5% 0.0%
No D3 % 0.2% 12.2% 43.4% 29.5% 8.8% 4.5% 1.5%
Table 6
Patient with Severe Psoriasis Completely Cleared on 50,000 IU D2 for>2 years (Vitamin D2 50,000 IU capsule
started daily on 2/25/16).
Date 25OHD iPTH Calcium Comments
2/27/2016 70.5 40 9.5 severe
5/27/2016 9.5 marked improvement
10/20/2016 9.6 mild
12/3/2016 9.6
12/15/2016 9.7
1/12/2017 9.4
1/28/2017 262 9.5
3/6/2017 297.6 9.6
4/13/2017 290.8 38 9.6 dermatology clinic visits stopped
6/10/2017 296.4 9.8 no signs
9/6/2017 9.4 no signs
12/6/2017 249.6 29 9.5
3/2/2018 308.4 32 9.6 no signs
24 hour Urine Calcium with Creatinine on 6/9/17
test value range
calcium 14.4 Not est.
24 hr calcium 316.8 100 to 300
creatinine 69.6 Not est.
ca/cr ratio 207 0 to 260
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starting on 60,000 IU/d in 2014 with home test kits from Grassroots
Health (www.grassrootshealth.net). His last 7 measurements on this
dose were 225, 166, 218, 247, 187, 236, 219, and 194 ng/ml, averaging
212 ng/ml (most recent 25OHD in July 2018). Calcium levels have been
monitored less frequently, and were normal at 9.4 and 9.7 mg/dl. He
has never experienced any adverse events while taking vitamin D.
None of the 3 individuals have ever developed hypercalcemia or any
other signs or symptoms of vitamin D toxicity while taking daily oral
doses of D3 ranging from 25,000 IU/d to 60,000 IU/d for several years.
All 3 have shown marked clinical improvement in their chronic medical
problems.
3.4. Comparison of the results of 3.1 with the results from four previously
discussed studies reporting changes in 25OHD3 blood levels after daily oral
supplementation with varying doses of vitamin D for 4 to 12 months, and one
study reporting changes in 25OHD levels after successful use of phototherapy
in treating patients with psoriasis after 1 to 4 months
Data comparisons were made at several time points, including
baseline, and after 1–4 months, 5 months or 12 months of treatment,
based on the data reported in the comparison study. (Note: this data
comparison is presented in Tables 7–10 in the supplemental data section.)
3.4.1. Brief summary of each of the comparison studies
3.4.1.1. Stamp [25]. A 4 month study with 164 healthy volunteers
using 10 different oral doses of vitamin D. Equilibrium 25OHD blood
levels were obtained after 4 months or longer of daily oral dosing.
Baseline values were not reported. The data provided by Stamp are
graphical, plotting individual equilibrium 25OHD blood levels for each
patient against the oral dose of vitamin D. For this report, all 25OHD
blood levels were estimated from the graphical data presented in the
manuscript (Table 8, supplemental data section). 25OHD blood levels
from a one month UVB phototherapy treated group was also presented.
These patients were found to develop 25OHD blood levels that were in
between those in observed in individuals taking 10,000 IU/d and
20,000 IU/d.
3.4.1.2. Heaney [37]. a 5month study with 67 healthy volunteers using
3 different oral doses of vitamin D vs placebo. Baseline 25OHD ranges
were not reported (Table 9, supplemental data section).
3.4.1.3. Ryan [43]. a 4month phototherapy study in 29 patients with
chronic plaque psoriasis, who were treated until complete clearing of
psoriasis skin lesions occurred. Clearing of the plaques was observed
after 1–4 months of treatment with NB-UVB phototherapy, at which
time follow-up 25OHD blood levels were obtained, and compared to
baseline levels (Table 8, supplemental data section). An untreated agematched
control group of psoriasis patients was also included for
comparison.
3.4.1.4. Garrett-Mayer [45]. a 12month study comparing the 25OHD
response to a daily oral dose of 4000 IU of vitamin D3 in African
American vs white men (Table 10, supplemental data section).
3.4.1.5. Marshall [46]. a 12month study examining the safety and
clinical efficacy of using an oral dose of 4000 IU/d of vitamin D3 in 52
low-risk prostate cancer patients (Table 10, supplemental data section).
