Vitamin D New implications for mood and blood pressure
Abstract: This article reviews the 2011 guidelines for the evaluation, treatment, and prevention of vitamin D deficiency as well as the research literature evidencing an association between vitamin D, blood pressure and depression. Studies reveal an association between vitamin D levels and both systolic blood pressure and depression.
Photo by Aleksandar Nakic / iStock ©
By Janis P. Puglisi, APRN, FNP-BC
itamin D is receiving increased attention in the healthcare literature because of a multitude of new studies purporting its beneficial effects when serum levels are sufficient. The purpose of this article is to review the 2011 Endocrine Society Guidelines on the evaluation, treatment, prevention of vitamin D deficiency, and to summarize the evidence regarding associations between vitamin D, BP, and depression.1 Vitamin D is an essential fat-soluble vitamin obtained via dietary sources, vitamin supplementation, or skin
V
exposure to sunlight. Vitamin D is available in two forms: as vitamin D2 and vitamin D3.1 Synthesis of vitamin D from exposure to solar UVB radiation is the result of the conversion of 7-dehydrocholesterol in the skin to vitamin D3.2,3 Excessive sunlight exposure does not cause vitamin D toxicity because UVB radiation degrades any excess vitamin D3.3 Dietary food sources and supplemental sources of vitamin D are available as vitamin D2 and vitamin D3.1 Risk factors for vitamin D deficiency include decreased exposure to sunlight, the season of the year (winter),
Key words: blood pressure, depression, hypertension, vitamin D
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Vitamin D: New implications for mood and blood pressure
reduced daylight (living in an area at increased distance from the equator), the use of sunscreen, darker skin pigmentation, clothing choices (covering the skin), aging, and a lack of supplementation or dietary intake of vitamin D food sources. Older adults are at very high risk for vitamin D deficiency because of a lesser ability to make vitamin D from sunlight and their often decreased sunseeking behavior. Others at risk of deficiency include children, patients who had bariatric surgery, those with fat malabsorption syndromes, hyperparathyroidism, Serum vitamin D reference ranges1,4 Lab value for 25 (OH)D
Institute of Medicine ranges
2011 Endocrine Society ranges
Deficiency
< 12 ng/mL
< 20 ng/mL
Insufficiency or inadequacy
12-20 ng/mL
21-29 ng/mL
Sufficiency
> 20 ng/mL
≥ 30 ng/mL
Vitamin D toxicity
Not available
100 ng/mL
The Endocrine Society 2011 guidelines state that “although it is not known what the safe upper value for 25(OH)D is for avoiding hypercalcemia, most studies in children and adults have suggested that the blood levels need to be above 150 ng/mL before there is any concern. Therefore, an upper limit of 100 ng/mL provides a safety margin in reducing risk of hypercalcemia.”
Screening recommendations for vitamin D deficiency1,3 Specific populations • Black and Hispanic children and adults • Pregnant and lactating women • Older adults (especially those with a history of falls) • Individuals who are institutionalized, those who frequently remain indoors, those who use daily sunscreen or cover up their skin with clothing • Obese individuals (BMI of 30 or greater) Individuals with chronic medical conditions or those taking specific medications • Bone disease (osteoporosis, osteomalacia, rickets) • Chronic kidney disease • Granulomatous diseases (sarcoidosis, berylliosis, coccidioidomycosis, histoplasmosis) • Hepatic disease • Hyperparathyroidism • Lactose intolerant • Malabsorption diseases (celiac disease, cystic fibrosis, postbariatric surgery, Crohn disease) • Medications (antiepileptic drugs, antifungal agents, antiretroviral therapy for HIV/AIDS, glucocorticoids, cholestyramine)
48 The Nurse Practitioner • Vol. 38, No. 12
chronic kidney disease, the obese, and those taking antiepileptic drugs (phenobarbital, phenytoin, carbamazepine), antifungal agents (such as ketoconazole), antiretroviral therapy for HIV/AIDS, glucocorticoids, and cholestyramine.1,2 Deficiency is common, as more than 50% of Hispanic and Black adolescents in Boston are deficient in vitamin D.1 Typical signs and symptoms of vitamin D deficiency include bone pain, muscle weakness, increased falls, fatigue, and possibly mood disorders. According to the June 2011 Endocrine Society Guidelines, vitamin D deficiency is defined as having a serum 25-hydroxyvitamin D (25 [OH]D) level less than 20 ng/mL (50 nmol/L) because this is the level necessary to maintain skeletal health.1 Vitamin D is insufficient for optimal health when between 20 to 29.9 ng/mL and is normal at values of 30 ng/mL or greater.1 (See Serum vitamin D reference ranges.) Screening is now recommended for Black and Hispanic children and adults, pregnant and lactating women, the obese (body mass index [BMI] of 30 or greater), those taking numerous medications or having various chronic medical conditions, which affect vitamin D synthesis or intestinal absorption.1 (See Screening recommendations for vitamin D deficiency.) Supplementation has been suggested for those living north of the 33rd latitude, which is parallel to Phoenix and Birmingham. In the absence of noontime sun exposure in locales north of the 33rd latitude, it would be difficult to obtain enough vitamin D from dietary sources to maintain the body’s requirement. Additionally, skin production of vitamin D is very low or missing in the winter months, making supplementation wise for individuals who will not be outside in the sun between late fall and mid-spring.1-3 The Institute of Medicine (IOM) established dietary references for calcium and vitamin D but noted that their task was not to establish serum cut points for vitamin D sufficiency. The IOM decried (prior to the 2011 Endocrine Society guidelines) that no central body had been recognized to establish useful serum clinical values.4 The IOM suggested 600 international units (IU) daily of vitamin D for children and adults 1 year of age to age 70, 800 IU daily for adults over age 70, and 600 IU for pregnant and lactating women.4,5 The National Osteoporosis Foundation supports the National Academy of Sciences Foundation recommendation of 800 to 1,000 IU of vitamin D daily for adults over the age of 50.6 However, the 2011 Endocrine Society guidelines acknowledge that many adults over 50 years of age will need 1,500 to 2,000 IU of vitamin D daily to keep a normal blood level of vitamin D (30 ng/mL or greater).1 Considering the race, age, chronic conditions, and obesity status of patients before interpreting their vitamin D levels will help clinicians decide if their adult patients ages 50 to 70 need www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
600 IU per the IOM, 800 IU to 1,000 IU per the National Osteoporosis Foundation, or perhaps at least 1,500 IU daily per the 2011 Endocrine Society guidelines.1,4,6 Clinical judgment based on risk factors, sequela of hypovitaminosis (falls, osteoporotic fractures), and the use of supplementation at the time of serum assessment will guide the nurse practitioner (NP) in determining whom to screen and which daily dose of vitamin D to suggest. Adults found to be deficient in serum vitamin D are treated with 50,000 IU weekly of vitamin D 2 or D3 for 8 weeks and are then given maintenance therapy of 1,500 to 2,000 IU daily thereafter.1 Reassessing serum 25 (OH)D levels is traditionally done in about 3 months because the half-life of vitamin D is approximately 20 days, which causes a steady state to be reached at about 80 to 90 days after four half-lives.3,7 Clinicians should be aware that many common vitamin brands in the United States contain only 400 IU of vitamin D, which was the previously recommended daily allowance. However, supplements of vitamin D2 or D3 with 1,000, 2,000, or 5,000 IU doses are now readily available in many pharmacies.
