Vitamin D: Lessons from the Veterans Population

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Vitamin D: Lessons from the Veterans Population Tariq Islam, MD, Prith Peiris, MD, Rebecca J. Copeland, MD, Maria El Zoghby, MD, and Alan N. Peiris, MD, PhD Vitamin D deficiency (25(OH)D \ 20 ng/mL) is likely to be present in about 40% of veterans and is associated with much higher health care costs and service use. The prevalence of vitamin D deficiency is likely to be higher in certain subgroups such as ethnic minorities, those who are chronically ill, and nursing home residents. The lack of adequate sunlight exposure and poor dietary intake are common contributors to this deficient state. Moreover, vitamin D deficiency has also been noted in individuals taking vitamin D supplements within the recommended daily intake. To achieve a 25(OH)D value in the normal range (30–100 ng/mL), many studies indicate a much higher daily oral intake than currently recommended is needed. Inadequate vitamin D dosing may account for failure of some studies to show

a benefit. Testing for vitamin D insufficiency levels remains suboptimal and serial monitoring in veterans to assess if a vitamin D–replete state has been achieved also remains less than adequate. The lack of evidence-based guidelines for testing and monitoring has hampered optimal management of this very common condition. The cardiovascular, immunologic, anti-infective, and oncologic benefits of a vitamin D–replete state are becoming recognized. Achieving a vitamin D–replete state may prolong longevity. Achieving adequate vitamin D status in US veterans is an important health measure that should be undertaken. (J Am Med Dir Assoc 2011; 12: 257–262)

According to the US Census Bureau, there are approximately 23 million veterans and many are enrolled in the veterans health care system. In the past decade there has been an explosion in the arena of vitamin D research. The mineral aspects of vitamin D have been well characterized for decades; however, recent research has focused on the autocrine and paracrine functions of vitamin D.1 A significant portion of this research has involved veterans and in many instances has been done through the research arm of the Veterans Health Administration. Veterans have a high prevalence of vitamin D deficiency and many challenges to achieving optimal health, including educational, socioeconomic, and financial stressors and a high prevalence of posttraumatic stress disorder.2 This vitamin D deficiency appears closely aligned

with across-the-board increases in health care costs and services among veterans.3 In this article, we evaluate aspects of vitamin D deficiency relating primarily to veterans and discuss its implications for public health.

Keywords: Vitamin D; veterans

METHODS A Medline (PubMed) search was done using the keywords ‘‘Vitamin D’’ and ‘‘Veterans.’’ The initial search revealed 373 articles, which were narrowed down to a core of 33 articles based on the appearance of the keywords in either the title or abstract. Articles not directly pertaining to veterans and vitamin D were excluded. DISCUSSION

Department of Internal Medicine, East Tennessee State University, Johnson City, TN (T.I., R.J.C., ME.Z., A.N.P.); Department of Anesthesiology, Mayo Clinic, Jacksonville, FL (P.P.); Medicine Service, Mountain Home VAMC, Mountain Home, TN (A.N.P.). This material is the result of work supported with resources and the use of facilities at Mountain Home VAMC. The contents of this paper do not represent the views of the Department of Veterans Affairs or the US government. Address correspondence to Alan N. Peiris, MD, PhD, Mountain Home VAMC, Medicine Service-111, Mountain Home, TN 37684. E-mail: [email protected]

Published by Elsevier Inc. on behalf of the American Medical Directors Association DOI:10.1016/j.jamda.2010.08.004 REVIEWS

Abnormalities of vitamin D metabolism in veterans have been recognized for more than 20 years. Rudman et al in 19894 reported that fracture cases in veterans from a North Chicago Nursing Home had significantly higher 25(OH)D, but significantly lower 1,25-(OH)2-D levels. This was attributed to impaired renal production of the latter vitamin D metabolite and was associated with an excessive rate of fractures. McMurtry et al5 in 1992 described the increased prevalence of vitamin D deficiency with an associated rise in parathyroid hormone levels despite adequate calories, calcium, and vitamin D intake in veterans in a nursing home in Richmond, Islam et al 257

258 Islam et al

Table 1.

