No longer debating vitamin D supplementation, now debating need for testing first – April 2013

Am Fam Physician. 2013 Apr 15;87(8)
Should Family Physicians Screen for Vitamin D Deficiency?

Yes: Targeted Screening in At-Risk Populations Is Prudent

LEIGH M. ECK, MD, University of Kansas Medical Center, Kansas City, Kansas

Vitamin D is critical for bone mineralization.1 Over the previous decade, vitamin D deficiency has received significant media attention for its association with many adverse health outcomes beyond bone health, including cancer, autoimmune diseases, infections, diabetes mellitus, and cardiovascular health.2 Because of this attention, there has been a notable increase in screening for vitamin D deficiency.3

Serum levels of vitamin D, a prohormone synthesized in the skin, are influenced by a multitude of factors, including sun exposure, skin pigmentation, age, adiposity, and dietary intake. The dominant function of vitamin D in its active hormonal form (1,25-dihydroxyvitamin D) is to maintain calcium and phosphate homeostasis.4 Measurement of serum 25-hydroxyvitamin D levels is the best current measure of vitamin D status.5

With the release of the Institute of Medicine's (IOM) report on dietary intake for calcium and vitamin D in November 2010, enthusiasm for assessing patients' vitamin D status for nonskeletal outcomes was dampened.6 In this report, the IOM examined outcomes other than bone health, including cancer, cardiovascular disease, diabetes, immune response, and reproductive outcomes, and determined that the existing science does not sufficiently support vitamin D screening for the prevention of these conditions.6 However, the IOM report also clearly substantiated the importance of vitamin D in a composite end point of bone health, specifically for calcium absorption, calcium retention, and increased bone mineral density, in addition to the prevention of rickets, osteomalacia, and fractures.

Soon after the IOM report was released, the Endocrine Society released a clinical practice guideline for the evaluation, prevention, and treatment of vitamin D deficiency, with an emphasis on caring for patients at risk of deficiency.7 Some risk factors for vitamin D deficiency include7:

• Black race and Hispanic ethnicity
• Body mass index greater than 30 kg per m2
• Chronic kidney disease
• Granuloma-forming disorders
• Hepatic failure
• Hyperparathyroid syndrome
• Malabsorption syndromes
• Medication use (e.g., antiseizure medications, glucocorticoids, AIDS medications, antifungals, cholestyramine [Questran])
• Older age with history of falls or nontraumatic fractures
• Osteomalacia
• Osteoporosis
• Pregnancy and lactation
• Rickets
• Some lymphomas

Most of these factors put patients at risk of osteoporosis. Given the role of vitamin D in bone mineralization,1 patients who are at risk of or who have osteoporosis should be considered as candidates for vitamin D screening. Although emerging data on the role of vitamin D in extraskeletal outcomes, such as autoimmunity, cancer, and cardiovascular disease, make it tempting to screen for deficiency in a broader population, large randomized controlled trials and dose response data are still underway.

In addition to the screening dilemma, there has been disagreement in recent reports on the target vitamin D level for optimal bone health.6,7 The IOM suggests that a 25-hydroxyvitamin D level of 20 ng per mL (50 nmol per L) is sufficient for bone health, based on integrated measures of calcium absorption, bone mineral density, osteomalacia, and rickets.6 However, based on iliac crest biopsy data,8 as well as two meta-analyses studying anti-fracture efficacy,9,10 the Endocrine Society guidelines recommend a 25-hydroxyvitamin D level of at least 30 ng per mL (75 nmol per L).7 Data from the National Health and Nutrition Examination Survey found that increased hip bone mineral density was associated with higher serum 25-hydroxyvitamin D levels.11 This was observed in younger and older adults, as well as in persons of different ethnic and racial backgrounds.

Although it is not time for general population-based screening for vitamin D deficiency, this issue will continue to develop. The extraskeletal benefits of vitamin D may prove scientifically sound in larger randomized controlled trials, resulting in future population-based screening. Until then, we should focus on screening populations at risk of or who have osteoporosis.

Address correspondence to Leigh M. Eck, MD, at leck2 at kumc.edu. Reprints are not available from the author.

Author disclosure: No relevant financial affiliations.

REFERENCES

• 1. Smith R, Dent CE. Vitamin D requirements in adults. Clinical and metabolic studies on seven patients with nutritional osteomalacia. Bibl Nutr Dieta. 1969;13:44–45.
• 2. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281.
• 3. Marcus MB. Vitamin D tests soar as deficiency, diseases linked. USA Today. July 13, 2008. http://www.usatoday.com/news/health/2008-07-13-vitamin-d-tests_N.htm. Accessed August 9, 2012.
• 4. Holick MF. Vitamin D: Physiology, Molecular Biology, and Clinical Applications. Totowa, N.J.: Humana Press; 1999.
• 5. Brannon PM, Yetley EA, Bailey RL, Picciano MF. Overview of the conference “Vitamin D and Health in the 21st Century: an Update.” Am J Clin Nutr. 2008;88(2):483S–490S.
• 6. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D . Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, DC: National Academies Press; 2011.
• 7. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline published correction appears in J Clin Endocrinol Metab. 2011;96(12):3908. J Clin Endocrinol Metab. 2011;96(7):1911–1930.
• 8. Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010;25(2):305–312.
• 9. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–2264.
• 10. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551–561.
• 11. Bischoff-Ferrari HA, Dietrich T, Oray EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004;116(9):634–639.