various supplementation doses and products within the few RCTs4,10,12; and studies varying in their report of either systolic and diastolic blood (SBP, DBP) pressure values versus the use of hypertension or normotension as an endpoint.13-15 The secondary analyses explore the association of serum vitamin D with BP and all found an inverse association between BP and serum vitamin D levels.11-15 Whether elevated diastolic BP is associated with low vitamin D levels, if laboratory test changes and/or changes in normal serum values for vitamin D during previous studies affected the findings, and if the season of the year or locale of the study affected the sample’s serum vitamin D findings due to seasonal alterations of the sun’s angle to the earth or subject’s limited sun exposure are what remain in question regarding vitamin D and BP. NHANES data analyzed from 1988 to 1994 and 2001 to 2006 determined that heart rate and SBP are significantly higher in those whose serum vitamin D levels were insufficient or deficient (defined as less than 15 ng/mL).14 However, results were weakened in this trial because both NHANES III (1988 to 1994) and the 2000 to 2006 NHANES trials had serum vitamin D test assays that drifted numerically because the DiaSorin radioimmunoassay test was reformulated during that time frame.4,14 Users of NHANES data have been cautioned to not make direct comparisons
■ Vitamin D and BP Vitamin D is essential for optimal health and has many functions beyond its well-known bone effects. Vitamin D receptors (VDRs) are found within many tissues, including the vascular Vitamin D is essential for optimal health endothelium, cardiomyocytes, and the brain.4,8 Because hypertension is a risk and has many functions beyond its factor for heart disease and stroke, it is well-known bone effects. imperative that all potential contributors to these conditions, including hypertension, be thoroughly understood to decrease their incidence.9 Observational data and a very between NHANES III (1988 to 1994) data and 2000 to 2006 limited number of randomized controlled trials (RCTs) are NHANES data.19 Another secondary analysis of NHANEs beginning to show that higher vitamin D levels may be asdata (N = 3,958) was analyzed and found that vitamin D sociated with lower BP.10-12 levels were inversely associated with SBP (P < 0.001) but not significantly with DBP (P = 0.19).15 ■ Review of literature on BP and vitamin D In a prehypertensive, prediabetic sample, White adult Evidence of the association between vitamin D and BP resubjects with prehypertension had lower serum vitamin D mains unclear. There have been multiple secondary analyses than normotensive subjects.13 Another study of older White of vitamin D levels from National Health and Nutrition adult men found a threefold higher prevalence of confirmed Examination Surveys (NHANES) data.13-15 To date, only a hypertension in men with serum vitamin D levels that were within the current definition for a vitamin D deficiency few RCTs of vitamin D supplementation exist that assess state.20 Although this latter study had a strong design utilizvitamin D’s effect upon BP.10,12,16-18 The association between BP and vitamin D is likely affected and complicated by the ing manual and 24-hour ambulatory BP readings, it was following: fluctuations in normal and abnormal vitamin D weakened by the use of subjects taking antihypertensive lab values between the earlier and later NHANEs trials; use medications.20 of different serum vitamin D tests (25 OH[D]) versus 1,25 There have been five RCTs on vitamin D’s effect on BP, dihydroxyvitamin D (1,25 [OH]2D); various supplementaand one 5-year trial is underway to assess the effect of vitamin D and omega-fatty acids on hypertension and tion interventions studied (with and without calcium)10,12,16-18; www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
cancer risk.10,12,16-18,21 Three of the five RCTs evaluated have no findings of a significant association between vitamin D supplementation and BP; however, there are weaknesses in each of these trials.16-18 In the most recent RCT of the three, no significant association was found between vitamin D and BP; weaknesses included a significant dropout rate (25%) in subjects who had significantly lower vitamin D levels (P < 0.001).16 The second RCT without significant findings involved an intervention of 100,000 IU of oral vitamin D3 supplement given once in December to English residents ages 63 to 76 whose levels were measured 5 weeks later.18 A limitation might be that the 5-week follow up may not have allowed enough time for the effects of vitamin D to manifest in vascular smooth muscle.18 Another early study that found no association between vitamin D and SBP (nor DBP) was a double-blinded RCT trial that dosed subjects with only 200 IU of vitamin D daily.17 In contrast, two RCTs have found an association between vitamin D and BP. An 8-week RCT of older subjects (mean age 74) found that vitamin D with calcium was
■ Vitamin D and depression VDRs are in abundance within the brain. It is unclear if any of the functions of vitamin D in the brain may be related to major depression, although many areas rich in receptors have been shown to have abundant enzyme activity for metabolizing previtamin D into calcitriol.8 A limited number of RCTs along with other evidence are beginning to accumulate reflecting that vitamin D may be associated with depression, and this literature is explored next.22-25