Table 7 shows the similarity in the median, mean and range of
25OHD blood levels observed at baseline between the current and
comparison studies.
Table 8 shows the remarkable similarity between the median and
range of 25OHD blood levels observed by Ryan after using NB-UVB
phototherapy in the treatment of psoriasis in 2010, versus after the
administration of daily 10,000 IU oral doses of vitamin D reported by
Stamp in 1977, and as observed in the current report in our patients
who took 10,000 IU/d of D3 after 1–4 months.
Table 9 shows that our 5 month mean 25OHD blood levels in both
the 5000 IU/d and 10,000 IU/d treatment groups are very similar to
those reported by Heaney in 2003 [38].
Table 10 shows the mean and range of 25OHD blood level in our
patients on 5000 IU/d (n=9) and 10,000 IU/d (n=49) at 12 months,
and how the 5000 IU/d data are very similar to those reported in patients
taking 4000 IU/d of vitamin D3 for 12 months by both Garrett-
Mayer [44] and Marshall [45].
4. Discussion
The possibility that oral vitamin D may be safe and effective in
treating the numerous medical problems found to be strongly linked to
vitamin D deficiency remains an area of great interest in medicine. A
2010 review of publications that use the term “vitamin D” in either the
title or abstract revealed an exponential increase in the publication rate
of peer-reviewed papers on the topic of vitamin D over the last 40 years
[3]. And at the time of the writing of this manuscript, there were a total
1602 vitamin D trials registered on the Clinicaltrials.gov website (August
2018).
Since 2009, we have been offering hospitalized patients daily supplementation
with 5000 IU to 10,000 IU of vitamin D3 to both correct
and prevent vitamin D deficiency. This was first shown to be safe and
effective in a 5-month study reported by Dr Robert Heaney in 2003
[37]. Our data shows that this protocol continues to be safe and effective,
even when used for extended periods of time, and with 25OHD
blood levels reaching as high as 202 ng/ml on 10,000 IU/d. Many of our
patients have prolonged hospital stays, and remain on supplementation
for many months. A total of 43% of our current patients have been
hospitalized for a year or longer, and a significant percentage were
found to be either deficient or insufficient in vitamin D at the time of
admission.
We previously reported that in a random sampling of 425 patients
admitted in 2009 to a post-acute care hospital, a total of 58% were<
20 ng/ml, with 84% being<30 ng/ml at the time of admission [50].
This continues to be a significant problem in our patients, as the sampling
of 777 recently admitted and long-term patients reported in this
study showed similar results, with 28.5% below 20 ng/ml, and 64.3%
below 30 ng/ml.
Before making the decision to follow this protocol in 2009, an extensive
review of the literature on vitamin D dosing, toxicity, and
clinical efficacy was done as discussed earlier. During this review, hypercalcemia
and its attendant symptoms was identified as the main
adverse reaction, but it was only associated with prolonged intake of
supra-physiologic doses of vitamin D, as noted in many reports and
reviews [16,17,20,24,29–33,36,38–40,42].
Several reviews on vitamin D toxicity and safety between 1999 and
2008 found no evidence of toxicity associated with daily intakes of
5000 IU to 10,000 IU a day [36,38–40,42]. And there were at least 2
reports in 2007 advocating that intakes of 10,000 IU should be recognized
as the tolerable upper intake level (UL), an intake that “is
likely to pose no risk of adverse events in almost all individuals in the
general population [39,39,40].
The reasoning for choosing 10,000 IU/d for the UL was two-fold.
The first was that rigorous review of published studies involving cases
of hypercalcemia related to vitamin D intake found it to be safe. The
second was due to the discovery, first reported in 1977 and later confirmed
and extended by others, that the body will make up to
10,000–25,000 IU a day in response to adequate sun exposure to the
skin [1–3,25–28,36,38–40]. It was reasoned that if the body makes
10,000 IU of vitamin D a day in response to whole body exposure for a
sufficient period of time, then it should be safe to take this dose on a
daily basis [39,39,40].