Vitamin D Studies among Veterans

Reference

Location

Rudman D, 1989

North Chicago

McMurtry CT, 1992

Sample size

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Population Characteristic

Outcome Investigated

Main Finding

153

Nursing home residents

Association of numbers of fractures with vitamin D level

Richmond, Virginia

57

Nursing home veterans

The vitamin D metabolite and nutritional status of institutionalized elderly males

Bauman WA, 1995

New York, New York

100

Veterans in New York with chronic spinal cord injury

Riley RL, 2002

Madison, Wisconsin

46

Male veterans hospitalized for hip fractures.

Relationships of serum calcium (Ca), phosphorus (PO4), albumin, alkaline phosphatase (Alk P), and parathyroid hormone (PTH) with serum 25hydroxyvitamin D (25[OH] D) in 100 subjects with chronic spinal cord injury Assessment of osteoporosis and institution of secondary prevention measures.

Cruse LM, 2006

Tampa, Florida

370

Veterans on prednisone

Assessment and treatment of glucocorticoid-induced osteoporosis

Drinka PJ, 2007

King, Wisconsin

609

Nursing home veterans

Peiris AN, 2008

Mountain Home, Tennessee

886

Veterans

Effect of various doses of vitamin D(2) and D(3), as well as ambulatory status (a surrogate for sun exposure), on 25-OH-D levels Health care costs associated with vitamin D deficiency

Impaired renal production of the latter vitamin D metabolite contributed to the excessive rate of fractures Despite apparently adequate calories, calcium, and vitamin D intake, hypovitaminosis D with compensatory PTH elevations occurred, regardless of season, in the nursing home population Secretion of PTH and the increase of circulating 1.25 (OH)2D are subject to control by negativefeedback mechanisms. Higher PTH levels may accelerate bone loss in patients with acute immobilization Male veterans with hip fractures received inadequate management for osteoporosis. Education of clinicians may improve outcomes for individuals with osteoporosis. Bone mineral density was obtained in less than half of the glucocorticoidtreated patients and less than a third were on bisphosphonates Nursing home residents should receive at least 800–1000 IU of D(3) per day in an effort to maintain optimal vitamin D levels Overall health care costs and service utilization were higher by 39% in the vitamin D–deficient group

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Akhter N, 2009

Chicago, Illinois

112

Youssef D, 2010

Mountain Home, Tennessee

52

Pepper KJ, 2009

Atlanta, Georgia

306

Vitamin D–insufficient veterans

The efficacy and safety of commonly prescribed treatment regimens

Benjamin A, 2009

Chicago, Illinois

307

African Americans veterans

Braddy KK, 2009

Hines, Illinois

To identify independent determinants of serum 25hydroxyvitamin D (25[OH] D) levels Prevalence of vitamin D deficiency/insufficiency in long-term care patients

Peiris AN, 2010

Mountain Home, Tennessee

Hall KL, 2010

Sunnybrook Health Sciences Centre, New York

Peiris AN, 2010

Mountain Home, Tennessee

2218

278

30

9447

African American veterans from the general medicine clinic Veterans

Veterans

Examined the effects of low serum 25-hydroxyvitamin D (25-OHD) on bone mineral density in African American veterans Relationship of serum 25 (OH)D levels to staphylococcal and Clostridium difficile infections

Insufficient 25(OH)D concentrations

Frequency of follow-up 25 (OH)D concentrations

Residents in a long-term care facility (LTC)

Daily average vitamin D available and consumed

Veterans

Whether seasonal bias was present for vitamin D testing among Northeast Tennessee veterans