■ Review of literature on vitamin D and depression Of the seven studies reviewed examining vitamin D and depression, five studies support an inverse association, while two do not.22,26-28 Within these studies, only two are doubleblinded RCTs, which had divergent findings and will be discussed first.23,27 The smaller RCT involved 128 patients ages 18 to 30 in Australia who were supplemented daily for 6 weeks with vitamin D 5,000 IU or placebo. Vitamin D provided no beneficial effects on depression scores measured by the Beck Depression Inventory. However, there were only 10 participants of 128 in this study with vitamin D insufVitamin D is readily available, making it a ficiency, which means if these subjects possible cost-effective intervention for were in both the experimental and conlowering BP or treating depression. trol groups, this would likely result in less than the statistically desirable 80% power to detect an effect. Additionally, the study ran for only 6 weeks, which is approximately half more effective than the calcium alone in suppressing SBP.12 of the 3 months needed for vitamin D to reach steady state.27 A later pilot study with three arms (placebo versus 200,000 IU D3 weekly versus calcitriol 0.5 mcg bid) demonstrated The author questioned whether adequate time had elapsed at steady state for vitamin D levels to peak and have an opan association between vitamin D and BP, showing a 9% portunity to affect Beck Depression Inventory scores. reduction in SBP versus placebo (P < 0.001) in the calcitriol In the larger, second RCT, there was an association be(D2) group.10 It is difficult to accept this latter study as tween vitamin D and depression in subjects who received robust science because it only had nine subjects with two either vitamin D doses of 20,000 IU, 40,000 IU or a placebo dropping out, and the groups varied at randomization.10 weekly for a year.23 Depression was again assessed by the However, an emerging trend of an association between higher SBP in those with lower serum vitamin D levels has Beck Depression Inventory, but this time, a statistically now been supported in two RCTs and also found observasignificant association was found between total Beck Deprestionally in multiple secondary analyses of NHANEs sion Inventory scores (P < 0.01) and scores for items 1 to 13 data.10,12,13-15 and 14 to 21 (P < 0.05).23 Findings of this second yearlong study were weakened by a 25% dropout rate, which may Further RCTs are needed at the current recommended have affected the study’s power and subsequent findings. daily doses per age to assess if vitamin D is a very inexpenThe clinical significance of a drop in a Beck Depression sive way to decrease BP, the incidence of hypertension, and Inventory score of 1 to 2 points is questionable, yet the study subsequent heart or cerebrovascular disease. While the eviwas strengthened by its yearlong intervention, which allowed dence is early and is still accumulating on vitamin D’s impact the participants to reach and then remain at steady-state on BP, the Endocrine Society in their June 2011 publication vitamin D levels. These levels may have been the reason for recommended that supplementation to prevent falls in the study’s positive findings. older adults was reasonable, but they did not yet recommend Of the remaining studies reviewed, a cross-sectional supplementation to prevent cardiovascular disease, alter trial of vitamin D and depression showed that vitamin D mood, or to improve quality of life.1
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Vitamin D: New implications for mood and blood pressure
levels were 14% lower in those with minor depression and major depressive disorder than in unaffected subjects (P < 0.001).26 Older subjects in England had an association between their vitamin D deficiency (less than 10 ng/mL [25 nmol/L]) with a Geriatric Depression Scale score that suggested depression.24 Another study found the likelihood of depression in those with deficient vitamin D (less than 20 ng/mL [50 nmol/L]) was significantly higher in comparison to those with normal vitamin D with the authors pointing out that it is still unclear if deficient vitamin D leads to or is a result of depression.25 An observational study of cardiovascular patients over 50 years of age with very low vitamin D levels (15 ng/mL [37.4 nmol/L] or less) had a nearly threefold increased risk of depression compared to those with optimal levels (greater than 50 ng/mL [125 nmol/L]).22 A secondary analysis of NHANES data from 1988 to 1994 found that in 7,970 subjects ages 15 to 39 that the likelihood for developing depression was significantly higher for those with vitamin D deficiency (defined as less than 20 ng/mL [50 nmol/L]) compared to sufficiency (30 ng/mL [75 nmol/L] or greater). 25 Despite the former NHANES analysis, another NHANES analysis of 2005 to 2006 data of 3,916 adults 20 years of age and older found no significant association between vitamin D and depression (measured by the Patient Health Questionnaire-9).28
with other known risk factors for low vitamin D, should be screened whenever possible. NPs may wish to avoid screening patients in the early fall when vitamin D levels are the highest and in winter or early spring when vitamin D levels are the lowest. Even for patients rarely outdoors, seasonal variations may occur because it is now recognized that the altered solar zenith angle in winter produces an 80% reduction in vitamin D synthesis even in Florida.2 It remains unclear if vitamin D may help patients lower their BP or improve their mood because evidence is conflicting; the Endocrine Society does not suggest that supplementation might decrease occurrence or risk of cardiovascular disease, depression, or improve quality of life.1 ■ Moving forward Research on vitamin D is being conducted at a vigorous pace. A search of the National Institutes of Health RePORT system in April 2012 revealed hundreds of studies investigating vitamin D’s link to cancer, hyperparathyroidism, multiple sclerosis, fatigue, depression, cardiovascular diseases, as well as a study funded in 2012 for $1.6 million that will assess vitamin D’s association with cardiovascular and cancer outcomes for women enrolled in the Women’s Health Study.29 As research continues with well-designed randomized controlled clinical trials, it is hoped that evidence-based decisions will be clearer as to whether vitamin D supplementation can prevent or treat hypertension and depression. Certainly, vitamin D is inexpensive and readily available so that if it were effective in lowering BP or depression, it would be a cost-effective intervention.
