An Update on Vitamin D: The Role in Chronic Disease, Clinical

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University of Kentucky
UKnowledge
DNP Practice Inquiry Projects
College of Nursing
2013
An Update on Vitamin D: The Role in Chronic
Disease, Clinical Practice Implications, and the
Current Status of Nurse Practitioner Knowledge
Sara E. Robertson
University of Kentucky, [email protected]
Recommended Citation
Robertson, Sara E., "An Update on Vitamin D: The Role in Chronic Disease, Clinical Practice Implications, and the Current Status of
Nurse Practitioner Knowledge" (2013). DNP Practice Inquiry Projects. Paper 2.
http://uknowledge.uky.edu/dnp_etds/2
This Practice Inquiry Project is brought to you for free and open access by the College of Nursing at UKnowledge. It has been accepted for inclusion in
DNP Practice Inquiry Projects by an authorized administrator of UKnowledge. For more information, please contact [email protected]
STUDENT AGREEMENT:
I represent that my Practice Inquiry Project is my original work. Proper attribution has been given to all
outside sources. I understand that I am solely responsible for obtaining any needed copyright
permissions. I have obtained needed written permission statement(s) from the owner(s) of each thirdparty copyrighted matter to be included in my work, allowing electronic distribution (if such use is not
permitted by the fair use doctrine).
I hereby grant to The University of Kentucky and its agents a royalty-free, non-exclusive, and irrevocable
license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter
known. I agree that the document mentioned above may be made available immediately for worldwide
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and indexing services in order to maximize the online discoverability of the document. I retain all other
ownership rights to the copyright of my work. I also retain the right to use in future works (such as
articles or books) all or part of my work. I understand that I am free to register the copyright to my work.
REVIEW, APPROVAL AND ACCEPTANCE
The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of
the advisory committee, and by the Associate Dean for MSN and DNP Studies, on behalf of the
program; we verify that this is the final, approved version of the student’s Practice Inquiry Project
including all changes required by the advisory committee. The undersigned agree to abide by the
statements above.
Sara E. Robertson, Student
Dr. Dorothy Brockopp, Advisor
An Update on Vitamin D:
The Role in Chronic Disease, Clinical Practice Implications,
and the Current Status of Nurse Practitioner Knowledge
Sara E. Robertson DNP, APRN
University of Kentucky
College of Nursing
Fall 2013
Dorothy Brockopp, PhD, RN Committee Chair
Kathy Hager, DNP, APRN Committee Member/Clinical Mentor
Sharon Lock, PhD, APRN Committee Member
Dedication
This capstone project is dedicated to the people who have supported me
throughout this process. I would like to dedicate this work to my dear friend and
colleague Whitney Nash for her support. Additionally, I would like to dedicate this work
to both my darling Gracie and Liane for inspiring me.
Acknowledgements
I would like thank my committee Kathy Hager and Sharon Lock for their support
throughout this process. I would especially like to thank my committee chair Dorothy
Brockopp for her time and patience. Her advice will not only help me be a better clinician
and researcher but most importantly will help me to better teach others.
iii
Table of Contents
Acknowledgements …………………………………………...iii
Table of Contents……………………………………………...iv
List of Tables ………………………………………………....v
Introduction to the DNP Capstone Report ……………….......1
Manuscript 1 ………………………………………………….4
Manuscript 2 ………………………………………………….28
Manuscript 3 ………………………………………………….49
DNP Capstone Conclusion …………………………………...70
Appendix A …………………………………………………..72
Capstone Bibliography ……………………………………….78
Capstone References ……………………………………….....88
iv
List of Tables
Table 1- General characteristic of cohort studies relating DM2 to vitamin D status ...25
Table 2 – Sources of vitamin D ………………………………………………………48
Table 3 – Demographic of the study sample …………………………………………66
Table 4 – Knowledge scores ………………………………………………………….66
Table 5 – Knowledge score components ……………………………………………..67
Table 6 – Knowledge score components eliminated from the final instrument ……...68
Table 7- Treatment preference for vitamin D deficiency …………………………….69
Table 8 – Likely use of resources for information on vitamin D …………………….69
v
Introduction to the Final DNP Capstone Report
Sara Robertson
University of Kentucky
1
In the late 20th century there was very little focus on low vitamin D levels as a
health concern. With the introduction of vitamin D fortified milk and food products in
the 1950’s, medical clinicians believed that vitamin D deficiency was no longer a health
concern. However, after the turn of the century research examining vitamin D levels in
adults demonstrating that a large portion of the United States population was vitamin D
deficiency. This discovery lead to hundreds of studies in the last decade which aim to
figure out the role of vitamin D in overall health and determine what clinical
consequences occur in a deficient state. Vitamin D deficiency has now been associated
with many acute and chronic conditions.
Specifically, the first manuscript in this capstone report focuses on the connection
between Vitamin D deficiency and Type 2 Diabetes (DM2). Although a cause and effect
relationship between vitamin D deficiency and increased risk of DM2 is still elusive,
many studies have demonstrated an association between the two chronic disease states.
A Literature Review from 2009 examining 12 articles demonstrated that patients who are
diabetic are more likely than the general population to have vitamin D deficiency.
Additionally, individuals who were deficient in vitamin D are more likely to get DM2
and to get the disease at an earlier age. Finally, diabetics who are concurrently vitamin D
deficient have poorer control of sugar levels. This research indicates that vitamin D
deficiency may play a role in the development and treatment of DM2, however, more
research is needed to examine that role.
The second manuscript in this capstone reviews the current clinical knowledge
regarding vitamin D deficiency. This article begins with the definition of vitamin D
insufficiency and deficiency and its correlation to chronic disease states. Next, the risk
2
factors and epidemiology of vitamin D deficiency are discussed. Finally the article
summarizes the latest information on appropriate clinical screening and treatment of
vitamin D deficiency.
The third manuscript in this capstone series details a research study completed in
2012 to determine the knowledge level of nurse practitioners regarding vitamin D
deficiency. A survey was distributed to nurse practitioners at a national conference. The
results indicate that nurse practitioners overall have poor knowledge of vitamin D
deficiency. Nurse practitioners are expected to make critical decisions regarding patient
care and it is important that they have a good understanding of vitamin D deficiency
ensuring that they can appropriately treat patients. The results of this study indicate that
more education is needed regarding vitamin D deficiency and its connection with chronic
disease.
3
The Association between Vitamin D Deficiency and Type 2 Diabetes Mellitus:
A Systematic Review
Sara E. Robertson
University of Kentucky
4
Abstract
Purpose: Type 2 Diabetes Mellitus (DM2) is a leading cause of morbidity and mortality
and vitamin D deficiency may promote poor glucose metabolism. This systematic review
examines the relationship between vitamin D deficiency and DM2.
Data Sources: An electronic search of articles published from 2005 to 2012 in CINAHL,
PubMed, Medline, EBSCO, Cochrane Library, EMBASE, and Pascal was performed.
Conclusion: Cohort studies show a relationship between low vitamin D status and
prevalence of DM2. Inverse correlations exist between low vitamin D status and β-cell
insulin secretion, insulin resistance, and fasting plasma glucose levels. Studies are limited
because of the cross-sectional design, poor follow-up, and lack of adjustments for
confounders. Two intervention studies show mixed results, but they include subtherapeutic doses of vitamin D and small sample sizes. Case studies demonstrated a 12%
decrease in sugar levels. The current evidence suggests that vitamin D does play a role in
effective glucose metabolism; however, more controlled intervention trials are needed to
fully explain this relationship.
Implications for Practice: Screening and treatment of vitamin D deficiency could help
in the prevention or treatment of DM2. Screening and treatment can prevent
complications and improve quality of life in a cost effective manner.
5
The Association between Vitamin D Deficiency and Type 2 Diabetes: A Systematic
Review
Background
The incidence of type 2 diabetes mellitus (DM2) is increasing at a disturbing rate
in the United States. According to the Centers for Disease Control (CDC), the prevalence
of DM2 is estimated at 25.8 million people or 8.3% of the population (Center for Disease
Control, 2011). Diabetes is the 7th leading cause of death, and also contributes to the
development of heart disease, stroke, high blood pressure, neuropathy, blindness, and
kidney disease. The CDC estimates the costs of diabetes and its associated morbidities to
be $174 billion but the immeasurable cost is in the loss of quality of life and the
premature death that commonly occur with the disease. DM2 is a result of genetics and
lifestyle factors such as diet and exercise but is primarily associated with obesity
(Chagas, Borges, Martini, & Rogero, 2012). Given that weight loss is difficult to achieve
and maintain it is essential that other potentially modifiable risk factors for type 2
diabetes be examined. One potential risk factor that is currently being investigated is the
occurrence of sub-optimal serum vitamin D levels. The purpose of this article is to
systematically review the association between vitamin D and type 2 diabetes mellitus,
and explore the possibility that enhancement of serum vitamin D to a prescribed level,
may augment current diabetes treatment and prevention strategies.
Vitamin D is a fat soluble vitamin which is dependent on consumption from foods
that are naturally rich in the vitamin or fortified such as fish, eggs, and milk.
Additionally, vitamin D can be synthesized under ultra-violet (UV) exposure in the skin
(Bohaty, Rocole, Wehling, & Waltman, 2008). Both methods provide the body with a
precursor vitamin that is converted to the active form of vitamin D via the liver and the
6
kidney. Once it appeared that rickets (associated with a lack of vitamin D) was a disease
of the past, many health providers did not give much recognition to vitamin D or the
implications of vitamin D deficiency. However, recently studies started emerging that
demonstrate large portions of the population suffers from hypovitaminosis D (Holick,
2007). A large cross-sectional cohort study that analyzed data from the National Health
and Nutrition Examination Survey (NHANES III) determined that 50.73% of all women
tested were deficient in vitamin D. This number increased to 72.46% when examining
Hispanic women (Zadshir, Tareen, Pan, Norris, & Martins, 2005). A second study by
Yetley examined data from the National Nutrition Monitoring System which determined
a 30% prevalence of vitamin D deficiency at the current standard and a 70% deficiency
when analyzed against a proposed higher standard vitamin D level (2008). Additionally,
females were more likely to have a greater deficiency then males in all ages except
children ages 1-5. Yetley also found that vitamin D levels have an inverse relationship to
body mass index (BMI). Furthermore, it appears that vitamin D deficiency can occur
even in people that live in sunny climates and are consistently exposed to the sun’s UV
rays. A study performed in Arizona found that even with a history of adequate sun
exposure, deficiency occurred in 25% of the population studied (Jacobs et al., 2008).
This study also provided data that reinforced increased prevalence in women, Hispanics,
Blacks, and obese individuals.
The most well-known function of vitamin D is to maintain calcium and
phosphorus homeostasis; however, the discovery that most cells on the body have a
vitamin D receptor suggests that the vitamin could have many more functions within the
body (Holick, 2012). Sub-optimal vitamin D is associated with multiple musculoskeletal
7
disorders including osteoporosis and osteoporosis related fractures, muscle pain,
weakness, and increased risk of falls (Binkley, 2012; Haroon & FitzGerald, 2012).
Additionally, vitamin D deficiency has been linked to several different forms of cancer
including colon, prostate and breast cancer (Mitchell, 2011). It has even been suggested
that vitamin D can also have an influence on common age-related morbidities including
dysphagia, urinary incontinence, and cognitive decline (Binkley, 2007). More recently,
evidence suggests that sub-optimal serum vitamin D levels may play a role in the
development of DM2. Evidence indicates that vitamin D may have a direct role in
insulin secretion and the utilization of insulin by peripheral tissue. It is hypothesized that
binding of circulating 1,25-dihydroxyvitamin D (the active form of vitamin D) to the
pancreatic β-cell vitamin D receptor promotes insulin secretion (Peechakara & Pittas,
2008). Additionally, the regulation of calcium levels by vitamin D can also indirectly
promote β-cell insulin secretion by maintaining a consistent flux of calcium into the cell.
Finally, it also appears that vitamin D stimulates the expression of insulin receptors on
target-tissues which facilitates the uptake and use of insulin (Penckofer, Kouba, Wallis,
& Emanuele, 2008).
Methods
An electronic search was conducted to identify studies that were published from
2005 to 2012 in the following databases: CINAHL, PubMed, Medline, EBSCO,
Cochrane Library, EMBASE, and Pascal. Articles were limited to English language.
Focus was placed on cohort and case control studies, as well as randomized controlled
trials (RCT) that examined the relationship between vitamin D deficiency and DM2.
Because metabolic syndrome has the same risk factors as DM2 and is a known precursor,
8
data examining the link between vitamin D and metabolic syndrome were also
investigated. Keywords used were: type 2 diabetes, DM2, metabolic syndrome, vitamin
D deficiency, hypovitaminosis D, β-cell function, and insulin resistance. Nine articles
were retrieved via the electronic search method. An additional three articles were found
while reviewing the references to those articles and other literature reviews on the topic.
The total number of articles reviewed was 12.
Inclusion/Exclusion Criteria
For inclusion to the systematic review, articles needed to focus on the relationship
between vitamin D and DM2 or metabolic syndrome. Because there were relatively few
randomized controlled trials, well designed cohort and case control studies were also
reviewed. Because there are so few studies that have examined the relationship between
vitamin D deficiency and DM2, all levels of evidence were included in the review.
Studies were critiqued by the Center for Evidence Based Medicine’s evidenced based
practice score. Limitations to each study, especially those that are lower levels of
evidence, are addressed in the results section. Studies that examined DM2 in children
and those that focused on type 1diabetes were excluded because of the variation of
insulin metabolism in children and the varied pathology and cause of type 1 diabetes.