Negative effect of vitamin D insufficiency on bone was observed only at very low levels of 25-OHD in African American veterans Vitamin D deficiency is intimately linked to adverse health outcomes and costs in veterans with staphylococcal and C difficile infections Ergocalciferol 50,000 IU 3 times weekly for 6 weeks appeared to be the most effective in achieving vitamin D sufficiency Significant negative linear association between 25 (OH)D and PTH Need to educate physicians regarding the high prevalence of vitamin D insufficiency/deficiency and need for better monitoring and treatment Veterans with vitamin D insufficiency have inadequate serial monitoring of 25(OH)D concentrations LTC residents require vitamin D micronutrient supplementation of at least 400 IU to achieve the recommended adequate intake of 600 IU Clinicians may have a seasonal bias, favoring testing for vitamin D status in the latter part of the year, however vitamin D levels were lowest at the beginning of the year

Islam et al 259

Virginia. Bauman et al6 reported in 1995 the presence of vitamin D deficiency in veterans with spinal cord injury. More recently, Kumari et al7 confirmed the presence of vitamin D deficiency in veterans. Hall et al8 found that none of the elderly patients in a veterans home met the recommended daily intake of 600 IU through dietary sources alone. Drinka et al,9 in a study of Wisconsin nursing home veterans unable to transfer independently, demonstrated that the average increase in 25(OH)D level per 100 IU of cholecalciferol in a 70-kg resident was 2.1 ng/mL versus 1.8 ng/mL for ergocalciferol and recommended nursing home residents should receive at least 800 to 1000 IU of cholecalciferol per day in an effort to maintain optimal vitamin D levels. Veterans on loop diuretics may have enhanced urinary calcium excretion and should be targeted to receive appropriate dosages of vitamin D and calcium.10 Benjamin et al11 noted a 25(OH)D level of 21.4 ng/mL in African American veterans with a prevalence of vitamin D insufficiency at 80% compared with corresponding values of 28.5 ng/mL and 53%, respectively in white veterans. Roesel12 reported the presence of vitamin D deficiency in Iraq and Afghanistan veterans with chronic musculoskeletal pain. Although the prevalence of vitamin D deficiency in veterans is high, testing for vitamin D deficiency remains suboptimal. A common perception is that vitamin D deficiency is a seasonal phenomenon. Levis et al13 concluded that the prevalence of vitamin D deficiency is considerable in adults living in Miami with only a modest increase in 25(OH)D during the summer. In a study of veterans in northeast Tennessee, the average 25(OH)D level was noted to be in the insufficient range throughout the year.14 Interestingly, testing for vitamin D in this population occurred during seasons least likely to detect a low vitamin D level, indicating that education of health care providers is paramount. Moreover, studies of veterans at several sites including a long-term care facility15 have reported inadequate monitoring of vitamin D status following diagnosis of vitamin D insufficiency. The lack of evidence-based guidelines for treatment can result in prolongation of the vitamin D deficient state or vitamin D toxicity. Inappropriate prescribing and omission of medications can occur consistently at all points of care within the Department of Veteran Affairs (VA) system.16 Pepper et al17 identified 36 different vitamin D replacement regimens. They concluded that 50,000 IU ergocalciferol 3 times weekly for 6 weeks may be the most efficacious in raising 25(OH)D levels. Anecdotal reports in veterans also support that large amounts of ergocalciferol can be used without apparent toxicity18; however, calcium intake may be a key determinant of toxicity. In a female veteran, the use of an inappropriately high dose of ergocalciferol along with switching from calcium carbonate to calcium citrate resulted in significant toxicity.19 In many instances the standard replacement of ergocalciferol does result in an improved 25(OH)D level but subsequent switching to recommended daily dosages of vitamin D such as 1000 IU often results in recurrence of the vitamin D–deficient state. This is supported by the study of veterans with spinal cord injury: dosages of 800 to 2000 IU vitamin 260 Islam et al