■ Implications for practice Many adults and children should now be routinely screened for vitamin D deficiency.1 NPs conducting annual preventive screening exams and counseling for osteoporosis should also ask patients about vitamin D intake, malabsorption syndromes, supplement Of the seven studies reviewed examining usage, sun exposure, sunscreen usage, and time spent outdoors in order to asvitamin D and depression, five studies support sess for potential vitamin D deficiency an inverse association, while two do not. states. Although controversy may exist in recommending sun exposure due to the risk of skin cancer, sensible sun exposure at midday for 5 to 30 minutes twice weekly of both In the meantime, many Americans are unaware that the arms and legs has been recommended to provide adequate recommended daily allowance of vitamin D has increased. vitamin D levels.2,3 Receiving a dose of sunlight while in a With American’s frequent sun avoidance patterns, the darker skin pigmentation of our growing minority population, bathing suit that leaves erythema 24 hours later provides increasing obesity, and much of the population living north approximately 20,000 IU of vitamin D, which does not cause of the 33rd latitude, many are at risk for vitamin D defitoxicity and may be reasonable for those at high risk of viciency. Patients are often unaware that their symptoms of tamin D insufficiency barring an increased skin cancer risk. muscle or bone pain may herald osteomalacia or, worse yet, In addition, 20,000 IU is much greater than eating a week’s bone disease with an increased risk of falls if they are vitamin worth of two daily servings of vitamin D rich foods because D deficient. The vitamin industry has been slow to revise these foods typically provide only 100 to 400 IU per serving its multivitamin supplements to include more than the (about 4,000 IU a week). previously recommended 400 IU daily. All of these factors Based upon emerging evidence, NPs should consider that make it necessary for astute NPs to be aware of the new patients who are hypertensive or depressed, particularly those www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
screening and treatment guidelines that alert providers to the many who are at risk for vitamin D deficiency and the possible sequel of their deficiency. REFERENCES 1. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1-20. 2. Holick MF. The Vitamin D Solution. New York, NY: Penguin Group. 2010:1-309 3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. 4. Ross AC, Taylor CL, Yaktine AL, et al., eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011. 5. Ross A C, Manson JE, Abrams S A, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab.2011; 96(1): 53-58. 6. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. http://nof.org/files/nof/public/content/resource/ 913/files/580.pdf. 7. Lehne, RA. Pharmacology for nursing care. 6th ed. St. Louis, Mo: Saunders. 2004: 1-1354 8. Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev. 2009;67(8):481-492. 9. Murphy SL, Xu J, Kochanek KD. Deaths: Preliminary Data for 2010. National Vital Statistics Reports, 60(4). Last modified January 11, 2012. http://www. cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. 10. Judd SE, Raiser SN, Kumari M, Tangpricha V. 1,25-Dihydroxyvitamin D3 reduces systolic blood pressure in hypertensive adults: a pilot feasibility study. J Steroid Biochem Mol Biol. 2010;121(1-2):445-447.
11. Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998(9129);352:709-710. 12. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a shortterm vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86(4):1633-1637. 13. Gupta AK, Brashear MM, Johnson WD. Prediabetes and prehypertension in healthy adults are associated with low Vitamin D levels. Diabetes Care. 2011;34(3):658-660. 14. Scragg RK, Camargo CA Jr, Simpson RU. Relation of serum 25-hydroxyvitamin D to heart rate and cardiac work (from the National Health and Nutrition Examination Surveys). Am J Cardiol. 2010;105(1):122-128. 15. Fraser A, Williams D, Lawlor DA. Associations of Serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006). PLos One. 2010;5(11):e13882. 16. Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med. 2010;267(5):462-472. 17. Pan WH, Wang CY, Li LA, Kao LS, Yeh SH. No significant effect of calcium and vitamin D supplementation on blood pressure and calcium metabolism in elderly Chinese. Chin J Physiol. 1993;36(3):85-94. 18. Scragg R, Khaw KT, Murphy S. Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. Eur J Clin Nutr. 1995;49(9):640-646. 19. Centers for Disease Control and Prevention. (2010). Revised analytical note for NHANES 2000-2006 and NHANES III (1998-1994) 25-Hydroxyvitamin D analysis. http://www.cdc.gov/nchs/data/nhanes/nhanes3/VitaminD_ analyticnote.pdf. 20. Burgaz A, Byberg L, Rautiainen S, et al. Confirmed hypertension and plasma 25(OH)D concentrations amongst elderly men. J Intern Med. 2011;269(2):211-218. 21. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-171. 22. May HT, Bair TL, Lappé DL, et al. Association of vitamin D levels with incident depression among a general cardiovascular population. Am Heart J. 2010;159(6):1037-1043. 23. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599-609. 24. Stewart R, Hirani V. Relationship between vitamin D levels and depressive symptoms in older residents from a national survey population. Psychosom Med. 2010;72(7):608-612. 25. Ganji V, Milone C, Cody MM, McCarty F, Wang YT. Serum vitamin D concentrations are related to depression in young adult US population: The Third National Health and Nutrition Examination Survey. Int Arch Med. 2010;3:29. 26. Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW. Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry. 2008;65(5):508-512. 27. Dean AJ, Bellgrove MA, Hall T, et al. Effects of Vitamin D supplementation on cognitive and emotional functioning in young adults—a randomised controlled trial. PLos One. 2011;6(11):e25966. 28. Zhao G, Ford ES, Li C, Balluz LS. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression among US adults. Br J Nutr. 2010;104(11):1696-1702. 29. Buring JE. Women’s Health Study: continued follow-up. Last modified April 17, 2012. Research Portfolio Online Reporting Tools at http://projectreporter. nih.gov/project_info_description.cfm?aid=8209207&icde=12075518&ddpar am=&ddvalue=&ddsub=&cr=64&csb=default&cs=ASC.
Janis P. Puglisi is a family nurse practitioner in primary/urgent care at General Medical Clinic, Greensboro, NC. The author is conducting dissertation research exploring the effects of vitamin D, inflammation, and blood pressure upon adults with coronary artery disease. The author has disclosed that she has no financial relationships related to this article. DOI-10.1097/01.NPR.0000437575.76024.a6
52 The Nurse Practitioner • Vol. 38, No. 12
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Abstract: This article reviews the 2011 guidelines for the evaluation, treatment, and prevention of vitamin D deficiency as well as the research literature evidencing an association between vitamin D, blood pressure and depression. Studies reveal an association between vitamin D levels and both systolic blood pressure and depression.