Studies that examined vitamin D deficiency in relation to other chronic health problems
such as renal disease, gastro-intestinal malabsorption syndromes, and parathyroid gland
pathologies were also excluded. Finally, studies where the primary subject focus was
pregnant women or women who were breast feeding were also excluded due to the
additional nutritional demands that occur in those unique physiologic states which could
affect serum vitamin D levels, requirements, and intake.
9
Results
In 2004, Chiu et al. were the first to directly measure insulin secretion and insulin
sensitivity and relate those to serum vitamin D levels. The results demonstrated that
vitamin D levels had a negative correlation with fasting plasma glucose levels and a
positive correlation with the insulin sensitivity index (ISI). These associations remained
after adjusting for age, sex, ethnicity, BMI, waist to hip ratio, systolic and diastolic blood
pressure, and season (p < .0001). This important study indicated that vitamin D seems to
be an independent factor in proper beta cell function and insulin sensitivity, two
important factors in the development of DM2. Since the release of that study there has
been increased interest in the relationship between vitamin D levels and type DM2.
There are very few randomized controlled intervention trials examining the
relationship between vitamin D and DM2. Therefore, the bulk of the evidence on this
relationship has been demonstrated through cohort studies. Of the cohort studies
reviewed there were four cross-sectional studies, one retrospective study, and four
prospective studies. In all of the cohort studies one outcome that was consistent was that
women had an increased prevalence of vitamin D deficiency over men. When examining
the relationship between vitamin D and DM2 the results are inconsistent.
In the largest cross-sectional study to date, 8,241 individuals (see table 1 for
characteristics of cohort studies) from the National Health and Nutrition Examination
Survey (NHANES), a random, national cohort, were examined to determine the
relationship between their vitamin D level and risk of having metabolic syndrome (Ford,
Ajani, McGuire, & Liu, 2005). After adjusting for multiple confounders, vitamin D
influenced risk of metabolic syndrome. The odds of having metabolic syndrome
10
decreased with each increasing quintile of vitamin D level (OR .85 - .38). Another crosssectional study looked at a non-diabetic population from the Framingham Offspring
Study (Liu et al., 2009). The results were similar to the NHANES study suggesting that
an increased vitamin D level is associated with decreased risk factors for DM2. More
specifically subjects in the higher tertile of vitamin D levels had a 1.6% lower fasting
plasma glucose, 9.8% fasting insulin secretion, and a 12.7% lower insulin resistance
score than subjects in the lowest tertile. This relationship remained after adjustments for
confounding factors.
In 2009, Wehr et al. also looked at the risk of metabolic syndrome based on
vitamin D status in a population of women with polycystic ovary syndrome (PCOS).
This study reinforced the data from the previous study that the odds of having metabolic
syndrome increases with decreased vitamin D levels. Results suggested an inverse
relationship between vitamin D levels and fasting and stimulated glucose levels, insulin
resistance based on the homeostatic model assessment (HOMA-IR), insulin secretion
based on the homeostatic model assessment (HOMA-β), and C-reactive protein (CRP).
This study is limited by adjustments for only age, BMI, and season. However, the
consistency of the findings is still suggestive of a significant relationship between vitamin
D and DM2.
Only one cross-sectional cohort study found no significant relationship between
vitamin D levels and DM2 (Snijder et al., 2006). However, there are several limitations
to the study. One main limitation was that the only outcome measured was incidence of
DM2 which may not be as sensitive as measuring direct physiologic changes in insulin
secretion and uptake. Additionally, the average age of the population studied was 75yo ±
11
6.5 years. This homogenous elderly population is not a representative sample of the
general population.
There were four prospective cohort studies reviewed. In 2006, data from the
Nurse’s Health study were reviewed (Pittas et al.). Results stated that women who
consumed >800 IU of vitamin D or more daily had 23% lower risk of DM2 compared
with women who consumed < 200 IU per day. The risk ratio (RR) was .87; however,
after adjustments for confounding variables the results were not significant (p = 0.67).
Limitations of the study included a poor follow-up rate (5%) and an almost homogenous
sample of Caucasian females. In another study, data were examined from the 1958
British Birth Cohort (Hypponen & Power, 2006). All subjects were born in 1958 and
were 45 years old at the time of data collection in 2003. Hemoglobin A1C (HbA1C) was
measured as an outcome to this study. Results demonstrated that increased vitamin D
levels were associated with decreased HbA1C (p<0.0001).
A prospective cohort study which looked at a random sample of men and women
in Finland, demonstrated at the higher quartile of vitamin D level verses the lowest
quartile an inverse relationship between vitamin D levels and risk of DM2 (RR=.70)
(Mattila et al., 2007). However, after adjustments for confounding variables the results
did not remain significant at p =.07. Finally, a study of 524 non-diabetic men and women
did demonstrate a significant relationship between vitamin D levels and diabetes
associated factors (Forouhi, Luan, Cooper, Boucher, & Wareham, 2008). Results
indicated that increased levels of vitamin D were associated with a lower 10-year risk of
hyperglycemia, lower insulin levels, and decreased insulin tissue resistance (HOMA-IR)
independent of confounders.
12
In one retrospective study that was reviewed, a convenience sample of postmenopausal women, was studied (Need, O'Loughlin, Horowitz, & Nordin, 2005). The
results suggested that vitamin D level influenced fasting glucose levels independent from
age and BMI. This relationship was strongest in women who had vitamin D levels that
were by definition deficient or < 20ng/mL. The authors inferred that since increased
fasting glucose levels are a direct indicator of metabolic syndrome and DM2 by
implication it was determined that vitamin D levels play a role in poor glucose
metabolism.
Of the cohort studies reviewed there were six that demonstrated a relationship
between vitamin D levels and DM2 or one of the significant factors known to play a role
in the development of diabetes. Two studies initially demonstrated a significant
relationship but significance did not remain after adjusting for confounding factors.
Finally, one study did not show any relationship. Many of the cohort studies were
plagued by poor follow-up, homogenous populations, and outcomes that are influenced
by multiple factors. These cohort studies suggest that future research on the topic of
vitamin D deficiency is warranted.
There are only two RTCs that examine the relationship of vitamin D and factors
that can contribute to metabolic syndrome and DM2. In one study, 314 Caucasian adults
who did not have diabetes received either 500 mg of calcium citrate and 700 IU of
vitamin D or placebos daily for three years (Pittas, Harris, Stark, & Dawson-Hughes,
2007). Participants were divided into two groups at baseline representing those with
normal glucose metabolism and those with impaired fasting glucose (IFG) levels. The
two groups were matched with controls for age, weight, and physical activity score.
13
There was a higher percentage of “never smokers” in both intervention groups 53% to
42% in the normal glucose subgroup and 36% to 32% in the IFG subgroup. The study
showed a significant increase in vitamin D levels in both of the intervention groups.
There was no significant difference in fasting plasma glucose levels, CRP, interleukin-6
levels, or incidence of DM2 between either of the intervention groups and their respective
placebo groups. However, in the IFG subgroup insulin resistance measured by HOMA-IR
increased significantly more in the placebo group than in the group that was taking
vitamin D. In the normal glucose group there was no difference in insulin resistance.
This study demonstrated a greater effect of vitamin D on the impaired group. Limitations
to this study include a relatively small sample size, a homogenous sample, and the
intervention included vitamin D and calcium supplementation rather than vitamin D
alone.
The second RCT was from the Women’s Health Initiative study. In one arm of
the study, randomly assigned postmenopausal women received 1000mg of elemental
calcium and 400 IU of vitamin D daily while the control group received a placebo in a
double-blinded fashion (de Boer et al., 2008). After a mean follow-up time of seven
years 2,291 women were diagnosed with diabetes. The hazard ratio for incidence of
diabetes between groups was 1.01 demonstrating a null result. There have been several
noted limitations to this study. One major limitation was that there was no certainty that
the control group did not take vitamin D either within a multivitamin or as a supplement.
Because of the double-blinded fashion control subjects were not instructed to refrain from
taking any supplemental vitamin D. Additionally, the amount of vitamin D used in the
14
intervention (400 IU) is a small dose that does not tend to affect overall serum vitamin D
levels.
Evidence from the RCTs suggests that there is an association between vitamin D
and insulin resistance; however, there was not an association between vitamin D and each
of the other outcomes tested. Both RCTs have significant limitations and based on the
results of the previous cohort studies more RCTs are needed to help determine the exact
relationship between vitamin D and DM2.
Finally, an article detailing two specific case studies was reviewed
(Schwalfenberg, 2008). One case study detailed a 63-year-old African American
diabetic who had an unchanging A1C of 8.4% on oral medications diet and exercise.
After it was determined her vitamin D level was severely deficient, she was started on
vitamin D replacement therapy at 2000 IU for two months and then 3000 IU for nine
months. After taking vitamin D for 6 months her HbA1C was reduced to 7.4%. The
author also reported that the patient experienced a greater number of hypoglycemic
episodes and consequently reduced her metformin dose from 500mg three times a day to
twice daily. Finally, the patient actually reported that she exercised less in the 6 months
that she was on vitamin D therapy, but her weight remained stable and her diabetes
improved. The second case study examined a 71-year-old white female with long term
diabetes treated with several oral medications. With an A1C of 13.3%, it was
recommended that she start insulin; however, the patient refused. Around the same time
her vitamin D deficiency was discovered. After nine months of vitamin D repletion and
no other change in her diabetic treatment regimen at 2000 IU per day, her HbA1C level
15
was reduced to 12.2%. In both case studies the dependent variable of vitamin D repletion
resulted in an average decrease in blood sugar levels of 12%.
Optimal Intake of Vitamin D in Relation to Type 2 Diabetes
According to Holick and Chen (2008), Vitamin D deficiency is currently defined
as <20 ng/mL of serum 25-hydroxyvitamin D [25(OH)D] which is the major circulating
form of vitamin D. Levels <30 ng/mL 25(OH)D are considered insufficient. The
threshold of 30ng/mL was determined to be adequate because above those levels bone
undergoes proper mineralization eliminating rickets. However, the recent discovery of
vitamin D receptors on almost every cell in the body including breast, prostate, muscle,
pancreatic and immune cells has prompted researchers to reexamine the minimum
acceptable level (Holick, 2007). Currently the Institute of Medicine (IOM) recommends
that children and adults up to 50 years old should receive 400 IU of vitamin D daily and
adults over age 70 need 600 IU, as well as 15 minutes of direct unprotected sunlight to
the hands and face every day (Institute of Medicine, 2010). These recommendations are
based on the 30ng/mL threshold to prevent rickets. According to Vieth et al. (2007)
studies are suggesting that higher levels of vitamin D intake are necessary to prevent
other pathologies associated with vitamin D including preventing cancer, reducing
fractures and reducing risk of chronic diseases such as diabetes. Specifically studies that
have examined fracture prevention have demonstrated decreased risk of fracture with
vitamin D levels up to 40ng/mL (Bischoff-Ferrari, Giovannucci, Willett, Dietrich, &
Dawson-Hughes, 2006). One recent study examined participants who were consistently
exposed to a sun-rich environment and women who were on taking 6400 IU of vitamin
D3 daily (Hollis, Wagner, Drezner, & Binkley, 2007). In both the natural and
16
supplemented vitamin D groups levels peaked between 40 to 60ng/mL and additional
sunlight or supplementation did not increase levels further. This indicates that an optimal
therapeutic range of vitamin D could be higher than the current standard. As for optimal
vitamin D levels and type 2 diabetes specifically, there is not enough data currently to
suggest an optimal level; however, the current best evidence indicates that vitamin D
levels of <20 ng/mL were associated with increased risk factors for metabolic syndrome
and DM2. Future research should evaluate serum vitamin D levels of 40 - 60ng/mL to
determine if higher serum levels result in better patient outcomes.
When examining the current evidence, particularly the RCTs, it is important to
understand the amount of vitamin repletion necessary to make a meaningful impact on
vitamin D levels. For example the small dose (400 IU) given to women in the Women’s
Health Initiative Study has only been shown to increase blood levels of vitamin D by 4
ng/mL over a six month period of time (Heaney, Davies, Chen, Holick, & Barger-Lux,
2003). Vitamin D dosed at this level is sub-therapeutic, especially in a deficiency state,
and would not be expected to produce meaningful outcomes. A recent study that
addressed prescribing regimens for vitamin D repletion found that >600,000 IU of
Vitamin D2 supplementation given for a mean of 60 days was necessary to achieve
sufficiency in 64% of cases. There were no reports of vitamin D toxicity (Pepper, Judd,
Nanes, & Tangpricha, 2009). Experts suggest that in future intervention trials a
substantial dose of 2000 IU per day is needed to raise vitamin D to optimal levels to truly
explore its role in the prevention or attenuation of DM2 (Vieth et al., 2007).
17
Gaps and Future Research
Currently there are several gaps in the research regarding vitamin D deficiency
and the presence of DM2. The most obvious gap is the lack of well-constructed
intervention trials with controls. These trials need to have larger sample sizes and
provide a vitamin D dose that is high enough to increase serum vitamin D levels above
40ng/mL. Additional cohort studies are also needed to confirm the effect of vitamin D
repletion on the two direct pathologies in DM2: β-cell insulin secretion and peripheral
uptake of insulin. These well controlled studies are also necessary to determine if
vitamin D is truly a contributing factor to the development of DM2 or merely a marker
for overall poor health.
Additionally, further research is needed to determine if the effects of vitamin D
repletion occur across ethnic populations. The prevalence of vitamin D deficiency is
highest in darker skinned individuals including black and Hispanic populations. Studies
that look at genetic polymorphisms or variation can help determine why there is ethnic
variation in the processing of vitamin D from sunlight and help determine risk. These
populations are known to be at the highest risk for diabetes. Both intervention and cohort
studies are needed to determine the effects of vitamin D in the prevention or in the
treatment of DM2 in those special populations.