D daily did not sufficiently raise 25(OH)D levels and were deemed not to have clinical utility.20 There has been some controversy regarding the potency of ergocalciferol (D2) compared with cholecalciferol(D3).21 The preponderance of evidence appears to suggest that cholecalciferol is more potent than ergocalciferol,22 although both are likely to be effective therapy. In veterans with chronic kidney disease, administration of ergocalciferol has a favorable effect on parathyroid hormone (PTH) levels if therapy results in an increase in 25-hydroxyvitamin D levels.23 The lack of a clearly defined optimal range for 25(OH)D levels also provides additional challenges to clinicians. The normal range for 25(OH)D values in many laboratories is between 30 and 100 ng/mL. Studies of humans with extensive sun exposure may result in values as high as 90 ng/mL24 and similar exposure in small mammals can result in much higher values.25 Bikle1 has proposed that, given the newly discovered actions of vitamin D, reconsideration of physiologic requirements is needed. Prior doses were geared to preventing rickets and not for optimal health. Vieth26 demonstrated that using dosages as large as 4000 IU is associated with a sense of well-being not seen with smaller dosages. Recent publications have reported dosages of cholecalciferol in excess of 10,000 IU daily for several months without evidence of toxicity in patients with multiple sclerosis.27 Current evidence indicates that many patients with osteoporosis receive inadequate vitamin D supplementation.28 In many veterans, associated glucocorticoid use accentuates bone loss. Cruse et al,29 in a study of veterans in Tampa, Florida, found that calcium and vitamin D were given to only half of the patients and bone mineral density testing was performed or ordered in less than half of the glucocorticoidtreated patients. In a study of veterans in Madison, Wisconsin, Riley et al30 reported only a third of veterans with hip fractures had documentation of calcium or multivitamin supplementation. They concluded that inadequate evaluation and treatment for osteoporosis was present despite the presence of recurrent fractures. In a study of African American inner-city veterans in Chicago, Akhter et al31 noted that the negative effect of vitamin D insufficiency on bone was observed only at very low levels of 25(OH)D, suggesting that the African American male skeleton is relatively resistant to the effects of secondary hyperparathyroidism. An increasing number of publications indicate that vitamin D has a powerful antimicrobial action through a variety of mechanisms including antimicrobial peptides such as defensin and cathelicidin.32 In veterans from northeast Tennessee, infections with methicillin-sensitive Staphlycoccus aureus and Clostridium difficile were more likely to be protracted and costly in vitamin D–deficient patients.33 No conclusions could be drawn regarding methicillin-resistant Staphylococcus aureus because of lack of concomitant vitamin D level availability. No place exemplifies the survival benefits of innate immunity in critically ill patients more than intensive care units. In veterans with vitamin D insufficiency in northeast Tennessee, intensive care admissions were more likely to be associated with higher mortality and longer JAMDA – May 2011

stays.34 Table 1 summarizes the results of vitamin D studies in veterans. Vitamin D deficiency has been linked to increased risk of multiple cancers. The antiproliferative effects of vitamin D3 is well established.35 Vitamin D use was associated with reduced risk of colonic neoplasia in a group of asymptomatic veterans.36 Many cancer patients show defects in immune competence. In a study of patients with head and neck cancer, vitamin D3 reduced the presence of immune suppressive CD34(1) cells and improved immune competence.37 In addition to potential anti-cancer effects, treatment of vitamin D deficiency may help ameliorate bone pain from metastatic cancer and improve muscle strength.38 A plethora of beneficial effects on the cardiovascular system have emerged linked to adequate vitamin D reserves.39 Judd et al,40 in a study of veterans in Atlanta, noted that active vitamin D therapy over the short term may ameliorate blood pressure. Statins are very commonly used medications among veterans and myopathy may be more common in vitamin D–deficient patients.41 Grimes42 has postulated that statins may work through activation of vitamin D receptors. Vitamin D deficiency along with renal impairment are common reasons for elevated parathyroid hormone levels. In vitamin D–deficient veterans in Salem, Virginia, Kovesdy et al43 found that treatment with calcitriol appears to be associated with significantly greater survival in patients with chronic kidney disease (CKD) not yet receiving dialysis. Similarly, Shoben et al,44 using a veterans database, reported oral calcitriol use was associated with lower mortality in nondialysis patients with CKD. Given the evidence that vitamin D supplementation may decrease all-cause mortality in adults and older people,45 maintaining a vitamin D–replete state has some importance. We may be on the cusp of discovering some profound costeffective health benefits of a vitamin D–replete state, although more prospective studies are needed to confirm the health benefits seen in many cross-sectional studies. The threshold for testing for vitamin D deficiency may need to be lowered and health providers educated on the criteria for testing and monitoring of this important hidden pandemic among veterans and the civilian population. The development of guidelines for testing, monitoring, and treating both acute and chronic vitamin D–deficient states needs urgent attention. Given the current preponderance of evidence indicating multiple health benefits with minimal risks, we propose an intensive effort be made for modest vitamin D replacement to achieve values in the normal range. Recent recommended increases to 1000 IU daily is a step in the right direction46; however, this value may not adequately replace vitamin D values in a significant number of patients. Vitamin D receptor polymorphisms may contribute to susceptibility to certain diseases through changes in sensitivity to vitamin D3.47 Therefore, there is a need to customize individual dosages by factoring in weight, race, sunlight exposure, age, and renal function and adjust the dosage through serial monitoring. It should be noted that patients with sarcoidosis, primary hyperparathyroidism may not be suitable for routine vitamin D replacement. REVIEWS