The data we present in this report support this hypothesis, as we
observed no adverse events in any patient taking 10,000 IU/d for an
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235
extended period of time. Some of our patients have been on this dose
for 7 years. Our data also suggests that even higher doses are safe to
take for prolonged periods of time, and are associated with the same
clinical benefits observed by others in the 1930s and 1940s.
We found intakes of 20,000 IU/d to 60,000 IU/d, associated with
25OHD blood levels ranging as high as 384 mg/dl, safe when taken on
an extended daily basis. Many of the 25OHD blood levels we have
observed are much higher than the currently defined upper limit of
normal of 100 ng/ml [27,38], yet we found no evidence of toxicity in
any individual who achieved these blood levels after taking these doses
for extended periods of time.
There were no differences in mean serum calcium levels, the distribution
of serum calcium levels, or any cases of vitamin D induced
hypercalcemia in patients on vitamin D vs those not on vitamin D in any
of our data sets. This is in spite of marked differences in the mean
25OHD levels (118.9 ng/ml vs 27.1 ng/ml), and in the ranges of 25OHD
blood levels (74.4–384.8 ng/ml vs 4.9–74.8 ng/ml) observed.
We also found that the mean and range of 25OHD levels from our
patients on 10,000 IU/d for 1 to 4 months (54 ng/ml, range 14–130 ng/
ml) were strikingly similar to the results observed in patients on 10,000
IU/d for at least 4-months reported in 1977 by Stamp (median 55 ng/
ml, range 40–110 ng/ml) [25], and to those obtained after 1 to 4-
months of phototherapy in patients with psoriasis reported in 2010 by
Ryan (median 59 ng/ml, 32–112 ng/ml) [43].
This lends strong support to the observations that the body makes at
least 10,000 IU of vitamin D in response to UVB radiation, and that
10,000 IU of vitamin D should be safe to take on a daily basis. This is a
very important finding, and lends more support to the recommendation
of increasing the UL to at least 10,000 IU/d.
It is important to note that the baseline median 25OHD level (23 ng/
ml) and range of 25OHD levels (9–46 ng/ml) in the Ryan study were
much lower than the values observed after phototherapy. This calls into
question the accuracy of considering a 25OHD blood level of at least
20 ng/ml as sufficient [47,48]. Other phototherapy studies in patients
with psoriasis have shown similar changes in 25OHD levels before and
after treatment [51]. No cases of hypercalcemia were observed in any of
the phototherapy reports.
As discussed earlier, phototherapy has been known to be effective in
treating rickets [5,13], tuberculosis [6–12] and psoriasis [14,43,51–53]
dating back to the 1890s, 1920s, 1930s and 1940s. Phototherapy and
sunshine are both currently recommended as treatments for psoriasis by
the National Psoriasis Foundation [52], and phototherapy is also recommended
for treating psoriasis by the American Academy of Dermatology
[53].
Unfortunately, we were unable to find any literature on 25OHD
blood levels with extended phototherapy for disease control in patients
with psoriasis. It is not currently known how high 25OHD blood levels
will become with prolonged phototherapy used to maintain remission
in psoriasis. This is an important void in the literature that needs to be
filled, as maintenance phototherapy administered 2–3 times a week is
required to maintain control in psoriasis [52,53]. If the phototherapy is
stopped, the disease will recur, unlike with TB or rickets.
It would be informative to know just how high 25OHD blood levels
can be with phototherapy, as it would give us more insight into what
the “normal range” of 25OHD blood levels might be. Our data on extended
daily dosing with 5000 IU/d and 10,000 IU/d show that the
25OHD curves don’t plateau until about 12 months, which was not
evident in the 5-month report from Heaney in 2003 [37]. It is not clear
if the same will be true with phototherapy.
Interestingly, also like TB and rickets, psoriasis has also been shown
to improve with oral vitamin D3. This was not only shown in the 1930s
[14], but again in the 1980s, 1990s and 2000s [54–58]. Topically applied
vitamin D has also been known to be an effective treatment for
psoriasis since the 1980s [59].