Finally, more research is needed to determine the best repletion practices as well
as the optimal serum level of vitamin D. Many experts believe that the current standard
of 30ng/mL is too low; however, there is currently not enough research to establish a
different standard. Suggestions for optimal levels range for 40ng/mL to 80ng/mL. With
concentrated repletion regimens (> 600,000 IU) that lasted a mean of two months, only
18
64% of cases achieved sufficient values greater than 30ng/mL. Additional research could
determine a more consistent time frame and daily or weekly regimen to increase the
success rates of vitamin D repletion.
Conclusion
Most diets in the United States do not provide sufficient vitamin D intake to
maintain adequate serum levels. In addition to poor intake, decreased sun exposure,
increased use of sunscreen and genetic variations in the conversion of the sun’s UV rays
to vitamin D are all causes of vitamin D deficiency. Providers need to be aware that
women, individuals with darker skin pigmentation, and those who are obese are at higher
risk for vitamin D deficiency. Vitamin D deficiency has been associated with many
chronic conditions including DM2. Specifically the evidence suggests that vitamin D
influences β-cells secretion of insulin and ameliorates insulin resistance. The outcome of
these effects is an inverse relationship between vitamin D and HbA1C, fasting plasma
glucose levels and incidence of metabolic syndrome. The possibility that a relatively
inexpensive vitamin can help delay onset or assist with the treatment of DM2 has a
number of public health implications. Clinicians should consider testing high-risk
individuals for vitamin D deficiency and supplement deficient patients, especially those
with DM2. Further research is necessary to determine the true impact of this costeffective and widely available intervention.
19
References
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Binkley, N. (2012). Vitamin D and osteoporosis-related fracture. [Review]. Arch
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Bischoff-Ferrari, H. A., Giovannucci, E., Willett, W. C., Dietrich, T., & Dawson-Hughes,
B. (2006). Estimation of optimal serum concentrations of 25-hydroxyvitamin D
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24
Table 1
General characteristics of cohort studies relating DM2 and vitamin D
First Author/Yr
Cohort
Outcome
Measure
Results
Wehr et al. (2009)
(cross – sectional)
Females with
PCOS
Mean age: 29
n=206
1 and 2 hr gtt;
HOMA – IR1;
HOMA – β2
QUICKI3; CRP4
Forouhi et al.
(2008)
(prospective)
Random nondiabetic men
and women
ages 40-69yo
n=524
2 hr gtt; insulin;
metabolic
syndrome risk z
score; HOMAIR;
- Vit. D prevalence = 72.8%
- Inverse correlation b/t vit. D and
fasting and stimulate glucose levels,
HOMA-IR, HOMA- β and fasting
and stimulated insulin, and CRP
- Women lower vit. D than men
- Vitamin D inversely associated with
10- year risk of hyperglycemia, 2hgtt, HOMA-IR, and metabolic
syndrome risk
Liu et al. (2008)
(cross-sectional)
Non-diabetics
from
Framingham
Offspring
Study
n=808
2 hr ggt;
insulin,
HOMA-IR;
ISI5; plasma
adiponectin
-vitamin D inversely associated with
waist circumference and BMI
-positively associated with ISI,
adiponectin and HDL
-higher tertile of vit D had 1.6%
lower fasting glucose; 9.8% lower
fasting insulin; 12.7% lower insulin
resistance score
Incidence of
DM2
-inverse association of vit. D levels
and risk of DM2
-RR 0.60 (p=0.01) between highest
quartile vitamin D and lowest
-further adjustment attenuated to RR
Matilla et al. (2007) random men
(Prospective)
and women
from Finland
n=4,079
25
Adjustments
Comments
for
confounding
factors
Season, BMI, No control group;
and age
low vitamin D
levels are associated
with features of
metabolic syndrome
Age, sex,
Higher vit. D is
smoking,
assoc. with lower
BMI, season future glucose,
and baseline insulin, and
metabolic
HOMA-IR.
variable
Independent of
confounders
Age, sex,
Positive assoc. not
BMI, waist
significant after
circumfeadjustments; vit D
rence,
and 2 hr gtt was not
smoking
significant; vit. D
status
associated with
increase in DM2
risk markers even in
nondiabetics
Age, sex,
Decreased RR of
season then
DM2 with higher
also BMI,
serum levels of
exercise,
vitamin D although
smoking,
relationship is
= .70 (p=.07)
education
HbA1C6
-HbAIC decreased with increased vit.
D levels up to 30ng/mL
- HbA1C in deficient vit. D group –
5.4%; sufficient group 5.1%
sex, season,
geography,
exercise and
social class
Incidence of
DM2
-women who consumed > 800 IU or
more of daily vitamin D intake had
23% less lower risk of DM2
compared with women who
consumed <200 qd
with RR .87 (p=.67)
Snijder et al. (2005) Men and
(cross-sectional)
women from
Amsterdam
n=1,235
Incidence of
DM2
-no significant association in
incidence of DM2 and vitamin D
levels
Need et al. (2005)
(retrospective)
Fasting plasma
glucose
-Vitamin D inversely related to
fasting glucose level. (p<.001)
-Greatest increase was in those with a
vit. D < 16ng/mL
Age, BMI,
exercise,
family
history DM2,
smoking,
ETOH,
coffee, diet,
HTN,
calcium
intake
Age, sex,
waist to hip
ratio,
exercise,
smoking,
ETOH,
season
Age, BM
Incidence of
DM2 and
fasting plasma
The odds of having metabolic
Age, sex,
syndrome decreased with each
race,
increasing quintile of vitamin D level. exercise,
Hypponon et al.
(2007)
(Prospective)
Pittas et al. (2006)
(Prospective)
Ford et al. (2005)
(cross-sectional)
Random men
and women in
England all
45 yo
n = 7,198
Random
women from
the nurse’s
health study
with 20 year
f/u
n=83,779/484
3
Convenience
sample of
postmenopausal
Females
n=753
Males and
females from
NHANES III
26
attenuated after
confounding
Association was
greater in obese
subjects
No history of
diabetes, CVD, or
cancer at baseline
Risk decreased
further when vit. D
intake combined
with increased
calcium intake
Non-significant pvalue
Mean age of
participants was
75yo ± 6.5 years
which may have
influenced results
Fasting serum
glucose increased as
vit. D levels
decreased
Vitamin D still
seemed to influence
risk of DM2 even
N=8,241
glucose level
OR .85 - .38
ETOH,
smoking,
diet, vitamin
use,
cholesterol,
CRP,
education,
season
after adjusting for
confounders
1.HOMA-IR: Homeostatic model assessment – Insulin Resistance 2. HOMA-β: Homeostatic model Assessment – β-cell
secretion 3. QUICKI: Quantitative insulin sensitivity check index 4. CRP: C-reactive protein 5. ISI: Insulin sensitivity index
6.HbAIC: Hemoglobin A1C
27
Update on Vitamin D Deficiency:
Clearing Up the Confusion for Nurse Practitioners
Sara E. Robertson
University of Kentucky
28
Abstract
Purpose: To provide an update on vitamin D for nurse practitioners. Media Reports and
conflicting information result in confusion regarding the screening, diagnosis and
management of vitamin D. The physiology of vitamin D, definitions of vitamin D
deficiency, risk factors for deficiency, and population statistics are reviewed. Screening
and treatment recommendations are also reviewed, including the recommended daily
allowance of vitamin D, sun exposure, and supplementation strategies.
Data Sources: Clinical studies, literature review articles, consensus guidelines, and the
Institute of Medicine (IOM) recommendations.
Conclusions: Although there is disagreement regarding the definition of vitamin D
deficiency, recent literature confirms the following information. Risk factors include
poor dietary intake, decreased sun exposure, darker skin pigmentation, genetics and
obesity. Vitamin D deficiency is common. Vitamin D repletion involves increasing
dietary intake, limited sun exposure, and vitamin D supplementation. For most
individuals vitamin D supplementation is a necessary component of repletion and
maintenance. High-dose vitamin D2 (50,000IU) and vitamin D3 can be used safely and
effectively.
Implications for Practice: Given that treatment of vitamin D deficiency is known to
promote bone health and is likely to enhance immune response and decrease morbidity,
understanding of appropriate screening, diagnosis, and management of vitamin D
deficiency is essential for the nurse practitioner.
Key words: vitamin D deficiency; hypovitaminosis D; vitamin D supplementation
29
What is Vitamin D?
When the minimum dose of vitamin D to prevent rickets was recognized, many
healthcare providers did pay attention to vitamin D or the implications of vitamin D
deficiency. In recent years, however, studies emerged demonstrating that large segments
of the United States (US) population suffer from vitamin D deficiency or
hypovitaminosis D (Holick, 2007). Vitamin D is a fat-soluble vitamin which is dependent
on oral consumption from foods that are naturally rich in the vitamin or fortified, such as
fish, eggs, and milk or vitamin D supplementation. Additionally, vitamin D can be
synthesized under ultra-violet (UV) exposure in the skin (Bohaty, Rocole, Wehling, &
Waltman, 2008).
Vitamin D from food, supplements, and sun exposure is biologically inert and
must undergo two hydroxylations before it is biologically active. Vitamin D is first
metabolized in the liver to 25-hydroxyvitamin D [25(OH) D3] also known as calcidiol.
Next, calcidiol is metabolized in the kidneys into 1,25-dihydroxyvitamin D [1,25(OH)2D]
also known as calcitriol. Calcitriol is the active from of vitamin D. This conversion is
tightly regulated by plasma parathyroid hormones and serum calcium and phosphate
levels (Holick & Chen, 2008). Because, calcitriol, has an extremely short half-life, it does
not offer an adequate reflection of vitamin D status; therefore, the intermediary form of
vitamin D, 25(OH)D or calcidiol, is routinely checked via serum concentration to
determine vitamin D status. Vitamin D, 25(OH)D has a half-life of 15 days. Serum
measurement of 25(OH)D does not reflect the amount of vitamin D that is stored in body
tissues, mainly adipose tissue (Hollis, Wagner, Drezner, & Binkley, 2007)
30
What is Vitamin D Deficiency?
Controversy exists regarding the definition of vitamin D deficiency and
insufficiency. Two organizations, The Endocrine Society and the Institute of Medicine
(IOM), differ in their definitions for vitamin D levels. The traditional definitions of
normal, insufficient, and deficient vitamin D, as defined by the Endocrine Society, are as
follows (the unit ng is currently used in current practice and lab reports):
Vitamin D deficiency: Serum 25OHD less than 50nmol/mL (20ng/mL)
Vitamin D insufficiency: Serum 25OHD between 50 – 72.5nmol/mL
(20-29ng/mL)
Vitamin D sufficiency: Serum 25OHD more than 75nmol/mL (30ng/mL)
These figures were determined by examining the relationship between vitamin D and
serum parathyroid hormone (PTH). PTH is increased when vitamin D is low suggesting
a positive feedback; however, when serum Vitamin D levels reach 30ng/mL to 40ng/mL
parathyroid hormones level off. Additionally, with an increase in serum vitamin D levels
from 20ng/mL to 30ng/mL calcium absorption from the gut is increased from 45% to
65% (Holick et al., 2011).
In November of 2010 the IOM released a report on the status of vitamin D in the
United States. The following are their definitions of normal and inadequate vitamin D
levels as defined by the IOM (the unit ng is used in current practice and lab reports):
At risk of vitamin D deficiency: Serum 25OHD less than 30nmol/L (12ng/mL)
At risk of vitamin D inadequacy: Serum 25OHD 30–49nmol/L (12–19ng/mL)
Sufficient in vitamin D: Serum 25OHD 50–125nmol/L (20–50ng/mL)
(Institute of Medicine, 2010)
31
These numbers were determined by examining the relationship between vitamin D levels
and bone health. The IOM states that a serum vitamin D level of 20ng/mL is what is
necessary for healthy bone development. The IOM did not consider vitamin D levels in
association with other disease states other than bone health for the establishment of the
current norms. Because of the sole focus on bone health, these new standards were met
with contention from providers in specialist communities such as endocrinology,
rheumatology, and oncology (Heaney & Holick, 2011; Maxmen, 2011).
What About Vitamin D and Other Diseases Besides Bone Health?
Even though the IOM report did not find sufficient evidence to definitively
associate vitamin D with disease states other than poor bone health, many studies are
suggesting that these associations could become more clear in the future. Vitamin D is
known to be the primary regulator of over 600 crucial genes. Additionally, the discovery
that most cells in the body have a vitamin D receptor suggests that the vitamin could have
many more functions within the body than previously thought (Holick, 2007). Vitamin D
has been found to be crucial for a healthy immune system and deficient states are
associated with higher rates of reactivated tuberculosis (Hewison, 2010). A study
performed at the Mayo Clinic in Minnesota, found that 93% of patients whose chief
complaint was nonspecific musculoskeletal pain were deficient in vitamin D (Plotnikoff
& Quigley, 2003). Vitamin D deficiency has been linked as a risk factor, as well as, a
factor in treatment to several different forms of cancer including colon, prostate and
breast cancer (Mitchell, 2011; Spina et al., 2006). Furthermore, it has been suggested
that vitamin D can also have an influence on common age-related morbidities including
32
falls, dysphagia, urinary incontinence, and cognitive decline (Binkley, 2007; BischoffFerrari, Giovannucci, Willett, Dietrich, & Dawson-Hughes, 2006).
Evidence also suggests that vitamin D deficiency may play a role in the
development of type 2 diabetes mellitus (DM2). Vitamin D may have a direct role in
insulin secretion and the utilization of insulin by peripheral tissue. It is hypothesized that
binding of circulating 1,25-dihydroxyvitamin D (the active form of vitamin D) to the
pancreatic β-cell vitamin D receptor promotes insulin secretion (Peechakara & Pittas,
2008). Additionally, the regulation of calcium levels by vitamin D can also indirectly
promote β-cell insulin secretion by maintaining a consistent flux of calcium into the cell.