Photo by Aleksandar Nakic / iStock ©
By Janis P. Puglisi, APRN, FNP-BC
itamin D is receiving increased attention in the healthcare literature because of a multitude of new studies purporting its beneficial effects when serum levels are sufficient. The purpose of this article is to review the 2011 Endocrine Society Guidelines on the evaluation, treatment, prevention of vitamin D deficiency, and to summarize the evidence regarding associations between vitamin D, BP, and depression.1 Vitamin D is an essential fat-soluble vitamin obtained via dietary sources, vitamin supplementation, or skin
V
exposure to sunlight. Vitamin D is available in two forms: as vitamin D2 and vitamin D3.1 Synthesis of vitamin D from exposure to solar UVB radiation is the result of the conversion of 7-dehydrocholesterol in the skin to vitamin D3.2,3 Excessive sunlight exposure does not cause vitamin D toxicity because UVB radiation degrades any excess vitamin D3.3 Dietary food sources and supplemental sources of vitamin D are available as vitamin D2 and vitamin D3.1 Risk factors for vitamin D deficiency include decreased exposure to sunlight, the season of the year (winter),
Key words: blood pressure, depression, hypertension, vitamin D
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The Nurse Practitioner • December 2013 47
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Vitamin D: New implications for mood and blood pressure
reduced daylight (living in an area at increased distance from the equator), the use of sunscreen, darker skin pigmentation, clothing choices (covering the skin), aging, and a lack of supplementation or dietary intake of vitamin D food sources. Older adults are at very high risk for vitamin D deficiency because of a lesser ability to make vitamin D from sunlight and their often decreased sunseeking behavior. Others at risk of deficiency include children, patients who had bariatric surgery, those with fat malabsorption syndromes, hyperparathyroidism, Serum vitamin D reference ranges1,4 Lab value for 25 (OH)D
Institute of Medicine ranges
2011 Endocrine Society ranges
Deficiency
< 12 ng/mL
< 20 ng/mL
Insufficiency or inadequacy
12-20 ng/mL
21-29 ng/mL
Sufficiency
> 20 ng/mL
≥ 30 ng/mL
Vitamin D toxicity
Not available
100 ng/mL
The Endocrine Society 2011 guidelines state that “although it is not known what the safe upper value for 25(OH)D is for avoiding hypercalcemia, most studies in children and adults have suggested that the blood levels need to be above 150 ng/mL before there is any concern. Therefore, an upper limit of 100 ng/mL provides a safety margin in reducing risk of hypercalcemia.”
Screening recommendations for vitamin D deficiency1,3 Specific populations • Black and Hispanic children and adults • Pregnant and lactating women • Older adults (especially those with a history of falls) • Individuals who are institutionalized, those who frequently remain indoors, those who use daily sunscreen or cover up their skin with clothing • Obese individuals (BMI of 30 or greater) Individuals with chronic medical conditions or those taking specific medications • Bone disease (osteoporosis, osteomalacia, rickets) • Chronic kidney disease • Granulomatous diseases (sarcoidosis, berylliosis, coccidioidomycosis, histoplasmosis) • Hepatic disease • Hyperparathyroidism • Lactose intolerant • Malabsorption diseases (celiac disease, cystic fibrosis, postbariatric surgery, Crohn disease) • Medications (antiepileptic drugs, antifungal agents, antiretroviral therapy for HIV/AIDS, glucocorticoids, cholestyramine)
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chronic kidney disease, the obese, and those taking antiepileptic drugs (phenobarbital, phenytoin, carbamazepine), antifungal agents (such as ketoconazole), antiretroviral therapy for HIV/AIDS, glucocorticoids, and cholestyramine.1,2 Deficiency is common, as more than 50% of Hispanic and Black adolescents in Boston are deficient in vitamin D.1 Typical signs and symptoms of vitamin D deficiency include bone pain, muscle weakness, increased falls, fatigue, and possibly mood disorders. According to the June 2011 Endocrine Society Guidelines, vitamin D deficiency is defined as having a serum 25-hydroxyvitamin D (25 [OH]D) level less than 20 ng/mL (50 nmol/L) because this is the level necessary to maintain skeletal health.1 Vitamin D is insufficient for optimal health when between 20 to 29.9 ng/mL and is normal at values of 30 ng/mL or greater.1 (See Serum vitamin D reference ranges.) Screening is now recommended for Black and Hispanic children and adults, pregnant and lactating women, the obese (body mass index [BMI] of 30 or greater), those taking numerous medications or having various chronic medical conditions, which affect vitamin D synthesis or intestinal absorption.1 (See Screening recommendations for vitamin D deficiency.) Supplementation has been suggested for those living north of the 33rd latitude, which is parallel to Phoenix and Birmingham. In the absence of noontime sun exposure in locales north of the 33rd latitude, it would be difficult to obtain enough vitamin D from dietary sources to maintain the body’s requirement. Additionally, skin production of vitamin D is very low or missing in the winter months, making supplementation wise for individuals who will not be outside in the sun between late fall and mid-spring.1-3 The Institute of Medicine (IOM) established dietary references for calcium and vitamin D but noted that their task was not to establish serum cut points for vitamin D sufficiency. The IOM decried (prior to the 2011 Endocrine Society guidelines) that no central body had been recognized to establish useful serum clinical values.4 The IOM suggested 600 international units (IU) daily of vitamin D for children and adults 1 year of age to age 70, 800 IU daily for adults over age 70, and 600 IU for pregnant and lactating women.4,5 The National Osteoporosis Foundation supports the National Academy of Sciences Foundation recommendation of 800 to 1,000 IU of vitamin D daily for adults over the age of 50.6 However, the 2011 Endocrine Society guidelines acknowledge that many adults over 50 years of age will need 1,500 to 2,000 IU of vitamin D daily to keep a normal blood level of vitamin D (30 ng/mL or greater).1 Considering the race, age, chronic conditions, and obesity status of patients before interpreting their vitamin D levels will help clinicians decide if their adult patients ages 50 to 70 need www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
600 IU per the IOM, 800 IU to 1,000 IU per the National Osteoporosis Foundation, or perhaps at least 1,500 IU daily per the 2011 Endocrine Society guidelines.1,4,6 Clinical judgment based on risk factors, sequela of hypovitaminosis (falls, osteoporotic fractures), and the use of supplementation at the time of serum assessment will guide the nurse practitioner (NP) in determining whom to screen and which daily dose of vitamin D to suggest. Adults found to be deficient in serum vitamin D are treated with 50,000 IU weekly of vitamin D 2 or D3 for 8 weeks and are then given maintenance therapy of 1,500 to 2,000 IU daily thereafter.1 Reassessing serum 25 (OH)D levels is traditionally done in about 3 months because the half-life of vitamin D is approximately 20 days, which causes a steady state to be reached at about 80 to 90 days after four half-lives.3,7 Clinicians should be aware that many common vitamin brands in the United States contain only 400 IU of vitamin D, which was the previously recommended daily allowance. However, supplements of vitamin D2 or D3 with 1,000, 2,000, or 5,000 IU doses are now readily available in many pharmacies.