The fact that sunshine, phototherapy, and vitamin D are all effective
in treating these 3 diseases, and because vitamin D is produced in the
skin by the action of UVB radiation on 7-dehydeocholesterol, makes it
very likely that correction of vitamin D deficiency induced by sunshine
and phototherapy is responsible for their clinical effects. This is what
motivated physicians to start using oral vitamin D to treat disease in the
1930s and 1940s [14–17,19–24], and which they ultimately found to be
quite effective.
In support of this hypothesis, it was shown in 2006 that the mechanism
by which vitamin D is able to kill tuberculosis is by turning on
a gene in the nucleus of white blood cells that makes an antibiotic
called cathelicidin [60]. The gene is unable to be turned on in a state of
vitamin D deficiency. Once the vitamin D deficiency is corrected, the
gene can be turned on and the disease cured, regardless of the method
used to correct the underlying state of vitamin D deficiency [24].
The decision to treat our psoriasis patients with vitamin D was made
due to the multiple reports cited earlier showing its clinical efficacy and
safety [14,54–59]. This includes the previous success of one of the
authors (PM) in treating psoriasis using oral vitamin D3 in doses ranging
up to 40,000 IU/d [57]. We were also confident that the doses we
used would be safe and effective due to the recent experience of two of
the authors (JA, PM) in safely using comparable doses of vitamin D in
treating asthma and skin cancer.
The reason one of the authors (PM) made the decision to titrate the
dose of vitamin D3 to see its effect on the skin cancer was due to a
number of factors. This included reports from 1980 to 2006, and again
in 2018, showing a strong relationship between vitamin D deficiency
and increased risk for a number of cancers [61–65], others reports from
the 1990s, and again in 2011, describing the ability of vitamin D to kill
human tumor cells in-vitro, including melanoma and basal cell cancers
[66–70], reports detailing the cellular mechanisms by which vitamin D
is able to arrest cancer cell growth from 2008 and 2012 [71,72], and a
clinical trial from 2007 that showed a decrease risk for a number of
cancers in individuals receiving daily oral vitamin D vs placebo [73].
There are also now reports from 2016 [74] and 2018 [75] showing
evidence of clinical efficacy of vitamin D in preventing cancer growth.
One is a case report on advanced pancreatic cancer [74], in which an
elderly patient, who was unable to tolerate chemotherapy, radiation, or
surgery, took 50,000 IU/d of D3 for 9 months and was found to have a
remarkable period of disease free progression, far beyond what would
have been expected with chemotherapy. The authors were so impressed
by this finding that they issued a call for more research in cancer patients
with vitamin D using doses in this range.
Consistent with data from the 1930′s, 1940s, 1980s and 1990s
discussed earlier, the three patients with psoriasis and the author with
asthma all safely showed marked clinical improvement on oral vitamin
D supplementation. However, they were able to do this using much
lower doses of vitamin D than were used in the 1930′s and 1940s. The
doses these individuals used, 20,000 IU/d to 50,000 IU/d, are an order
of magnitude lower than the doses of 60,000 IU/d to 300,000 IU/d used
for asthma, 150,000 IU/d to 600,000IU/d for RA, and 100,000 IU/d to
150,000IU/d for TB. They were also within or much closer to the range
of vitamin D estimated to be produced in the skin from sunshine, i.e.
10,000 IU/d to 25,000 IU/d, which likely explains why they were
clinically effective, but without causing toxicity from hypercalcemia.
There appears to be a dose response relationship between the clinical
effectiveness of vitamin D and its toxicity. In the case of the individual
with asthma, the only time he has had an exacerbation is when
he dropped the dose of vitamin D3 to 5000 IU/d.
His experience is also consistent with the results of a recent clinical
trial in which vitamin D3 supplementation was found to be ineffective
in treating patients with asthma [76]. In this trial, 100,000 IU of vitamin
D3 was given once, followed by 4000 IU/d of vitamin D3 given
for 28 weeks, and was found to be ineffective in reducing the rate of
first treatment failure or exacerbation in 201 adults with persistent
asthma and vitamin D insufficiency, as compared to 207 control patients
treated with placebo. The authors concluded that “These findings
do not support a strategy of therapeutic vitamin D3 supplementation in
P.J. McCullough, et al. Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
236
patients with symptomatic asthma.”