Finally, it also appears that vitamin D stimulates the expression of insulin receptors on
target-tissues which facilitates the uptake and use of insulin (Penckofer, Kouba, Wallis,
& Emanuele, 2008).
What Are the Risk Factors for Vitamin D Deficiency?
Risk for vitamin D deficiency is multifaceted and can include non-pathologic
factors such as dietary intake, sun exposure, race, genetics, and obesity. Pathologic risk
factors for vitamin D deficiency (which are beyond the scope of this report) include liver
failure, nephritic syndrome, chronic kidney disease, and diseases of the parathyroid
gland.
Nutrition
As demonstrated in table 2, only a few foods supply a noteworthy amount of
vitamin D. Of those foods, fish and cod liver by far contain the greatest amount of
vitamin D. A lack of fresh fish can be an issue in many parts of the country (especially
the Midwest) where fish is not fresh and therefore is not part of daily or even weekly diet.
33
Unfortunately fatty fish that is high in vitamin D, can also contain high levels of mercury
which would limit the intake for pregnant women. Additionally, conditions such as
lactose-intolerance limit the intake of milk and other dairy products. Due to the fact that
most foods have very little vitamin D and dairy products are poorly tolerated by some
individuals, diet is generally regarded as a poor source for vitamin D (Holick, 2011).
Finally, vitamin D is poorly transferred via breast milk. When breast milk is the sole
source of nutrition, infants are at high risk for vitamin D deficiency (Hollis & Wagner,
2004).
UV Light Exposure
Considering the minimal impact of diet on vitamin D status, ultra-violet (UV)
light exposure from the sun is a primary and sufficient source of vitamin D. Due to the
consistent findings, however, of low vitamin D levels throughout the United States
population the importance of sun exposure in maintaining adequate vitamin D levels is
being called into question (Adams & Hewison, 2010). Melanin is the pigment that is
primarily responsible for skin color. Highly pigmented skin does not absorb vitamin D as
well as skin with less melanin. Vitamin D is synthesized in the skin by the action of UVB. High melanin content in the skin reduces UV-B exposure and consequently cuts the
conversion of 7-dehydrocholesterol (7-DHC) to pre-vitamin D which is the first step in a
chain of reactions that ends in active vitamin D (Hollis et al., 2007). As global
immigration becomes more prevalent, individuals with high skin melanin content are
living at higher latitudes. The decrease in sun intensity found at higher latitudes and in
more seasonal climates, impacts the ability to synthesize an adequate amount of vitamin
D from sunlight and results in higher rates of vitamin D deficiency in individuals with
34
darker skin pigmentation. It has been demonstrated that even with significant, long-term
sun exposure populations with darker skin have decreased levels of vitamin D (Binkley et
al., 2007; Nesby-O'Dell et al., 2002; Sahu et al., 2009).
Use of Sunscreen
Topical sunscreen agents interfere with the exposure of skin to UV-B radiation,
thereby decreasing the amount of UV-B converted to pre-vitamin D. The higher the sun
protection factor (SPF) the more that the sunscreen, by definition, will decrease UV-B
exposure (Tsiaras & Weinstock, 2011). There are very few studies that have measured
the effect of sunscreen use on vitamin D levels.
Study results on the use of sunscreen and vitamin D differ. One study, completed
in 1988, found that serum vitamin D levels were 64% lower in 20 individuals who were
habitual sunscreen users than their 20 sun-exposure matched control subjects (Matsuoka,
Wortsman, Hanifan, & Holick). However, a randomized controlled trial in Australia,
noted little difference between placebo and control groups in relation to the effect of
sunscreen use on serum vitamin D levels (Marks et al., 1995). With this mixed
information it is difficult to determine the role sunscreen use plays in vitamin D
deficiency. It has been suggested that typical sunscreen use may play only a minimal role
considering that most individuals apply less than the suggested, effective amount of
sunscreen initially and only 43% of individuals reapply at regular intervals (American
Academy of Dermatology, 2008).
Genetics
Genetics is also an emerging factor in the development of vitamin D deficiency.
After examining genetic profiles of various groups of Hispanic and African Americans
35
and analyzing serum vitamin D levels, Engelman et al. found that polymorphisms in the
vitamin D binding protein (VDP) gene do exist and in some cases were associated with
lower levels of serum vitamin D (2008). As with many other disease states, genetics is an
emerging field and further studies are needed to confirm if certain genetic mutations can
lead to vitamin D deficiency.
Obesity
Obesity is another risk factor in the development of vitamin D deficiency.
Vitamin D is readily absorbed by adipose tissue and is saved for subsequent release and
metabolism when there is a need during the winter months. However, when there is a
larger pool of adipose tissue, the sequestration of vitamin D is associated with poor
bioavailability (Holick, 2007). Therefore, levels of vitamin D in obese individuals tend to
be 57% lower than their age-matched, normal weight controls (Wortsman, Matsuoka,
Chen, Lu, & Holick, 2000).
What is the Epidemiology of Vitamin D Deficiency?
Many studies have determined that large segments of the United States population
are either insufficient or deficient in vitamin D. A large cross-sectional cohort study that
analyzed data from the National Health and Nutrition Examination Survey (NHANES
III) determined that mean levels of 25(OH) D3 were lower in Latinos and African
Americans than their white counterparts. Additionally, women had lower levels of
vitamin D across all age ranges and races (Zadshir, Tareen, Pan, Norris, & Martins,
2005). This study determined that 34% of white men and 45% of white women had
insufficient levels of vitamin D. Insufficiency rates were even higher in minority
populations. Seventy-six percent of Latino men and 77% of Latino women were
36
insufficient while 55% of black men and 72% of black women had inadequate levels of
vitamin D. Even though sun-exposure can impact and sometimes improve vitamin D
levels, several studies demonstrate that even in sun-rich areas inadequate levels of
vitamin D is still pervasive in the population. Jacobs et al. states that even in sun-rich
Arizona 25% of the population is deficient in vitamin D (<20ng/mL). When identifying
subjects who are insufficient and deficient (<30ng/mL), the percentage increases to 76%.
Again, minorities have higher rates of insufficiency and deficiency than their white
counterparts. While 75% of whites were either insufficient or deficient, 87% of Latinos
and 88% of Blacks were lacking adequate vitamin D (2008). A study that examined
subjects in sun-rich Florida determined that 39% of their overall study population was
deficient in vitamin D compared with 25% in the Arizona study (Levis et al., 2005). In a
study performed in sun-rich Honolulu, Hawaii, it was found that 51% of the 93 university
students tested had low vitamin D status (Binkley et al., 2007).
What is the Current Dietary Allowance of Vitamin D?
Even though there is overwhelming evidence that indicates that large segments of
the United States populations, and especially the darker-skinned minority populations,
have low levels of vitamin D, the IOM stated in their report that most North Americans
have sufficient intake of vitamin D to support bone health (Institute of Medicine, 2010).
As stated previously the IOM determined that currently there is not enough scientific
evidence to definitively link vitamin D to other diseases such as cancer, diabetes,
rheumatologic conditions or increased risk for infection; therefore, adequate levels of
vitamin D for the prevention of other pathologies were not considered in the
recommendations. Even though the committee stated that most individuals have
37
sufficient intake of vitamin D, by current standards, they recommended that the Food and
Nutrition Board increase the recommended daily allowance (RDA) of vitamin D for
adults ages 18-70 years old from 400IU to 600IU per day. These types of inconsistencies
have fueled further criticism of the IOM report. Medical providers have challenged the
homogeneity of the committee members, the institute’s consistent recommendations for
the entire North American population regardless of race or residential latitudes, and many
disagree with the IOM’s sentiment that with few exceptions, all North Americans are
receiving enough vitamin D (Maxmen, 2011; Plotnikoff, 2011).
Who Should be Screened for Vitamin D Deficiency?
The IOM report did not provide any recommendations regarding the screening of
vitamin D. By increasing the recommended daily intake level, the committee suggested
that all individuals that consume 600IU of vitamin D per day will maintain blood levels
greater than the 20ng/mL needed for bone health (Institute of Medicine, 2001). The
Endocrine Society, however, does suggest in their guidelines that individuals at high risk
for deficiency should be screened (Holick et al., 2011). Because of its longer half-life, the
intermediary form of vitamin D, calcidiol, or 25(OH)D, should be the only lab test used
for the screening of serum vitamin D (Hollis et al., 2007).
What is the Best Way to Treat Vitamin D Deficiency?
The IOM report provided little structure for vitamin D repletion in the case of
vitamin D deficiency. Patient education regarding appropriate food intake is an
important factor in the treatment for vitamin D deficiency. However, most foods provide
only a small amount of the recommended dietary intake of vitamin D. Additionally,
38
barriers such as lack of personal taste for fish, cost of fish, mercury content, and dietary
intolerances make dietary changes challenging.
Because there are a limited number of foods that contain significant amounts of
vitamin D and prolonged sun exposure is associated with an increased risk of skin
cancer, vitamin D supplementation is a safe and effective method of achieving adequate
serum levels (American Academy of Dermatology, 2008). According to the Endocrine
Society guidelines, most high-risk individuals will need vitamin D supplementation to
achieve and maintain sufficient serum levels of vitamin D (Holick et al., 2011). The IOM
report suggests that the goal for treatment be lowered to 20ng/mL, whereas, the
Endocrine Society report recommends that patients maintain a level of 30ng/mL to
50ng/L. Finally, the IOM report recommends 60ng/mL as the upper threshold of safe
serum vitamin D levels (Institute of Medicine, 2010). At levels above 60ng/mL it is
unknown what potential negative or adverse effects may occur.
There are two different forms of vitamin D supplementation currently available
on the market, vitamin D2 or ergocalciferol and vitamin D3 or cholecalciferol. Vitamin D2
is obtained from plant material and enters the circulation via the same pathway as
supplemented foods. Vitamin D3, while also taken orally, is more similar to 7dehydrocholesterol that is formed when UV light enters the skin (Stechschulte, Kirsner,
& Federman, 2009). Vitamin D3 is also found in natural fish sources such as cod liver oil,
salmon, mackerel, and herring. Studies demonstrate that both vitamin D2 and vitamin D3
have similar capacity to increase serum vitamin D levels (Cannell, Hollis, Zasloff, &
Heaney, 2008). Vitamin D2 is available by prescription only. It is a high dose capsule,
50,000IU, which allows for weekly dosing and is only useful in the treatment of deficient
39
states. Conversely, vitamin D3 which is available over-the-counter, provides variable
dosing from 200IU to 4000IU. This type of dosing is traditionally more useful in daily
maintenance or treatment of mild insufficiency.
Most traditional regimens for vitamin D repletion include several weeks of highdose therapy (either once weekly or three times a week for 4 to 12 weeks) and then
maintenance on lower dose therapy. In 2008, Pepper et al. evaluated a variety of repletion
regimens that included only vitamin D2. The study concluded that regimes which
contained at least 600,000IU of vitamin D2 appeared to be the most effective in treating
vitamin D deficiency and that the actual regimen of how this was achieved was
inconsequential. In 2011, Papaioannou et al. challenged the traditional regimen in a
study of 65 elderly, hip-fracture patients with low vitamin D. The subjects were
randomized into 3 treatment groups. The groups differed only by the bolus amount of
vitamin D given at the start of therapy. One group was placebo and did not receive a
bolus while the second and third groups received a one-time bolus of 50,000IU and
100,000IU of vitamin D2 respectively. After the one-time bolus dose all three groups
were given 2,000IU of vitamin D3 to take daily for 90 days. Surprisingly, the results of
the serum 25(OH)D levels, demonstrated no difference among the three groups. This
suggests that high (bolus) doses of vitamin D2 may not always be necessary for vitamin D
repletion.
There is not one method to treating vitamin D deficiency. Further studies are
needed to determine if weekly high-dose therapy or daily low-dose therapy is best for
repletion. It appears that vitamin D repletion by any method should be successful;
40
therefore, the nurse practitioner should consider patient compliance and patient
preferences regarding high-dose versus low-dose regimens.
Conclusion
There are still many inconsistencies and controversies surrounding vitamin D
deficiency which can be very confusing for the nurse practitioner. Achieving goals of
serum 25(OH)D levels of greater than or equal to 30ng/mL will not cause harm to the
patient and may have increased benefit over a maintenance level of greater than
20ng/mL. Patients who are at high-risk for vitamin D deficiency should be screened.
There is no consensus on “best-practice” repletion strategies; however, use of vitamin D2
and/or vitamin D3 seem to be equally effective in mitigating deficiency and do not appear
to cause harm as long as serum 25(OH)D levels stay below 60ng/mL. Nurse practitioners
should be aware of the risk factors for vitamin D deficiency, screen high risk patients,
and initiate a treatment and maintenance regimen to sustain a sufficient state.
41
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47
Table 2
Sources of vitamin D
Food
IUs per serving
Cod liver oil (1 tbsp).
1,360
Salmon (3oz)
447
Mackerel (3.5oz, cooked)
345
Sardines (1.75 oz, canned) 250
Tuna fish (3 oz, canned)
200
Milk (1cup, fortified)
117
Orange juice (1 cup, fortified)
100
Cereal (1 cup, fortified)
100
Margarine (1 tbsp, fortified) 68
Egg (1whole)
41
Swiss cheese (1 oz)
18
IU = International Unit
(Institute of Medicine, 2010)
48
Vitamin D Knowledge among Nurse Practitioners
Sara E. Robertson
University of Kentucky
49
Abstract
Purpose: To explore Nurse Practitioner (NP) knowledge of vitamin D and vitamin D
deficient states and appropriate testing, risk factors, and treatment of low levels of
vitamin D.
Data Sources: A descriptive, exploratory survey of 100 NPs at a national conference. A
17 item questionnaire included four main sections: demographic information, knowledge
items, and treatment of vitamin D as well as a question on frequently used sources for
information on vitamin D.