various supplementation doses and products within the few RCTs4,10,12; and studies varying in their report of either systolic and diastolic blood (SBP, DBP) pressure values versus the use of hypertension or normotension as an endpoint.13-15 The secondary analyses explore the association of serum vitamin D with BP and all found an inverse association between BP and serum vitamin D levels.11-15 Whether elevated diastolic BP is associated with low vitamin D levels, if laboratory test changes and/or changes in normal serum values for vitamin D during previous studies affected the findings, and if the season of the year or locale of the study affected the sample’s serum vitamin D findings due to seasonal alterations of the sun’s angle to the earth or subject’s limited sun exposure are what remain in question regarding vitamin D and BP. NHANES data analyzed from 1988 to 1994 and 2001 to 2006 determined that heart rate and SBP are significantly higher in those whose serum vitamin D levels were insufficient or deficient (defined as less than 15 ng/mL).14 However, results were weakened in this trial because both NHANES III (1988 to 1994) and the 2000 to 2006 NHANES trials had serum vitamin D test assays that drifted numerically because the DiaSorin radioimmunoassay test was reformulated during that time frame.4,14 Users of NHANES data have been cautioned to not make direct comparisons
■ Vitamin D and BP Vitamin D is essential for optimal health and has many functions beyond its well-known bone effects. Vitamin D receptors (VDRs) are found within many tissues, including the vascular Vitamin D is essential for optimal health endothelium, cardiomyocytes, and the brain.4,8 Because hypertension is a risk and has many functions beyond its factor for heart disease and stroke, it is well-known bone effects. imperative that all potential contributors to these conditions, including hypertension, be thoroughly understood to decrease their incidence.9 Observational data and a very between NHANES III (1988 to 1994) data and 2000 to 2006 limited number of randomized controlled trials (RCTs) are NHANES data.19 Another secondary analysis of NHANEs beginning to show that higher vitamin D levels may be asdata (N = 3,958) was analyzed and found that vitamin D sociated with lower BP.10-12 levels were inversely associated with SBP (P < 0.001) but not significantly with DBP (P = 0.19).15 ■ Review of literature on BP and vitamin D In a prehypertensive, prediabetic sample, White adult Evidence of the association between vitamin D and BP resubjects with prehypertension had lower serum vitamin D mains unclear. There have been multiple secondary analyses than normotensive subjects.13 Another study of older White of vitamin D levels from National Health and Nutrition adult men found a threefold higher prevalence of confirmed Examination Surveys (NHANES) data.13-15 To date, only a hypertension in men with serum vitamin D levels that were within the current definition for a vitamin D deficiency few RCTs of vitamin D supplementation exist that assess state.20 Although this latter study had a strong design utilizvitamin D’s effect upon BP.10,12,16-18 The association between BP and vitamin D is likely affected and complicated by the ing manual and 24-hour ambulatory BP readings, it was following: fluctuations in normal and abnormal vitamin D weakened by the use of subjects taking antihypertensive lab values between the earlier and later NHANEs trials; use medications.20 of different serum vitamin D tests (25 OH[D]) versus 1,25 There have been five RCTs on vitamin D’s effect on BP, dihydroxyvitamin D (1,25 [OH]2D); various supplementaand one 5-year trial is underway to assess the effect of vitamin D and omega-fatty acids on hypertension and tion interventions studied (with and without calcium)10,12,16-18; www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
cancer risk.10,12,16-18,21 Three of the five RCTs evaluated have no findings of a significant association between vitamin D supplementation and BP; however, there are weaknesses in each of these trials.16-18 In the most recent RCT of the three, no significant association was found between vitamin D and BP; weaknesses included a significant dropout rate (25%) in subjects who had significantly lower vitamin D levels (P < 0.001).16 The second RCT without significant findings involved an intervention of 100,000 IU of oral vitamin D3 supplement given once in December to English residents ages 63 to 76 whose levels were measured 5 weeks later.18 A limitation might be that the 5-week follow up may not have allowed enough time for the effects of vitamin D to manifest in vascular smooth muscle.18 Another early study that found no association between vitamin D and SBP (nor DBP) was a double-blinded RCT trial that dosed subjects with only 200 IU of vitamin D daily.17 In contrast, two RCTs have found an association between vitamin D and BP. An 8-week RCT of older subjects (mean age 74) found that vitamin D with calcium was
■ Vitamin D and depression VDRs are in abundance within the brain. It is unclear if any of the functions of vitamin D in the brain may be related to major depression, although many areas rich in receptors have been shown to have abundant enzyme activity for metabolizing previtamin D into calcitriol.8 A limited number of RCTs along with other evidence are beginning to accumulate reflecting that vitamin D may be associated with depression, and this literature is explored next.22-25