A follow-up clinical trial using vitamin D3 with higher daily doses,
in the range of at least 10,000 IU/d to 25,000 IU/d, is clearly needed
before this conclusion can be reached. Their results only prove that
4000 IU/d is ineffective in treating patients with asthma, not that vitamin
D is ineffective in treating asthma.
We have consistently found that supplementing individuals with
vitamin D using daily dosing equivalent to 100% to 200% of the estimates
of daily production from sunshine to not only be safe, but also
effective in treating diseases strongly linked to vitamin D deficiency.
The 4000 IU/d vitamin D3 dose used in this asthma study is the
maximum daily dose currently recommended by the Institute of
Medicine [47,48,77], but only represents 16% to 40% of the amount of
vitamin D estimated to be produced from sun exposure to the skin, i.e.
10,000 IU/d to 25,000 IU/d. The patients in the asthma study were
clearly deficient, with mean baseline 25OHD levels of 18.8 ng/ml.
These values increased to a 25OHD mean of 42 ng/ml (range,
6.3–97.3 ng/mL) by week 12 in the treatment group, and persisted at
this mean level through week 28, but remained less than 20 ng/ml in
the placebo group.
These on treatment values are less than the median and range observed
by Ryan in the phototherapy study after 1–4 weeks (median
59 ng/ml, range 32–112 ng/ml), and in our 10,000 IU/d group at 5
months (mean 77 ng/ml, range 63–110 ng/ml) and 12 months (mean
96 ng/ml, range 53–148 ng/ml). They are also much lower than the
25OHD levels observed in the author (JA) with asthma (96.6, 161.1,
and 106.9 ng/ml).
Similar remarkable clinical benefits using doses in this range have
previously been reported in a patient with Parkinson’s disease treated
with 4000 IU/d of 25OHD3 (roughly equivalent to 40,000 IU/d of D3
(25)) for a year in 1997 [78], and in a pancreatic cancer patient treated
with 50,000 IU/d for 9 months reported in 2016 [74]. Based on these
case reports, our experience, and the reports from the 1930s and 1940s
discussed earlier, the failure of many clinical trials involving vitamin
D3, that have been reported in the last few decades appear to be related
to the use of insufficient dosing of vitamin D, which have typically
ranged from 800 IU to 2000 IU/d.
It is interesting to note that both Dowling [79] and Howard [17] in
the 1940s observed random calcifications occur at times in patients
treated with large doses of vitamin D, with both also observing that the
calcifications resolved over time along with the hypercalcemia with
cessation of vitamin D intake. The main treatment for vitamin D induced
hypercalcemia appears to be stopping the vitamin D intake, and
supportive care if necessary. Once the vitamin D levels fall, the hypercalcemia
improves, calcifications will dissolve if present, symptoms
abate, and patients recover uneventfully [17,33,79]. See an expanded
discussion of these references in the supplemental data section.
It was with this broad background of information on dosing, safety,
and toxicity, recommendations for the new UL of 10,000 IU/d, the
clinical trial evidence on the effectiveness of vitamin D in treating
asthma in the 1930s, psoriasis in the 1930s, 1980s and 1990s, rickets in
the 1920s, RA in the 1940s, TB in the 1940s, epilepsy in 1974 and 2012
[80,81], Parkinson’s disease in 1997 [78,82], estimates of vitamin D
production in the skin made in the 1970s and 1980s ranging from
10,000 IU/d to 25,000 IU/d, and the strong link between vitamin D and
cancer discussed earlier, that we began to supplement hospitalized
patients in 2009 with 5000 IU/d to 10,000 IU/d of vitamin D3, and
have safely continued to do so through today.
A few years after implementing this protocol, a national debate over
vitamin D dosing, safety, clinical efficacy and toxicity erupted in 2011
with the publication of 2 contrasting sets of recommendations, one from
the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM)
[47,48,77], and the other from the Endocrine Society [27]. This debate
remains unsettled and continues today [83].