Conclusions: NP knowledge of vitamin D is inconsistent to poor. NPs were able to
consistently identify a limited number of risk factors for low vitamin D. Identification of
the appropriate lab testing occurred 59% of the time and NPs identified laboratory result
thresholds for diagnosis only 51% of the time. Almost 40% of NPs did not know that
vitamin D could reach toxic levels in the body. Only 2% of NPs were able to accurately
identify the current recommended daily allowance of vitamin D for adults and only 16%
identified the correct RDA for the elderly. NPs were unaware that several chronic
diseases have been associated with low vitamin D. Even though vitamin D
supplementation was commonly used for treatment, the recommended dosage and
frequency of treatment varied greatly.
Implications for Practice: It is crucial that NPs have the knowledge they need to assess
and treat vitamin D deficiency. Maintaining adequate vitamin D levels is a cost-effective
way to prevent or adjunctively treat many chronic diseases. NPs need additional
education on the diagnosis and treatment of vitamin D deficiency.
Key words: vitamin D deficiency; hypovitaminosis D; vitamin D supplementation
50
Vitamin D Knowledge among Nurse Practitioners
Background
Vitamin D is a fat soluble vitamin that is most recognized for its role in bone
health where deficiency results in rickets/osteomalacia due to poor calcium absorption in
the gut (Binkley, 2012). Decreased vitamin D levels are sub-divided into 2 categories,
insufficiency and deficiency, and are defined by the Endocrine Society as follows the unit
ng is used in current practice and lab reports:
Vitamin D deficiency: Serum 25OHD less than 50nmol/mL (20ng/mL)
Vitamin D insufficiency: Serum 25OHD between 50 – 72.5$nmol/mL (20-29
ng/mL)
Vitamin D sufficiency: Serum 25OHD more than 75nmol/mL (30ng/mL) (Holick
et al., 2011).
Risk factors for vitamin D deficient states include: poor intake of dietary vitamin D, lack
of ultraviolet (UV) light exposure, darker skin color, use of sunscreen, genetics, and
obesity (Engelman et al., 2008; Holick, 2007).
Vitamin D is known to be the primary regulator of over 600 crucial genes. In
addition most cells in the body have a vitamin D receptor suggesting that the vitamin
could have many more functions in the body than previously thought (Holick, 2012).
Recent evidence suggests that vitamin D deficiency could play a role in the development
of all types of diabetes due to its roles in insulin secretion and the utilization of insulin by
peripheral tissue (Takiishi, Gysemans, Bouillon, & Mathieu, 2012). Vitamin D deficiency
51
is also linked to several forms of cancer including colon, prostate and breast cancer
(Mitchell, 2011; Spina et al., 2006). Vitamin D deficiency has also been associated with
increased cardiovascular risk; decreased immune response to infection; increased risk of
autoimmune disease and cognitive decline (Balion et al., 2012; Hewison, 2012;
Muscogiuri et al., 2012).
It has been demonstrated that large sections of the US population maintain low
levels of vitamin D. A large cross-sectional cohort study that analyzed data from the
National Health and Nutrition Examination Survey (NHANES III) determined that mean
levels of 25(OH) D3 were lower in Latinos and African Americans than their white
counterparts. Additionally, women had lower levels of vitamin D across all age ranges
and races (Zadshir, Tareen, Pan, Norris, & Martins, 2005). This study determined that
34% of white men and 45% of white women had insufficient levels of vitamin D.
Insufficiency rates were even higher in minority populations. Vitamin D levels were
insufficient in 76.2% of Latino men and 77% of Latino women while 55% of black men
and 72% of black women also had inadequate levels of vitamin D. Even though sunexposure can impact and sometimes improve vitamin D levels, several studies
demonstrate that even in sun-rich areas inadequate levels of vitamin D are still pervasive
in the population. Jacobs et al. (2008) states that even in sun-rich Arizona 25% of the
population is deficient in vitamin D (<20ng/mL). When identifying subjects who are
insufficient and deficient (<30ng/mL) the percentage increases to 76%. Again, minorities
have higher rates of insufficiency and deficiency than their white counterparts. While
75% of whites were either insufficient or deficient, 87% of Latinos and 88% of Blacks
were lacking adequate vitamin D (2008). Another study that examined subjects in sunny
52
Florida determined that 39% of their overall study population was deficient in vitamin D
compared with 25% in the Arizona study (Levis et al., 2005). In a study performed in
sun-rich Honolulu, Hawaii, it was found that 51% of the 93 university students tested had
low vitamin D status (Binkley et al., 2007).
According to the American Association of Nurse Practitioners, 89% of the
140,000 nationally licensed Nurse Practitioners (NPs) are prepared in a primary care
focus (adult, family, gerontology, pediatric or women’s health) (2013). With current
reports stating that such large portions of the population have low levels of vitamin D, it
is likely that the nurse practitioner provider will need to recognize and treat patients with
low vitamin D. It is important to ascertain the current level of knowledge of NPs
regarding recognition, diagnosis and treatment of vitamin D deficient states. This
includes knowledge of risk factors for vitamin D deficiency, appropriate lab testing and
interpretation, as well as treatment options. It is crucial that NPs have the knowledge
they need to effectively manage low vitamin D in order to mediate risk of poor bone
health, musculoskeletal pain, and many chronic disease states.
Purpose
The purpose of this study was to explore NP knowledge of vitamin D and vitamin D
deficient states as well as appropriate testing, risk factors and treatment of low levels of
vitamin D.
Methods
Design, Study Sample and Data Collection Procedures
In this descriptive, exploratory study, a cross-sectional survey approach was used.
After obtaining permission from the American Association of Nurse Practitioners
53
(AANP), surveys were made available to nurse practitioner attending the AANP 2012
national conference in Orlando, Florida. Questionnaires were placed on a table in the
hallway of the convention center. The investigator stood beside the table and asked nurse
practitioners if they would be willing to respond to the survey. Questionnaires were
returned to a sealed collection box near the table. One-hundred and fifty six surveys were
distributed and collection was stopped when the number of completed and returned forms
reached 100. Participation was limited to actively practicing nurse practitioners.
Students and nurse practitioners who were not actively practicing were excluded from the
study.
Instrument
The investigator designed survey was developed using: a) an extensive review of the
literature and b) current guidelines issued by the Endocrine Society regarding vitamin
D (Holick et al., 2011). The 17 item questionnaire includes four main sections:
demographic information, knowledge items, two questions on treatment and a single
question on identifying resources used by nurse practitioners to learn about vitamin D
deficient states. The demographic section includes four questions. The knowledge items
consist of both multiple choice items and one question that required participants to rank
answers in order. Initially the knowledge survey was a total of ten questions and
included four questions on laboratory testing and interpretation of laboratory results, two
questions on risk factors for vitamin D deficiency, one question on vitamin D content in
foods and sunlight, two questions on recommended daily intake levels of vitamin D by
the Food and Drug Administration (FDA), and one question on vitamin D and associated
chronic conditions. However after statistical analysis the knowledge survey was reduced
54
to six questions. The two questions pertaining to risk factors, the question on sources of
vitamin D and association of vitamin D with chronic conditions were eliminated from the
final knowledge assessment. Each question contained multiple parts and all parts needed
to be correct for the entire question to be considered correct. The four questions were
eliminated because the number of correct answers to those questions was so low that
those questions were not useful in delineating NP knowledge. Before the elimination of
the questions the highest NP knowledge score was 6 points out of 10 which was also the
case after the elimination of the questions. Additionally, the nature of the questions
(needing to get multiple parts within the question correct to achieve an overall correct
response) proved to be too challenging for most participants. Even though the four
questions were not used in the total knowledge score, participant responses were
analyzed and results reported below.
Human Subjects and Research Approval Procedures
Prior to data collection all research team members met institutional researcher training
requirements and the study protocol gained approval as exempt research by the
University of Kentucky Institutional Review Board (IRB). As approved by the IRB
survey participants were informed in a preamble statement that their participation implied
consent and that no identifying information would accompany their survey submission.
Data Analysis
The Statistical Software for the Social Sciences (SPSS) version 20.0 was used to
analyze data. Both inferential and descriptive statistics were used to analyze data.
Descriptive statistics included frequencies, means, standard deviations, and ranges.
Comparisons and associations were calculated using independent t- tests and Pearson
55
product moment correlations. Results were reported as significant when a threshold of p
< 0.05 was met.
Results
Of the 100 participants in this sample 70% were nurse practitioners certified in
family practice. Four other specialties were also represented. Length of practice as a NP
was reported M = 9.77 years (SD = 8.26) with a range of <1 to 40 years (see Table 3).
Eighty percent of the participants reported evaluating and treating vitamin D deficiency
in their practice.
Participant knowledge on vitamin D was based on answers to 6 multiple choice
questions. Scores ranged from zero to six with six representing the greatest knowledge
(see table 4). The mean knowledge score of nurse practitioner respondents was 2.30 (SD
= 1.31). The t-test for independent samples indicated a significant difference in the
mean knowledge score between nurse practitioners who reported assessing and treating
vitamin D deficiency in practice (t=2.903, p<.05, M=2.49, SD=1.27) compared to those
who do not regularly assess vitamin D (M=1.55, SD=1.23). No difference was found in
the mean knowledge score when comparing Adult NP/Family NP versus other
represented specialties (p=.670). An examination of NP years of practice revealed a
small correlation that was not significant (r=.086, p=.413).
Each knowledge score component was analyzed by frequency of correct versus
incorrect answer (see Table 5). Only 59% of respondents were able to identify the
correct laboratory test used to determine serum vitamin D levels. Only 51% and 41% of
respondents were able to identify the correct serum laboratory threshold for vitamin D
insufficiency and deficiency, respectively. When asked about vitamin D and toxicity,
56
only 61% responded correctly that vitamin D can reach levels of toxicity which could
potentially be fatal. Finally, only 2% of respondents knew the current recommended
daily allowance (RDA) of vitamin D for adults and on 16% could identify the current
RDA for elderly individuals greater than 70 years old.
Four questions that were separated from the knowledge score asked participants
about risk factors for vitamin D deficiency, sources of vitamin D, and chronic diseases
associated with vitamin D deficiency (see Table 6). When participants were given a list
of seven potential patients and asked to identify the risk of that patient having vitamin D
deficiency, their mean score was 3.64 (SD 1.33, ranger 0-7). Respondents were most
likely to misidentify two types of patients: a) Latino males who work outdoors and b) 3
month old Caucasian infants who are exclusively breastfed both of whom are high risk.
The patients who were more likely to be identified correctly were Latina woman who
work indoors and Caucasian women who work a desk job both of whom are also high
risk. Only 2 of the respondents were able to identify the correct risk status for all 7
potential patients.
When participants were given a list of patient characteristics and asked to identify
which of the characteristics indicate high risk or low risk for vitamin D deficiency,
respondent’s mean score was 4.71 (SD 1.0, range 0-7). The most common characteristics
that participants misidentified were: having brown or olive skin tone (high risk), having
white skin tone with freckles (low risk), and having dark black skin (high risk). Most of
the respondents were able to correctly identify that little sun exposure and obesity were
both high risk characteristics for vitamin D deficiency. None of the respondents were able
to correctly identify all seven risk variables.
57
When given a list of sources of vitamin D and asked to rank them in order from
best to least participants overall did very poorly. Most participants only ranked one or
two items in the correct order (M=1.56, SD 1.54, range 0-7)
Participants were also asked about specific chronic diseases and their association
with vitamin D. All of the diseases on the list have been associated with low vitamin D
status. It is important to note that little research has investigated causality between low
vitamin D and these chronic diseases; however, in all cases patients with these chronic
diseases are found to have an increased incidence of vitamin D deficiency. Greater than
87% of respondents clearly identified that osteoporosis, osteomalacia, and muscle or
bone pain are chronic conditions that are highly associated with vitamin D deficient
states. Conversely, respondents were less likely (20 to 50%) to associate vitamin D
deficiency with individuals who have asthma, type 2 diabetes, and increased number or
severity of infections. Other chronic diseases such as cancer, depression and autoimmune
disease were identified as associated with vitamin D deficient states 56 to 68% of the
time.
Nurse practitioners were then asked about their treatment preferences for vitamin
D deficiency (see Table 7). Sixty-six percent of respondents stated that they would
recommend an increase in intake of vitamin D rich foods as a part of their treatment plan.
Respondents also recommended vitamin D supplementation a majority of the time;
however, the dosage of supplement and frequency varied greatly with the very high dose
50,000 IU weekly dose recommended by 66% of NP respondents. Lastly, 75% of nurse
practitioners stated that they would increase sun exposure as part of the treatment plan;
however, sun exposure carries its own inherent risks.
58
Finally, participants were asked to identify which sources they were likely to use
for new information on vitamin D. The data suggests that NPs obtain their information
from a variety of sources including colleague discussion, physician and NP targeted
journal articles, medical internet sites (non-journals) such as Web MD or the Mayo clinic,
and medical conference presentations. NPs also responded that they sometimes or often
use Wikipedia (51%) and non-medical magazines such as Ladies Home Journal or Good
Housekeeping (27%) for medical information (see Table 8).
Discussion
Accurate knowledge regarding vitamin D deficiency is critical if NPs are going to
make optimal patient care decisions related to vitamin D deficient states. Finding of this
study show that NP knowledge of vitamin D and its deficient states is inconsistent. Even
though NPs were able to identify some risk factors for vitamin D deficiency such as
decreased sun exposure and obesity, other important risk factors such as darker skin color
and breastfed infants were missed. NPs that are unaware of all of the major risk factors
for vitamin D deficiency may not screen patient’s appropriately not only leading to an
unrecognized problem but also lack of treatment.