■ Review of literature on vitamin D and depression Of the seven studies reviewed examining vitamin D and depression, five studies support an inverse association, while two do not.22,26-28 Within these studies, only two are doubleblinded RCTs, which had divergent findings and will be discussed first.23,27 The smaller RCT involved 128 patients ages 18 to 30 in Australia who were supplemented daily for 6 weeks with vitamin D 5,000 IU or placebo. Vitamin D provided no beneficial effects on depression scores measured by the Beck Depression Inventory. However, there were only 10 participants of 128 in this study with vitamin D insufVitamin D is readily available, making it a ficiency, which means if these subjects possible cost-effective intervention for were in both the experimental and conlowering BP or treating depression. trol groups, this would likely result in less than the statistically desirable 80% power to detect an effect. Additionally, the study ran for only 6 weeks, which is approximately half more effective than the calcium alone in suppressing SBP.12 of the 3 months needed for vitamin D to reach steady state.27 A later pilot study with three arms (placebo versus 200,000 IU D3 weekly versus calcitriol 0.5 mcg bid) demonstrated The author questioned whether adequate time had elapsed at steady state for vitamin D levels to peak and have an opan association between vitamin D and BP, showing a 9% portunity to affect Beck Depression Inventory scores. reduction in SBP versus placebo (P < 0.001) in the calcitriol In the larger, second RCT, there was an association be(D2) group.10 It is difficult to accept this latter study as tween vitamin D and depression in subjects who received robust science because it only had nine subjects with two either vitamin D doses of 20,000 IU, 40,000 IU or a placebo dropping out, and the groups varied at randomization.10 weekly for a year.23 Depression was again assessed by the However, an emerging trend of an association between higher SBP in those with lower serum vitamin D levels has Beck Depression Inventory, but this time, a statistically now been supported in two RCTs and also found observasignificant association was found between total Beck Deprestionally in multiple secondary analyses of NHANEs sion Inventory scores (P < 0.01) and scores for items 1 to 13 data.10,12,13-15 and 14 to 21 (P < 0.05).23 Findings of this second yearlong study were weakened by a 25% dropout rate, which may Further RCTs are needed at the current recommended have affected the study’s power and subsequent findings. daily doses per age to assess if vitamin D is a very inexpenThe clinical significance of a drop in a Beck Depression sive way to decrease BP, the incidence of hypertension, and Inventory score of 1 to 2 points is questionable, yet the study subsequent heart or cerebrovascular disease. While the eviwas strengthened by its yearlong intervention, which allowed dence is early and is still accumulating on vitamin D’s impact the participants to reach and then remain at steady-state on BP, the Endocrine Society in their June 2011 publication vitamin D levels. These levels may have been the reason for recommended that supplementation to prevent falls in the study’s positive findings. older adults was reasonable, but they did not yet recommend Of the remaining studies reviewed, a cross-sectional supplementation to prevent cardiovascular disease, alter trial of vitamin D and depression showed that vitamin D mood, or to improve quality of life.1
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Vitamin D: New implications for mood and blood pressure
levels were 14% lower in those with minor depression and major depressive disorder than in unaffected subjects (P < 0.001).26 Older subjects in England had an association between their vitamin D deficiency (less than 10 ng/mL [25 nmol/L]) with a Geriatric Depression Scale score that suggested depression.24 Another study found the likelihood of depression in those with deficient vitamin D (less than 20 ng/mL [50 nmol/L]) was significantly higher in comparison to those with normal vitamin D with the authors pointing out that it is still unclear if deficient vitamin D leads to or is a result of depression.25 An observational study of cardiovascular patients over 50 years of age with very low vitamin D levels (15 ng/mL [37.4 nmol/L] or less) had a nearly threefold increased risk of depression compared to those with optimal levels (greater than 50 ng/mL [125 nmol/L]).22 A secondary analysis of NHANES data from 1988 to 1994 found that in 7,970 subjects ages 15 to 39 that the likelihood for developing depression was significantly higher for those with vitamin D deficiency (defined as less than 20 ng/mL [50 nmol/L]) compared to sufficiency (30 ng/mL [75 nmol/L] or greater). 25 Despite the former NHANES analysis, another NHANES analysis of 2005 to 2006 data of 3,916 adults 20 years of age and older found no significant association between vitamin D and depression (measured by the Patient Health Questionnaire-9).28
with other known risk factors for low vitamin D, should be screened whenever possible. NPs may wish to avoid screening patients in the early fall when vitamin D levels are the highest and in winter or early spring when vitamin D levels are the lowest. Even for patients rarely outdoors, seasonal variations may occur because it is now recognized that the altered solar zenith angle in winter produces an 80% reduction in vitamin D synthesis even in Florida.2 It remains unclear if vitamin D may help patients lower their BP or improve their mood because evidence is conflicting; the Endocrine Society does not suggest that supplementation might decrease occurrence or risk of cardiovascular disease, depression, or improve quality of life.1 ■ Moving forward Research on vitamin D is being conducted at a vigorous pace. A search of the National Institutes of Health RePORT system in April 2012 revealed hundreds of studies investigating vitamin D’s link to cancer, hyperparathyroidism, multiple sclerosis, fatigue, depression, cardiovascular diseases, as well as a study funded in 2012 for $1.6 million that will assess vitamin D’s association with cardiovascular and cancer outcomes for women enrolled in the Women’s Health Study.29 As research continues with well-designed randomized controlled clinical trials, it is hoped that evidence-based decisions will be clearer as to whether vitamin D supplementation can prevent or treat hypertension and depression. Certainly, vitamin D is inexpensive and readily available so that if it were effective in lowering BP or depression, it would be a cost-effective intervention.