In 2011, the IOM defined vitamin D deficiency as<20 ng/ml
[47,48,77], while the Endocrine Society considered levels<30 ng/ml
to be insufficient [27]. The IOM warned against achieving 25OHD levels>
50 ng/ml due to concerns for increased mortality risk, while the
Endocrine Society maintained a 25OHD blood level of 100 ng/ml as the
upper limit of normal. The IOM stated that a 25OHD blood level of
20 ng/ml or above was sufficient for the majority of the population, and
that an intake of 600 IU/d would achieve this result in most people.
They also assumed that all the vitamin D that a person gets is obtained
from the diet, and recommended avoidance of sunshine due to the risk
of developing skin cancer [48].
However, several reports have shown that prolonged sun exposure
or phototherapy results in mean and median 25OHD blood levels 2–3
times higher than the IOMs estimate for sufficiency [25,41,43,51,85],
and can result in complete control of a disease, as has been shown for
psoriasis, tuberculosis and rickets. See an expanded discussion of the
issues surrounding this debate in the supplemental data section.
There is also a discussion in the supplemental section of the 25OHD
blood levels obtained in 1971 when the first accurate measurements of
25OHD were made [41]. They measured 25OHD blood levels in several
groups of people. In a group of 8 lifeguards, mean 25OHD blood levels
were 64.4 ± 8.7 ng/ml, with a range of range 53–79 ng/ml.
Several more recent studies also support the safety of 25OHD blood
levels>50 ng/ml [85–93]. These are discussed in detail in the supplemental
data section.
We have not observed any cases of hypercalcemia, nephrolithiasis,
or any other signs or symptoms of toxicity in any of our patients who
achieved 25OHD blood levels ranging from 100 ng/ml to 384 ng/ml
while taking daily supplemental doses of vitamin D ranging from 5000
IU/d to 60,000 IU/d.
Several other groups of investigators have also recently reported no
increased risk for the development of kidney stones with vitamin D
supplementation [94–100].
5. Conclusion
Daily oral intake of vitamin D3 ranging from 5000 IU/d to 60,000
IU/d for several years was well tolerated and safe in both our patients
and staff. The mean 25OHD blood levels in our patients appear to take
around 12 months to plateau on 5000 IU/d and 10,000 IU/d.
The average 25OHD values we observed in patients taking 10,000
IU/d at 12 months (96 ng/ml) and 16 months (97 ng/ml) are almost
identical to what is currently considered to be the upper limit of normal
(100 ng/ml) and are approximately 50% higher than those observed in
our patients taking 5000 IU/d for the same period of time.
Serum 25OHD levels above 100 ng/ml, ranging to as high as
202 ng/ml, were commonly observed in patients on prolonged daily
oral dosing with 10,000 IU. Serum 25OHD blood levels over 200 ng/ml,
ranging as high as 384 ng/ml, were also observed in several individuals
taking vitamin D doses>10,000 IU/d. However none of these 25OHD
blood levels were associated with hypercalcemia, nephrolithiasis, or
any other adverse health effects in our study population.
Estimates of 25OHD blood levels associated with toxicity from hypercalcemia
have varied over time [1,27,33,36,38,40,42,48], with recent
evidence suggesting that 25OHD blood levels up to 400 ng/ml are
safe [33]. Our data are consistent with this value.
The use of doses ranging from 25,000 IU/d to 60,000 IU/d was
associated with remarkable clinical benefits in several individuals with
psoriasis, asthma and skin cancer, without the development of hypercalcemia
or clinical toxicity.
These case findings are consistent with case reports on pancreatic
cancer in 2016 [74], Parkinson’s disease in 1997 [78,82], and psoriasis
in the 2000s [57], and clinical trials with psoriasis in the 1930s [14],
1980s [54,55], and 1990s [56,58], asthma in the 1930s [15], rheumatoid
arthritis in the 1930s and 1940s [16,17], tuberculosis in the
1940s [19–24,79], rickets [5,18], and epilepsy in the 1970s [80] and
2000s [81].
Both the baseline, and on treatment median and range of 25OHD
P.J. McCullough, et al. Journal of Steroid Biochemistry and Molecular Biology 189 (2019) 228–239
237
blood levels in our 10,000 IU/d group of patients after 1–4 months were
very similar to those observed in both the NB-UVB phototherapy study
reported by Ryan in 2010 [43], which were obtained at the time of
complete clearing of psoriasis skin lesions, as well as in the 10,000 IU/d
group of patients reported by Stamp in 1977 [25], who were supplemented
daily for at least 4 months before a follow-up 25OHD level was
obtained.