Even when patient risk is screened appropriately, many critical elements of
vitamin D testing and treatment can be confusing. NPs need to be able to identify the
appropriate lab test used for serum vitamin D assessment and the critical lab levels that
indicate vitamin D deficiency states. When it comes to treatment NP knowledge is again
inconsistent. Sixty-six percent of NP participants stated that they would increase food
intake of vitamin D as part of their treatment plan; however, very few NPs were able to
correctly identify the current RDA for vitamin D in either the adult or elderly population.
59
Most NPs were unable to correctly rank foods containing the most to least vitamin D
which indicates that NPs may not know what foods are high in vitamin D. Additionally,
even though it is important to incorporate vitamin D rich sources into a treatment plan,
NPs also need to consider that only a few foods supply a noteworthy amount of vitamin
D and that some of the best sources are fish. The importance of fish can be an issue in
many parts of the country where fish is not fresh; therefore, not a part of the daily or even
weekly diet. Incorporating fish in a diet is a special challenge for pregnant women
because the same fatty fish that is high in vitamin D can also be high in mercury, limiting
weekly intake. NPs need to have a better awareness of current recommendations and
which sources of vitamin D are best in order to appropriately guide patients.
Additionally, even though most NPs state that they would provide some level of
vitamin D supplementation as a part of their treatment plan, surprisingly 40% of
respondents were unaware of the risk of vitamin D toxicity and death. Vitamin D is a fat
soluble vitamin and although rare, cases of toxicity are reported annually usually in cases
where serum vitamin D levels are greater than 200ng/mL (Lowe, Cusano, Binkley,
Blaner, & Bilezikian, 2011; Maji, 2012). Furthermore, there was a wide range of
supplementation strategies used by NPs in current practice with doses ranging from 400
to 2000IU daily to 50,000 IU per week. This suggests that there is marked variation in
current vitamin D repletion strategies. Finally, 75% of nurse practitioners would
recommend an increase in sun exposure as part of their treatment plan; however, use of
sunscreen blocks the UVB rays that are essential to vitamin D production. Sun exposure
without the use of sunblock would expose patients to the harmful effects of the UV rays.
The American Academy of Dermatology recommends against the use of UV light
60
exposure as a treatment for vitamin D deficiency stating that the risks associated with
exposure do not outweigh benefits especially when other forms of supplementation are
available (2008).
In addition to inconsistent NP knowledge regarding vitamin D assessment and
treatment, there is also a lack of awareness of the potential consequences and/or comorbid conditions that are associated with low levels of vitamin D. Even though many
NPs associate bone diseases such as bone pain, osteoporosis and osteomalacia with
vitamin D deficiency, NPs were less aware that cancer, increased risk for severe
infections, asthma, depression and autoimmune disease all have been associated with
vitamin D deficiency. It is important that NPs are aware of the association between
vitamin D deficiency and chronic disease. This knowledge can be used to screen
additional patients who may not have traditional vitamin D risk factors and appropriate
vitamin D repletion in those patients could augment traditional treatment strategies for
their condition.
Finally, NPs are asked to make critical decisions regarding patient care and it is
important that the NP obtains accurate information from credible sources. It is not
surprising that most NPs turn to peer-reviewed medical journals for medical updates and
information on vitamin D. Conference speakers and reliable colleagues can also be a
resource for NPs. However NPs should be aware that medical websites, sites such as
Wikipedia, and non-medical magazines are not optimal sources of information.
Information in any of these sources may not be evidence based and can potentially
increase confusion about medical topics. NPs should be reminded that evidence based
61
practice is the gold standard for treatment and that medical journals are the best source
for peer- reviewed articles and information.
Limitations
Findings of the study are limited to a convenience sample of only 100
respondents. The sample was relatively homogenous with 80% of the respondents
reporting their specialty as family nurse practitioner. The choice for respondent
anonymity eliminated the ability for future follow up. Notwithstanding these limitations
this study brings insight into the knowledge base of NPs regarding vitamin D deficient
states and holds implications for education and practice.
Implications for Practice
Nurse practitioners should consider assessment for vitamin D deficiency in any
patient with traditional risk factors or commonly associated co-morbid conditions. If
nurse practitioners decide to treat vitamin D deficient states, they need to accumulate a
knowledge base regarding risk factors, appropriate lab testing and evaluation, and
treatment standards. Treatment plans should be based on thorough knowledge of the
sources of vitamin D, vitamin D supplementation strategies and risks of treatment. NPs
should carefully consider the risks of having patients increase sun exposure (without
sunscreen) before recommending sun exposure as a treatment for low vitamin D. Diet
alone is generally regarded as a poor source of vitamin D especially in individuals who
will not eat fish and/or dairy products and even though increasing dietary intake can be a
valid part of a treatment plan, changing diet alone may not be sufficient. NPs should also
be aware of the recommendations created by the Endocrine Society for testing and
treatment and use those recommendations as a guide to practice.
62
References
American Academy of Dermatology. (2008). Position statement on vitamin D Retrieved
March 16, 2011, from http://www.aad.org/Forms/Policies/Uploads/PS/PSVitamin%20D.pdf
American Academy of Nurse Practitioners. (2013). Nurse Practitioners in Primary Care,
from http://www.aanp.org/images/documents/publications/NPsInPrimaryCare.pdf
Balion, C., Griffith, L. E., Strifler, L., Henderson, M., Patterson, C., Heckman, G., . . .
Raina, P. (2012). Vitamin D, cognition, and dementia: a systematic review and
meta-analysis. [Meta-Analysis Research Support, Non-U.S. Gov't Review].
Neurology, 79(13), 1397-1405. doi: 10.1212/WNL.0b013e31826c197f
Binkley, N. (2012). Vitamin D and osteoporosis-related fracture. [Review]. Arch
Biochem Biophys, 523(1), 115-122. doi: 10.1016/j.abb.2012.02.004
Binkley, N., Novotny, R., Krueger, D., Kawahara, T., Daida, Y. G., Lensmeyer, G., . . .
Drezner, M. K. (2007). Low vitamin D status despite abundant sun exposure.
Journal of Clinical Endocrinology and Metababolism, 92(6), 2130-2135. doi:
jc.2006-2250 [pii] 10.1210/jc.2006-2250
Engelman, C. D., Fingerlin, T. E., Langefeld, C. D., Hicks, P. J., Rich, S. S.,
Wagenknecht, L. E., . . . Norris, J. M. (2008). Genetic and environmental
determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in
Hispanic and African Americans. Journal of Clinical Endocrinology and
Metabolism, 93(9), 3381-3388. doi: jc.2007-2702 [pii] 10.1210/jc.2007-2702
63
Hewison, M. (2012). Vitamin D and immune function: an overview. [Review].
Proceedings of the Nutrition Society, 71(1), 50-61. doi:
10.1017/S0029665111001650
Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3),
266-281. doi: 357/3/266 [pii]10.1056/NEJMra070553
Holick, M. F. (2012). Vitamin D: extraskeletal health. Rheumatic Diseases Clinics of
North America, 38(1), 141-160. doi: 10.1016/j.rdc.2012.03.013
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A.,
Heaney, R. P., . . . Weaver, C. M. (2011). Evaluation, treatment, and prevention
of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal
of Clinical Endocrinology and Metabolism, 96(7), 1911-1930. doi: jc.2011-0385
[pii] 10.1210/jc.2011-0385
Jacobs, E. T., Alberts, D. S., Foote, J. A., Green, S. B., Hollis, B. W., Yu, Z., & Martinez,
M. E. (2008). Vitamin D insufficiency in southern Arizona. American Journal of
Clinical Nutrition, 87(3), 608-613. doi: 87/3/608 [pii]
Levis, S., Gomez, A., Jimenez, C., Veras, L., Ma, F., Lai, S., . . . Roos, B. A. (2005).
Vitamin d deficiency and seasonal variation in an adult South Florida population.
Journal of Clinical Endocrinololgy and Metabolism, 90(3), 1557-1562. doi:
10.1210/jc.2004-0746
Lowe, H., Cusano, N. E., Binkley, N., Blaner, W. S., & Bilezikian, J. P. (2011). Vitamin
D toxicity due to a commonly available "over the counter" remedy from the
Dominican Republic. [Case Reports]. J Clin Endocrinol Metab, 96(2), 291-295.
doi: 10.1210/jc.2010-1999
64
Maji, D. (2012). Vitamin D toxicity. Indian J Endocrinol Metab, 16(2), 295-296. doi:
10.4103/2230-8210.93773
Mitchell, D. (2011). The relationship between vitamin d and cancer. Clinical Journal of
Oncology Nursing, 15(5), 557-560. doi: G730L92J32405328 [pii]
10.1188/11.CJON.557-560
Muscogiuri, G., Sorice, G. P., Ajjan, R., Mezza, T., Pilz, S., Prioletta, A., . . . Giaccari, A.
(2012). Can vitamin D deficiency cause diabetes and cardiovascular diseases?
Present evidence and future perspectives. [Review]. Nutr Metab Cardiovasc Dis,
22(2), 81-87. doi: 10.1016/j.numecd.2011.11.001
Spina, C. S., Tangpricha, V., Uskokovic, M., Adorinic, L., Maehr, H., & Holick, M. F.
(2006). Vitamin D and cancer. Anticancer Research, 26(4A), 2515-2524.
Takiishi, T., Gysemans, C., Bouillon, R., & Mathieu, C. (2012). Vitamin D and diabetes.
Rheumatic Diseases Clinics of North America, 38(1), 179-206. doi:
10.1016/j.rdc.2012.03.015
Zadshir, A., Tareen, N., Pan, D., Norris, K., & Martins, D. (2005). The prevalence of
hypovitaminosis D among US adults: data from the NHANES III. Ethnicity and
Disease, 15(4 Suppl 5), S5-97-101.
65
Table 3
Demographics of the study sample (N=100)
Characteristic
NP Specialty Certification
Family
Adult
Pediatric
Acute Care
Psychiatric
Dual Certification
Currently treating vitamin D deficiency
Yes
No
Years Practicing
<1year
2-5 years
6-10 years
11-15 years
16-20 years
21 – 25 years
>25 years
N
%
70
17
1
4
1
5
70
17
1
4
1
5
80
20
80
20
7
23
28
13
9
2
5
7
23
28
13
9
2
5
Table 4 Knowledge scores (range 0-6)
Total Score
0
1
2
3
4
5
6
N
8
24
22
25
18
3
0
_
%
8
24
22
25
18
3
0
66
Table 5 Knowledge score
components_____________________________________________________
Component
Which laboratory test is used to determine Vitamin D levels?
Correct
Incorrect
What is the serum lab value for vitamin D insufficiency?
Correct
Incorrect
What is the serum lab value for vitamin D deficiency?
Correct
Incorrect
Can vitamin D toxicity occur?
Correct
Incorrect
What is the RDA of vitamin D for Adults ages 19 – 69yo?
Correct
Incorrect
What is the RDA of vitamin D for elderly adults >70yo?
Correct
Incorrect
67
N
59
41
51
49
41
59
61
39
2
98
16
84
Table 6 Knowledge score components eliminated from final Instrument
Question 1: A list of potential patients was given and participants were asked to mark (√)
their perception of each patient’s risk for having less than normal vitamin D levels. They
could choose high risk, low risk or I don’t know. Descriptions of the patients included:
%correct
(N=100)
55 year old Latino Male who works outside riding horses
6%
A Caucasian 3 month old who is exclusively breastfed
33%
An obese 39 year old African American female
86%
A Caucasian 9 year old girl with a normal BMI
78%
A 32 year old Caucasian female with a normal BMI that runs marathons
80%
A 22 year old Latina female who is underweight and works at a grocery store 91%
A 45 year old Caucasian female who is overweight and works a desk job
97%
Question 2: A list of specific risk factors and participants were asked to mark (√) their
perception of each characteristic and its risk relationship for less than normal vitamin D
levels.
% correct
(N=100)
Being underweight
17%
Relatively little time in the sun
95%
Beige skin with brown or olive tone- Mediterranean/Latino
38%
Obesity
74%
White –very fair skin with freckles
19%
Dietary intake high in fatty fish
73%
Dark Black skin
48%
Question 3: Participants were asked to rank in order from 1 to 7 the best sources of
vitamin D (best=1) to the worst (worst=7) sources of vitamin D. The sources are listed
below.
a. Fortified milk (1 cup)
b. Tuna, canned (3.6oz)
c. Egg yolk (1 egg)
d. Raw broccoli (1 cup)
e. Wild salmon(3.6 oz)
f. Exposure to sunlight (15 minutes)
g. Whole grain cereal (1 cup)
Question 4: Participants were given a list of chronic conditions and asked if those
conditions are associated with vitamin D. The answer choices were yes, no, or maybe.
Yes no
maybe
(N=100)
Type 2 diabetes
50
13
37
Osteomalcia/falls
94
2
4
Increased risk of falls
72
11
17
68
Muscle/bone pain
Cancer
Asthma
Osteoporosis
Increased severity frequency of infections
Depression
Autoimmune disease
87
56
19
94
50
68
64
1
10
43
0
11
8
7
12
34
38
6
39
24
29
Table 7 Treatment preference for vitamin D deficiency
Treatment
(N=100)
Increase intake of vitamin D rich foods
31
Increase sun exposure
25
400-1000IU daily vitamin D supplementation
90
2000IU daily vitamin D supplementation
60
50,000IU weekly vitamin D supplementation
34
Consider
Not consider
66
75
10
40
66
Table 8 Likely use of resources for information on vitamin D (N=100)
Source
Never
Often
Colleague discussion
20%
Conference Speaker
35%
Internet website other than journal (Web MD, Mayo) 15%
Medical (Physician targeted) journal articles
20%
Medical (NP targeted ) journal articles
16%
Internet – Wikipedia
49%
Non medical magazine
73%
69
Sometimes
52%
47%
49%
45%
41%
35%
24%
Very
28%
18%
36%
35%
43%
16%
3%
Conclusion to Final DNP Capstone Report
Sara E Robertson
University of Kentucky
70
Vitamin D deficiency is pervasive in the United States population and has now
been associated with many acute and chronic conditions, especially bone disease and type
2 diabetes. Nurse practitioners are expected to make critical decisions regarding patient
care and it is important that they have a good understanding of vitamin D deficiency
ensuring that they can appropriately treat patients. The research in this capstone indicates
that NPs have a significant knowledge deficit regarding the assessment and treatment of
vitamin D deficiency. Optimal knowledge should include the definition of vitamin D
insufficiency and deficiency and its correlation to chronic disease states, the risk factors
and epidemiology of vitamin D deficiency, and the latest information on appropriate
clinical screening and treatment of vitamin D deficiency as detailed in the second
manuscript.