■ Implications for practice Many adults and children should now be routinely screened for vitamin D deficiency.1 NPs conducting annual preventive screening exams and counseling for osteoporosis should also ask patients about vitamin D intake, malabsorption syndromes, supplement Of the seven studies reviewed examining usage, sun exposure, sunscreen usage, and time spent outdoors in order to asvitamin D and depression, five studies support sess for potential vitamin D deficiency an inverse association, while two do not. states. Although controversy may exist in recommending sun exposure due to the risk of skin cancer, sensible sun exposure at midday for 5 to 30 minutes twice weekly of both In the meantime, many Americans are unaware that the arms and legs has been recommended to provide adequate recommended daily allowance of vitamin D has increased. vitamin D levels.2,3 Receiving a dose of sunlight while in a With American’s frequent sun avoidance patterns, the darker skin pigmentation of our growing minority population, bathing suit that leaves erythema 24 hours later provides increasing obesity, and much of the population living north approximately 20,000 IU of vitamin D, which does not cause of the 33rd latitude, many are at risk for vitamin D defitoxicity and may be reasonable for those at high risk of viciency. Patients are often unaware that their symptoms of tamin D insufficiency barring an increased skin cancer risk. muscle or bone pain may herald osteomalacia or, worse yet, In addition, 20,000 IU is much greater than eating a week’s bone disease with an increased risk of falls if they are vitamin worth of two daily servings of vitamin D rich foods because D deficient. The vitamin industry has been slow to revise these foods typically provide only 100 to 400 IU per serving its multivitamin supplements to include more than the (about 4,000 IU a week). previously recommended 400 IU daily. All of these factors Based upon emerging evidence, NPs should consider that make it necessary for astute NPs to be aware of the new patients who are hypertensive or depressed, particularly those www.tnpj.com
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Vitamin D: New implications for mood and blood pressure
screening and treatment guidelines that alert providers to the many who are at risk for vitamin D deficiency and the possible sequel of their deficiency. REFERENCES 1. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1-20. 2. Holick MF. The Vitamin D Solution. New York, NY: Penguin Group. 2010:1-309 3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. 4. Ross AC, Taylor CL, Yaktine AL, et al., eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011. 5. Ross A C, Manson JE, Abrams S A, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab.2011; 96(1): 53-58. 6. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. http://nof.org/files/nof/public/content/resource/ 913/files/580.pdf. 7. Lehne, RA. Pharmacology for nursing care. 6th ed. St. Louis, Mo: Saunders. 2004: 1-1354 8. Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev. 2009;67(8):481-492. 9. Murphy SL, Xu J, Kochanek KD. Deaths: Preliminary Data for 2010. National Vital Statistics Reports, 60(4). Last modified January 11, 2012. http://www. cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. 10. Judd SE, Raiser SN, Kumari M, Tangpricha V. 1,25-Dihydroxyvitamin D3 reduces systolic blood pressure in hypertensive adults: a pilot feasibility study. J Steroid Biochem Mol Biol. 2010;121(1-2):445-447.
11. Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998(9129);352:709-710. 12. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a shortterm vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86(4):1633-1637. 13. Gupta AK, Brashear MM, Johnson WD. Prediabetes and prehypertension in healthy adults are associated with low Vitamin D levels. Diabetes Care. 2011;34(3):658-660. 14. Scragg RK, Camargo CA Jr, Simpson RU. Relation of serum 25-hydroxyvitamin D to heart rate and cardiac work (from the National Health and Nutrition Examination Surveys). Am J Cardiol. 2010;105(1):122-128. 15. Fraser A, Williams D, Lawlor DA. Associations of Serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006). PLos One. 2010;5(11):e13882. 16. Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med. 2010;267(5):462-472. 17. Pan WH, Wang CY, Li LA, Kao LS, Yeh SH. No significant effect of calcium and vitamin D supplementation on blood pressure and calcium metabolism in elderly Chinese. Chin J Physiol. 1993;36(3):85-94. 18. Scragg R, Khaw KT, Murphy S. Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. Eur J Clin Nutr. 1995;49(9):640-646. 19. Centers for Disease Control and Prevention. (2010). Revised analytical note for NHANES 2000-2006 and NHANES III (1998-1994) 25-Hydroxyvitamin D analysis. http://www.cdc.gov/nchs/data/nhanes/nhanes3/VitaminD_ analyticnote.pdf. 20. Burgaz A, Byberg L, Rautiainen S, et al. Confirmed hypertension and plasma 25(OH)D concentrations amongst elderly men. J Intern Med. 2011;269(2):211-218. 21. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-171. 22. May HT, Bair TL, Lappé DL, et al. Association of vitamin D levels with incident depression among a general cardiovascular population. Am Heart J. 2010;159(6):1037-1043. 23. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599-609. 24. Stewart R, Hirani V. Relationship between vitamin D levels and depressive symptoms in older residents from a national survey population. Psychosom Med. 2010;72(7):608-612. 25. Ganji V, Milone C, Cody MM, McCarty F, Wang YT. Serum vitamin D concentrations are related to depression in young adult US population: The Third National Health and Nutrition Examination Survey. Int Arch Med. 2010;3:29. 26. Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW. Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry. 2008;65(5):508-512. 27. Dean AJ, Bellgrove MA, Hall T, et al. Effects of Vitamin D supplementation on cognitive and emotional functioning in young adults—a randomised controlled trial. PLos One. 2011;6(11):e25966. 28. Zhao G, Ford ES, Li C, Balluz LS. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression among US adults. Br J Nutr. 2010;104(11):1696-1702. 29. Buring JE. Women’s Health Study: continued follow-up. Last modified April 17, 2012. Research Portfolio Online Reporting Tools at http://projectreporter. nih.gov/project_info_description.cfm?aid=8209207&icde=12075518&ddpar am=&ddvalue=&ddsub=&cr=64&csb=default&cs=ASC.
Janis P. Puglisi is a family nurse practitioner in primary/urgent care at General Medical Clinic, Greensboro, NC. The author is conducting dissertation research exploring the effects of vitamin D, inflammation, and blood pressure upon adults with coronary artery disease. The author has disclosed that she has no financial relationships related to this article. DOI-10.1097/01.NPR.0000437575.76024.a6
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