Contrary of the assertions of the Institute of Medicine that sunshine
should be avoided due to the risk of developing skin cancer [47,48,77],
sunshine and phototherapy have been shown to be safe and effective
treatments for rickets [5,13], tuberculosis [6–12,24], and psoriasis
[43,51], and are currently recommended for the treatment of psoriasis
[52,53].
Clinical trials using doses of vitamin D within the range of amounts
estimated to be made in the body from sun exposure to the skin, i.e.
10,000 IU/d to 25,000 IU/d [1–3,25–28,36,38–40], and up to 50,000
IU/d appear to be warranted. These studies are likely to be both safe
and clinically effective for a number of disease states. If toxicity from
hypercalcemia were to occur, it is not life threatening, and is easily
reversible with cessation of vitamin D supplementation [17,33,79].
Consideration should also be given to revising the UL to 10,000 IU/
d, as has been previously advocated [39,40].
Conflicts of Interest
The authors have no conflicts of interest to disclose.
Funding
This research was performed without external funding.
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239
 

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Tristan Loscha

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Wow, that is interesting. Have you asked Ray about it ?

No ,others asked him about D.
What he recommends seems to be 50-60ng/ml as target for lab-D.
mentioning of 5000IU/d was attributed to him,with him believing that 10000IU can be fine,for comparative reasons of cutaneous synthesis and oral dosing studies i presume.
Fact is,to reach 50-60ng/ml,after individuals averaged responses,we need 5000IU + presupposed 3000IU,coming from UV supposedly?This presupposition is rarely mentioned,and to reach 50-60ng/ml,
you need a considerable sunexposure even for the meager-looking 3000IU presupposed in more general
mainstream second-hand informing studies and reviews for practitioners and the layman-press.
So,to reach peats Goal,we need 5000IU D3 oral,and daily 3000IU from god knows where.,in total,8000IU/d
from all sources.
 

baccheion

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I'm personally in the 1 : 1 : 1 calcium:phosphorus:magnesium with ~800-1,200 mg phosphorus camp. 300-500 IU/kg D3, adding at least 1 mg MK-4 and 100 mcg MK-7 per 10,000 IU. Half as much calcium if going over ~40,000 IU. Unsure why I'm so biased toward it. Also think getting into 40s (ng/mL) is sufficient if not trying to do anything special, pushing to the top of the range if trying to heal.
 
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Tristan Loscha

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I'm personally in the 1:1:1 calcium:phosphorus:magnesium with ~800-1,200 mg phosphorus camp. 300-500 IU/kg D3, adding at least 1 mg MK-4 and 100 mcg MK-7 per 10,000 IU. Half as much calcium if going over ~40,000 IU. Unsure why I'm so biased toward it. Also think getting into 40s (ng/mL) is sufficient if not trying to do anything special, pushing to the top of the range if trying to heal.

Good thinking and dosage recc.
What was eye opening to me were graphs i came along that showed me that the claimed 30ng/ml was an arbitrary value,
and various mortalities decreased further,down to 70ng/ml,and BDNF values that hit rock bottom in spring for all of those unfortunate not to supplement this precious material.
 

baccheion

Member
Joined
Jun 25, 2017
Messages
2,100
Good thinking and dosage recc.
What was eye opening to me were graphs i came along that showed me that the claimed 30ng/ml was an arbitrary value,
and various mortalities decreased further,down to 70ng/ml,and BDNF values that hit rock bottom in spring for all of those unfortunate not to supplement this precious material.
I base the 40s (ng/mL) recommendation on a study of African tribes that were outside all day long. Serum 25(OH)D was around the mid 40s.

If Caucasians were to do the same in that area, their serum would go even higher. On the other hand, lighter skin is adapted to lower sunlight. The only hesitation centers around blacks being said to need less vitamin D, on average, for the same effect. On the other hand, the difference is calculable and can be made specific given genetic testing results.
 

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