Even though vitamin D deficiency research is in a nascent stage, early research
indicates that recognition and treatment could benefit patients. Through examining the
current state of knowledge regarding vitamin D deficiency one can identify areas for
education as well as future research potential. The potential of Vitamin D
supplementation, which is easily accessible and inexpensive, to benefit public health is
immense and worth the attention of both researchers and clinicians now and in the future.
71
Appendix A
The Nurse Practitioner and Vitamin D: Knowledge and Practices
Please indicate your answer to the following questions.
Demographic Information
1.Are you currently practicing in a nurse practitioner role?
_____ yes
______ no
2.Which of the following best describes your nurse practitioner specialty certification? (If
you are certified in more than one specialty please mark all that apply).
_____ Adult Nurse Practitioner (ANP)
_____ Neonatal Nurse Practitioner
_____ Family Nurse Practitioner (FNP)
_____ Acute Care Nurse Practitioner
_____ Pediatric Nurse Practitioner (PNP)
_____ Psych Nurse Practitioner
3. How many years have your been practicing as a nurse practitioner? _________
Knowledge Survey
1.Which of the following vitamin D substrates is the one most routinely used in serum
laboratory testing of vitamin D?
_____ vitamin D hydroxylase
_____ 25-hydroxyvitamin D – 25(OH)D
_____ 1,25-dihydroxyvitamin D1,25(OH)
_____ previtamin D
_____ I don’t know
2.At which of the following thresholds would you consider a patient to be insufficient of
vitamin D?
_____ <60ng/mL
_____ <50ng/mL
_____ <40ng/mL
_____ < 30ng/mL
72
_____ <20ng/mL
_____ <10ng/mL
3. At which of the following thresholds would you consider a patient to be deficient of
vitamin D?
_____ <60ng/mL
_____ <50ng/mL
_____ <40ng/mL
_____ < 30ng/mL
_____ <20ng/mL
_____ <10ng/mL
4. Is it possible for a patient to have a serum level of vitamin D that is toxic which can
result in death?
_____ yes
_____ no
5. The following is a list of potential patients. Please mark (√) your perception of each
patient’s risk for having decreased serum vitamin D levels.
Average
Risk for
low
vitamin D
Low
Risk for
low
vitamin
D
I don’t
Know
Patient description
High
Risk for
low
vitamin D
A 55 year old Latino Male who
works outside riding horses
_______
_______
_______
_______
A Caucasian 3 month old who is
exclusively breast fed
_______
_______
_______
_______
An obese 39 year old African
American female
_______
_______
_______
_______
A Caucasian 9 year old girl with a
normal body mass index
_______
_______
_______
_______
_______
_______
_______
_______
A 32 year old Caucasian female
with a normal BMI who runs
marathons
73
A 22 year old Latina female who
is underweight and works at a
grocery store
A 45 year old Caucasian female
who is overweight and works a
desk job
_______
_______
_______
______
______
_______
_______
______
6.The following is a list of patient characteristics. Please mark (√) your perception of
each characteristic and its relationship to risk of decreased serum vitamin D levels.
Characteristic
Know
High risk
Average risk Low Risk
I don’t
Being Underweight
_______
_______
_______
_______
Relatively little
time in the sun
_______
_______
_______
_______
Beige skin with brown
or olive tone –
Mediterranian/Latino
_______
_______
_______
_______
Obesity
_______
_______
_______
_______
White – very fair skin
tone with freckles
_______
_______
_______
_______
Dietary intake high
In fatty fish
_______
_______
_______
_______
Dark Black Skin
_______
_______
_______
_______
7.If you determine that your patient’s vitamin D level is insufficient (mildly less than
normal), which of the following are you most likely recommend? (Select all that apply).
_____ increase intake of foods that contain vitamin D
_____ increased indoor exercise
_____ Vitamin D supplementation of 400-1,000 IU daily
74
_____ Vitamin D supplementation of 2,000IU daily
_____ Vitamin D supplementation of 50,000IU per week
_____increase sun exposure
_____ I do not treat vitamin D insufficiency
_____ I do not currently test for vitamin D insufficiency
8. If you determine that your patient’s vitamin D level is deficient (markedly less than
normal), which of the following are you most likely recommend? (Select all that apply).
_____ increase intake of foods that contain vitamin D
_____ increased indoor exercise
_____ Vitamin D supplementation of 400-1,000 IU daily
_____ Vitamin D supplementation of 2,000IU daily
_____ Vitamin D supplementation of 50,000IU per week
_____increase sun exposure
_____ I do not treat vitamin D insufficiency
_____ I do not currently test for vitamin D insufficiency
9. The following is a list of foods/activities that contain vitamin D. Please rank in order
from number 1 to number 7 the best sources of vitamin D. (Number 1 being the best
source and Number 7 being the worst source).
fortified milk (1 cup)
_____
Tuna, canned (3.6oz)
_____
Egg yolk - 1
_____
Broccoli – 1 cup raw
_____
Wild salmon (3.6oz)
_____
Exposure to 15 min.
of sunlight
_____
whole grain cereal –1 cup
_____
75
10.What is the recommended daily allowance (RDA) of vitamin D (in international units
= IU) set by the Food and Drug Administration for individuals 19 -69 years old.
_____ 400 IU
_____ 600 IU
_____ 800 IU
_____ 1200 IU
_____ 2000 IU
11. What is the recommended daily allowance (RDA) of vitamin D (in international
units = IU) set by the Food and Drug Administration for individuals greater than 70 years
old.
_____ 400 IU
_____ 600 IU
_____ 800 IU
_____ 1200 IU
_____ 2000 IU
12. Which of the following conditions/states so you believe to be associated with low
serum levels of vitamin D? (Please select all that apply)
_____ type 2 diabetes
_____ osteomalacia/rickets
_____ increased risk of falls
_____ muscle/bone pain
_____ cancer
_____ asthma
_____ osteoporosis
infections
_____ increased severity/ frequency of
_____ depression
_____ autoimmune diseases
_____ none of the above is associated with low vitamin D
76
13. The following is a list of resources which can be used to obtain clinical data
regarding vitamin D. Please mark (√) the line that correctly indicates how often you have
used each of the following resources in the last year for clinical information regarding
vitamin D.
Resource
Very Often
Sometimes
Not at all
Discussion with Colleagues
_______
_______
_______
Conference Speaker
_______
_______
_______
Internet –Non Journal medical
Site (Web MD; Mayo clinic)
_______
_______
_______
Medical Journal Articles
(ie. New England Journal of Medicine;
Lancet; Journal of the American
Academy of Family Practice
Physicians)
_______
_______
_______
Nurse Practitioner targeted
medical journals (ie. Clinical Advisor;
Journal of the American Academy
of Nurse Practitioners).
_______
_______
_______
Internet - Wikipedia
_______
_______
_______
Non-Medical Magazine
(Ladies Home Journal;
Good Housekeeping)
_______
_______
_______
77
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consequences on musculoskeletal health. [Review]. Curr Rheumatol Rep, 14(3),
286-293. doi: 10.1007/s11926-012-0244-8
Heaney, R. P., Davies, K. M., Chen, T. C., Holick, M. F., & Barger-Lux, M. J. (2003).
Human serum 25-hydroxycholecalciferol response to extended oral dosing with
cholecalciferol. American Journal of Clinical Nutrition, 77, 204-210.
Heaney, R. P., & Holick, M. F. (2011). Why the IOM recommendations for vitamin D
are deficient. Journal of Bone and Mineral Research, 26(3), 455-457. doi:
10.1002/jbmr.328
Hewison, M. (2010). Vitamin D and the immune system: new perspectives on an old
theme. Endocrinol Metab Clin North Am, 39(2), 365-379, table of contents. doi:
S0889-8529(10)00012-5 [pii] 10.1016/j.ecl.2010.02.010
80
Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3),
266-281. doi: 357/3/266 [pii]10.1056/NEJMra070553
Holick, M. F. (2011). Vitamin D: A D-Lightful Solution for Health. J Investig Med. doi:
10.231/JIM.0b013e318214ea2d
Holick, M. F. (2012). Vitamin D: extraskeletal health. Rheumatic Diseases Clinics of
North America, 38(1), 141-160. doi: 10.1016/j.rdc.2012.03.013
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A.,
Heaney, R. P., . . . Weaver, C. M. (2011). Evaluation, treatment, and prevention
of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal
of Clinical Endocrinology and Metabolism, 96(7), 1911-1930. doi: jc.2011-0385
[pii] 10.1210/jc.2011-0385
Holick, M. F., & Chen, T. C. (2008). Vitamin D deficiency: a worldwide problem with
health consequences. American Journal of Clinical Nutrition, 87(suppl), 1080S1086S.
Hollis, B. W., & Wagner, C. L. (2004). Assessment of dietary vitamin D requirements
during pregnancy and lactation. [Review]. Am J Clin Nutr, 79(5), 717-726.
Hollis, B. W., Wagner, C. L., Drezner, M. K., & Binkley, N. C. (2007). Circulating
vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define
adequate nutritional vitamin D status. Journal of Steroid Biochemistry &
Molecular Biology, 103(3-5), 631-634. doi: S0960-0760(06)00390-6
[pii]10.1016/j.jsbmb.2006.12.066
81
Hypponen, E., & Power, C. (2006). Vitamin D status and glucose homeostasis in the
1958 British birth cohort. Diabetes Care, 29, 2244-2246.
Institute of Medicine. (2010). Dietary reference intakes for calcium and vitamin D.
Washington DC: National Academy Press.
Jacobs, E. T., Alberts, D. S., Foote, J. A., Green, S. B., Hollis, B. W., Yu, Z., & Martinez,
M. E. (2008). Vitamin D insufficiency in southern Arizona. American Journal of
Clinical Nutrition, 87(3), 608-613. doi: 87/3/608 [pii]
Levis, S., Gomez, A., Jimenez, C., Veras, L., Ma, F., Lai, S., . . . Roos, B. A. (2005).
Vitamin d deficiency and seasonal variation in an adult South Florida population.
Journal of Clinical Endocrinololgy and Metabolism, 90(3), 1557-1562. doi:
10.1210/jc.2004-0746
Liu, E., Meigs, J. B., Pittas, A. G., McKeown, N. M., Economos, C. D., Booth, S. L., &
Jacques, P. F. (2009). Plasma 25-hydroxyvitamin D is associated with markers of
the insulin resistant phenotype in nondiabetic adults. Journal of Nutrition, 139,
329-334.
Lowe, H., Cusano, N. E., Binkley, N., Blaner, W. S., & Bilezikian, J. P. (2011). Vitamin
D toxicity due to a commonly available "over the counter" remedy from the
Dominican Republic. [Case Reports]. J Clin Endocrinol Metab, 96(2), 291-295.
doi: 10.1210/jc.2010-1999
Maji, D. (2012). Vitamin D toxicity. Indian J Endocrinol Metab, 16(2), 295-296. doi:
10.4103/2230-8210.93773
Marks, R., Foley, P. A., Jolley, D., Knight, K. R., Harrison, J., & Thompson, S. C.
(1995). The effect of regular sunscreen use on vitamin D levels in an Australian
82
population. Results of a randomized controlled trial. [Clinical Trial Randomized
Controlled Trial Research Support, Non-U.S. Gov't]. Archives of Dermatology,
131(4), 415-421.
Matsuoka, L. Y., Wortsman, J., Hanifan, N., & Holick, M. F. (1988). Chronic sunscreen
use decreases circulating concentrations of 25-hydroxyvitamin D. A preliminary
study. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.].
Archives of Dermatology, 124(12), 1802-1804.
Mattila, C., Knekt, P., Mannisto, S., Rissanen, H., Laaksonen, M., Montonen, J., &
Reunanen, A. (2007). Serum 25-hydroxyvitamin D concentration and subsequent
risk of type 2 diabetes. Diabetes Care, 30(10), 2569-2570
Maxmen, A. (2011). Nutrition advice: the vitamin D-lemma. Nature, 475(7354), 23-25.
doi: 475023a [pii] 10.1038/475023a
Mitchell, D. (2011). The relationship between vitamin d and cancer. Clinical Journal of
Oncology Nursing, 15(5), 557-560. doi: G730L92J32405328
[pii]10.1188/11.CJON.557-560
Muscogiuri, G., Sorice, G. P., Ajjan, R., Mezza, T., Pilz, S., Prioletta, A., . . . Giaccari, A.
(2012). Can vitamin D deficiency cause diabetes and cardiovascular diseases?
Present evidence and future perspectives. [Review]. Nutr Metab Cardiovasc Dis,
22(2), 81-87. doi: 10.1016/j.numecd.2011.11.001
Need, A. G., O'Loughlin, P. D., Horowitz, M., & Nordin, C. (2005). Relationship
between fasting serum glucose, age, body mass index and serum 25
83
hydroxyvitamin D in postmenopausal women. Clinical Endocrinology, 62, 738741.