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25. Teixeira DS, Castro LC, Nobrega YK, et al. 25-hydroxy-vitamin D levels among Callithrix penicillata primate species raised in captivity. J Med Primatol 2010;39:77–82. 26. Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J 2004; 3:8. 27. Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74: 1852–1859. 28. Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215–3224. 29. Cruse LM, Valeriano J, Vasey FB, Carter JD. Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men. J Clin Rheumatol 2006;12:221–225. 30. Riley RL, Carnes ML, Gudmundsson A, Elliott ME. Outcomes and secondary prevention strategies for male hip fractures. Ann Pharmacother 2002;36:17–23. 31. Akhter N, Sinnott B, Mahmood K, et al. Effects of vitamin D insufficiency on bone mineral density in African American men. Osteoporos Int 2009;20:745–750. 32. Zasloff M. Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J Am Soc Nephrol 2007;18:2810–2816. 33. Youssef D, Bailey B, El Abbassi A, et al. Healthcare costs of Staphylococcus aureus and Clostridium difficile infections in veterans: Role of vitamin D deficiency. Epidemiol Infect 2010;138:1322–1327. 34. McKinney JD, Balley BA, Garrett LH, Peiris P, et al. Relationship between vitamin D status and ICU outcomes in veterans. J Am Med Dir Assoc 2010. doi:10.1016/j.jamda.2010.04.004. 35. Love-Schimenti CD, Gibson DF, Ratnam AV, Bikle DD. Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells. Cancer Res 1996;56:2789–2794.

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36. Lieberman DA, Prindiville S, Weiss DG, Willett W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003;290:2959–2967. 37. Lathers DM, Clark JI, Achille NJ, Young MR. Phase IB study of 25-hydroxyvitamin D(3) treatment to diminish suppressor cells in head and neck cancer patients. Hum Immunol 2001;62:1282–1293. 38. Van Veldhuizen PJ, Taylor SA, Williamson S, Drees BM. Treatment of vitamin D deficiency in patients with metastatic prostate cancer may improve bone pain and muscle strength. J Urol 2000;163:187–190. 39. Pilz S, Tomaschitz A, Drechsler C, et al. Vitamin D deficiency and myocardial diseases. Mol Nutr Food Res 2010;54:1103–1113. 40. 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;121:445–447. 41. Bell DS. Resolution of statin-induced myalgias by correcting vitamin D deficiency. South Med J 2010;103:690–692. 42. Grimes DS. Are statins analogues of vitamin D? Lancet 2006;368: 83–86. 43. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med 2008;168:397–403. 44. Shoben AB, Rudser KD, de Boer IH, et al. Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol 2008;19: 1613–1619. 45. Simon JA. Review: Vitamin D supplementation decreases all-cause mortality in adults and older people. Evid Based Med 2008;13:47. 46. Dawson-Hughes B. Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am J Clin Nutr 2004;80:1763S–1766S. 47. Halsall JA, Osborne JE, Pringle JH, Hutchinson PE. Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and nonfamilial susceptibility in psoriasis. Pharmacogenet Genomics 2005;15: 349–355.

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