Nesby-O'Dell, S., Scanlon, K. S., Cogswell, M. E., Gillespie, C., Hollis, B. W., Looker,
A. C., . . . Bowman, B. A. (2002). Hypovitaminosis D prevalence and
determinants among African American and white women of reproductive age:
third National Health and Nutrition Examination Survey, 1988-1994. American
Journal of Clinical Nutrition, 76(1), 187-192.
Papaioannou, A., Kennedy, C. C., Giangregorio, L., Ioannidis, G., Pritchard, J., Hanley,
D. A., . . . Adachi, J. D. (2011). A randomized controlled trial of vitamin D dosing
strategies after acute hip fracture: no advantage of loading doses over daily
supplementation. BMC Musculoskeletal Disorders, 12, 135. doi: 1471-2474-12135 [pii] 10.1186/1471-2474-12-135
Peechakara, S. V., & Pittas, A. G. (2008). Vitamin D as a potential modifier of diabetes
risk. Nature Clinical Practice Endocrinology & Metabolism, 4(4), 182-183. doi:
ncpendmet0762 [pii]10.1038/ncpendmet0762
Penckofer, S., Kouba, J., Wallis, D. E., & Emanuele, M. A. (2008). Vitamin D and
diabetes: let the sunshine in. Diabetes Education, 34(6), 939-940, 942, 944
passim. doi: 34/6/939 [pii]10.1177/0145721708326764
Pepper, K. J., Judd, S. E., Nanes, M. S., & Tangpricha, V. (2009). Evaluation of vitamin
D repletion regimens to correct vitamin D status in adults. Endocrine Practice,
15(2), 95-103. doi: G745782VG0R08230 [pii]
84
Pittas, A. G., Dawson-Hughes, B., Li, T., Van Dam, R. M., Willett, W. C., Manson, J. E.,
& Hu, F. B. (2006). Vitamin D and calcium intake in relation to type 2 diabetes in
women. Diabetes Care, 29(3), 650-656.
Pittas, A. G., Harris, S. S., Stark, P. C., & Dawson-Hughes, B. (2007). The effects of
calcium and vitamin D supplementation on blood glucose and markers of
inflammation in nondiabetic adults. Diabetes Care, 30(4), 980-986. doi: dc061994 [pii]10.2337/dc06-1994
Plotnikoff, G. A. (2011). Update on vitamin D Retrieved May 3 2011, from
http://www.acamnet.com/plotnikoffsyllabuse2011.pdf
Plotnikoff, G. A., & Quigley, J. M. (2003). Prevalence of severe hypovitaminosis D in
patients with persistent, nonspecific musculoskeletal pain. Mayo Clinic
Proceedings, 78(12), 1463-1470.
Robins, A. H. (1991). Biological perspectives on human pigmentation. Cambridge:
Cambridge University Press.
Sahu, M., Bhatia, V., Aggarwal, A., Rawat, V., Saxena, P., Pandey, A., & Das, V. (2009).
Vitamin D deficiency in rural girls and pregnant women despite abundant
sunshine in northern India. [Article]. Clinical Endocrinology, 70(5), 680-684. doi:
10.1111/j.1365-2265.2008.03360.x
Schwalfenberg, G. (2008). Vitamin D and diabetes: improvement of glycemic control
with vitamin D3 repletion. Canadian Family Physician, 54(6), 864-866. doi:
54/6/864 [pii]
85
Snijder, M., van Dam, R. M., Visser, M., Deeg, D., Seidell, J., & Lips, P. (2006). To:
Mathieu C, Gysemans C,Giulietti A, Bouillion R. [Comment on: Vitamin D and
diabetes; 48:1247-1257(2005)]. Diabetologogia, 49, 217-218.
Spina, C. S., Tangpricha, V., Uskokovic, M., Adorinic, L., Maehr, H., & Holick, M. F.
(2006). Vitamin D and cancer. Anticancer Research, 26(4A), 2515-2524.
Stechschulte, S. A., Kirsner, R. S., & Federman, D. G. (2009). Vitamin D: bone and
beyond, rationale and recommendations for supplementation. [Review]. American
Journal of Medicine, 122(9), 793-802. doi: 10.1016/j.amjmed.2009.02.029
Takiishi, T., Gysemans, C., Bouillon, R., & Mathieu, C. (2012). Vitamin D and diabetes.
Rheumatic Diseases Clinics of North America, 38(1), 179-206. doi:
10.1016/j.rdc.2012.03.015
Tsiaras, W. G., & Weinstock, M. A. (2011). Factors influencing vitamin D status.
[Review]. Acta Dermato-Venereologica, 91(2), 115-124. doi: 10.2340/000155550980
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Heaney, R. P., . . . Zittermann, A. (2007). The urgent need to recommend an
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cholecalciferol. American Journal of Clinical Nutrition, 77, 204-210.
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10.231/JIM.0b013e318214ea2d
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North America, 38(1), 141-160. doi: 10.1016/j.rdc.2012.03.013
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A.,
Heaney, R. P., . . . Weaver, C. M. (2011). Evaluation, treatment, and prevention
of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal
of Clinical Endocrinology and Metabolism, 96(7), 1911-1930. doi: jc.2011-0385
[pii] 10.1210/jc.2011-0385
Holick, M. F., & Chen, T. C. (2008). Vitamin D deficiency: a worldwide problem with
health consequences. American Journal of Clinical Nutrition, 87(suppl), 1080S1086S.
Hollis, B. W., & Wagner, C. L. (2004). Assessment of dietary vitamin D requirements
during pregnancy and lactation. [Review]. Am J Clin Nutr, 79(5), 717-726.
Hollis, B. W., Wagner, C. L., Drezner, M. K., & Binkley, N. C. (2007). Circulating
vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define
adequate nutritional vitamin D status. Journal of Steroid Biochemistry &
Molecular Biology, 103(3-5), 631-634. doi: S0960-0760(06)00390-6
[pii]10.1016/j.jsbmb.2006.12.066
91
Hypponen, E., & Power, C. (2006). Vitamin D status and glucose homeostasis in the
1958 British birth cohort. Diabetes Care, 29, 2244-2246.
Institute of Medicine. (2010). Dietary reference intakes for calcium and vitamin D.
Washington DC: National Academy Press.
Jacobs, E. T., Alberts, D. S., Foote, J. A., Green, S. B., Hollis, B. W., Yu, Z., & Martinez,
M. E. (2008). Vitamin D insufficiency in southern Arizona. American Journal of
Clinical Nutrition, 87(3), 608-613. doi: 87/3/608 [pii]
Levis, S., Gomez, A., Jimenez, C., Veras, L., Ma, F., Lai, S., . . . Roos, B. A. (2005).
Vitamin d deficiency and seasonal variation in an adult South Florida population.
Journal of Clinical Endocrinololgy and Metabolism, 90(3), 1557-1562. doi:
10.1210/jc.2004-0746
Liu, E., Meigs, J. B., Pittas, A. G., McKeown, N. M., Economos, C. D., Booth, S. L., &
Jacques, P. F. (2009). Plasma 25-hydroxyvitamin D is associated with markers of
the insulin resistant phenotype in nondiabetic adults. Journal of Nutrition, 139,
329-334.
Lowe, H., Cusano, N. E., Binkley, N., Blaner, W. S., & Bilezikian, J. P. (2011). Vitamin
D toxicity due to a commonly available "over the counter" remedy from the
Dominican Republic. [Case Reports]. J Clin Endocrinol Metab, 96(2), 291-295.
doi: 10.1210/jc.2010-1999
Maji, D. (2012). Vitamin D toxicity. Indian J Endocrinol Metab, 16(2), 295-296. doi:
10.4103/2230-8210.93773
Marks, R., Foley, P. A., Jolley, D., Knight, K. R., Harrison, J., & Thompson, S. C.
(1995). The effect of regular sunscreen use on vitamin D levels in an Australian
92
population. Results of a randomized controlled trial. [Clinical Trial Randomized
Controlled Trial Research Support, Non-U.S. Gov't]. Archives of Dermatology,
131(4), 415-421.
Matsuoka, L. Y., Wortsman, J., Hanifan, N., & Holick, M. F. (1988). Chronic sunscreen
use decreases circulating concentrations of 25-hydroxyvitamin D. A preliminary
study. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.].
Archives of Dermatology, 124(12), 1802-1804.
Mattila, C., Knekt, P., Mannisto, S., Rissanen, H., Laaksonen, M., Montonen, J., &
Reunanen, A. (2007). Serum 25-hydroxyvitamin D concentration and subsequent
risk of type 2 diabetes. Diabetes Care, 30(10), 2569-2570
Maxmen, A. (2011). Nutrition advice: the vitamin D-lemma. Nature, 475(7354), 23-25.
doi: 475023a [pii] 10.1038/475023a
Mitchell, D. (2011). The relationship between vitamin d and cancer. Clinical Journal of
Oncology Nursing, 15(5), 557-560. doi: G730L92J32405328
[pii]10.1188/11.CJON.557-560
Muscogiuri, G., Sorice, G. P., Ajjan, R., Mezza, T., Pilz, S., Prioletta, A., . . . Giaccari, A.
(2012). Can vitamin D deficiency cause diabetes and cardiovascular diseases?
Present evidence and future perspectives. [Review]. Nutr Metab Cardiovasc Dis,
22(2), 81-87. doi: 10.1016/j.numecd.2011.11.001
Need, A. G., O'Loughlin, P. D., Horowitz, M., & Nordin, C. (2005). Relationship
between fasting serum glucose, age, body mass index and serum 25
93
hydroxyvitamin D in postmenopausal women. Clinical Endocrinology, 62, 738741.
Nesby-O'Dell, S., Scanlon, K. S., Cogswell, M. E., Gillespie, C., Hollis, B. W., Looker,
A. C., . . . Bowman, B. A. (2002). Hypovitaminosis D prevalence and
determinants among African American and white women of reproductive age:
third National Health and Nutrition Examination Survey, 1988-1994. American
Journal of Clinical Nutrition, 76(1), 187-192.
Papaioannou, A., Kennedy, C. C., Giangregorio, L., Ioannidis, G., Pritchard, J., Hanley,
D. A., . . . Adachi, J. D. (2011). A randomized controlled trial of vitamin D dosing
strategies after acute hip fracture: no advantage of loading doses over daily
supplementation. BMC Musculoskeletal Disorders, 12, 135. doi: 1471-2474-12135 [pii] 10.1186/1471-2474-12-135
Peechakara, S. V., & Pittas, A. G. (2008). Vitamin D as a potential modifier of diabetes
risk. Nature Clinical Practice Endocrinology & Metabolism, 4(4), 182-183. doi:
ncpendmet0762 [pii]10.1038/ncpendmet0762
Penckofer, S., Kouba, J., Wallis, D. E., & Emanuele, M. A. (2008). Vitamin D and
diabetes: let the sunshine in. Diabetes Education, 34(6), 939-940, 942, 944
passim. doi: 34/6/939 [pii]10.1177/0145721708326764
Pepper, K. J., Judd, S. E., Nanes, M. S., & Tangpricha, V. (2009). Evaluation of vitamin
D repletion regimens to correct vitamin D status in adults. Endocrine Practice,
15(2), 95-103. doi: G745782VG0R08230 [pii]
94
Pittas, A. G., Dawson-Hughes, B., Li, T., Van Dam, R. M., Willett, W. C., Manson, J. E.,
& Hu, F. B. (2006). Vitamin D and calcium intake in relation to type 2 diabetes in
women. Diabetes Care, 29(3), 650-656.
Pittas, A. G., Harris, S. S., Stark, P. C., & Dawson-Hughes, B. (2007). The effects of
calcium and vitamin D supplementation on blood glucose and markers of
inflammation in nondiabetic adults. Diabetes Care, 30(4), 980-986. doi: dc061994 [pii]10.2337/dc06-1994
Plotnikoff, G. A. (2011). Update on vitamin D Retrieved May 3 2011, from
http://www.acamnet.com/plotnikoffsyllabuse2011.pdf
Plotnikoff, G. A., & Quigley, J. M. (2003). Prevalence of severe hypovitaminosis D in
patients with persistent, nonspecific musculoskeletal pain. Mayo Clinic
Proceedings, 78(12), 1463-1470.
Robins, A. H. (1991). Biological perspectives on human pigmentation. Cambridge:
Cambridge University Press.
Sahu, M., Bhatia, V., Aggarwal, A., Rawat, V., Saxena, P., Pandey, A., & Das, V. (2009).
Vitamin D deficiency in rural girls and pregnant women despite abundant
sunshine in northern India. [Article]. Clinical Endocrinology, 70(5), 680-684. doi:
10.1111/j.1365-2265.2008.03360.x
Schwalfenberg, G. (2008). Vitamin D and diabetes: improvement of glycemic control
with vitamin D3 repletion. Canadian Family Physician, 54(6), 864-866. doi:
54/6/864 [pii]
95
Snijder, M., van Dam, R. M., Visser, M., Deeg, D., Seidell, J., & Lips, P. (2006). To:
Mathieu C, Gysemans C,Giulietti A, Bouillion R. [Comment on: Vitamin D and
diabetes; 48:1247-1257(2005)]. Diabetologogia, 49, 217-218.
Spina, C. S., Tangpricha, V., Uskokovic, M., Adorinic, L., Maehr, H., & Holick, M. F.
(2006). Vitamin D and cancer. Anticancer Research, 26(4A), 2515-2524.
Stechschulte, S. A., Kirsner, R. S., & Federman, D. G. (2009). Vitamin D: bone and
beyond, rationale and recommendations for supplementation. [Review]. American
Journal of Medicine, 122(9), 793-802. doi: 10.1016/j.amjmed.2009.02.029
Takiishi, T., Gysemans, C., Bouillon, R., & Mathieu, C. (2012). Vitamin D and diabetes.
Rheumatic Diseases Clinics of North America, 38(1), 179-206. doi:
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