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No: Screening Is Unnecessary, and Routine Supplementation Makes More Sense

COLIN KOPES-KERR, MD, Touro University College of Osteopathic Medicine, Vallejo, California

There are numerous problems with regularly measuring serum vitamin D levels to assess for deficiency. 1 One issue is the lack of standardization in the screening process. The accepted test is to measure levels of 25-hydroxyvitamin D because of its half-life of three weeks. However, there are six commonly used assay techniques, none of which are standardized. One study that examined the methodology and interpretation of vitamin D measurement set a lenient target requiring that laboratories obtain only 80 percent of their results within 30 percent of the all-laboratory trimmed mean (i.e., an average that removes a small percentage of the largest and smallest values before calculating the mean); only 59 percent of surveyed laboratories could meet this standard.2 Measuring vitamin D levels is also expensive, costing between $50 and $220 per test in commercial laboratories for patients without insurance.

Another challenge is that the level of 25-hydroxy-vitamin D that should be considered normal is unclear. The Institute of Medicine 3,4 and the Endocrine Society 5 announced that levels less than 20 ng per mL (50 nmol per L) are considered deficient, which is lower than in previous guidelines. The Endocrine Society also defined insufficiency as less than 30 ng per mL (75 nmol per L), and levels greater than 30 ng per mL are considered sufficient.5 In the largest study to date, 1,917 men and women were followed for 6.7 years to determine clinical outcomes (fractures) related to serum 25-hydroxyvitamin D levels. The adjusted relative risk for hip fractures was 0.64 among persons with 25-hydroxyvitamin D levels greater than 25 ng per mL (62.4 nmol per L) compared with those who had lower levels.1 This is roughly consistent with the Institute of Medicine and Endocrine Society guidelines. A German study found that pathologic demineralization of bone occurred in patients with serum 25-hydroxyvitamin D levels less than 30 ng per mL.6 A recent guideline from the European Menopause and Andropause Society defines adequate plasma 25-hydroxyvitamin D levels to be between 30 and 90 ng per mL (75 and 225 nmol per L), because these levels are associated with stable parathyroid hormone secretion and intestinal calcium absorption.7 The association of 25-hydroxyvitamin D levels with other morbid outcomes linked to vitamin D deficiency or insufficiency have not been adequately evaluated.

Another problem with vitamin D screening is that treatment implications are unclear. A physician would, presumably, give supplemental oral vitamin D to patients with low levels of 25-hydroxyvitamin D, but the nonlinear pharmacokinetics of different forms of vitamin D are not well defined, and there are multiple confounding factors. These factors include

• calcium intake,
• seasonal variations of 25-hydroxyvitamin D levels,
• sun exposure,
• air pollution levels,
• exercise,
• obesity (resistance to standard doses of vitamin D),
• comorbid conditions, and
• medications.

No study has demonstrated that the measurement of serum 25-hydroxyvitamin D levels offers outcome benefits over clinical assessment alone. Although observational studies suggest an association between lower vitamin D levels and systemic non-bone disease, such as cancer and heart disease, there are many other possible explanations. For example, persons with chronic disease may be less active, less likely to get sun exposure, and more likely to smoke and struggle with obesity. To date, randomized controlled trials have not found that vitamin D supplementation improves any of these clinical outcomes.8

Finally, there is the issue of cost-effectiveness. The only published cost-analysis of 25-hydroxyvitamin D testing concluded that if 10 percent or more of screening test results showed deficient levels that required intervention, then testing would be more cost-effective than universal supplementation without screening.2 The Endocrine Society has issued a formal recommendation against any form of individual vitamin D screening.5 British Columbia's Medical Services Commission issued a similar guideline in 2010.9 Many experts, despite the lack of clinical trial evidence, have suggested that routine vitamin D supplementation alone, without routine testing, is the superior clinical strategy because it is cheaper, easier to implement, and more efficient.10,11 The recent U.S. Preventive Services Task Force guideline on vitamin D and calcium supplementation calls into question, based on a lack of quality evidence, the value of routine supplementation and casts further doubt on any policy of routine testing of vitamin D levels.12 Although the evidence remains incomplete, these issues argue strongly against screening for serum 25-hydroxyvitamin D levels as an interim strategy.

Colin Kopes-Kerr, MD, is an assistant medical editor of American Family Physician.
Address correspondence to Colin Kopes-Kerr, MD, at colin.drlifestyle.kopeskerr at gmail.com. Reprints are not available from the author.
Author disclosure: No relevant financial affiliations.

REFERENCES

• 1. Isenor JE, Ensom MH. Is there a role for therapeutic drug monitoring of vitamin D level as a surrogate marker for fracture risk? Pharmacotherapy. 2010;30(3):254–264.
• 2. Carter GD, Carter CR, Gunter E, et al. Measurement of vitamin D metabolites: an international perspective on methodology and clinical interpretation J Steroid Biochem Mol Biol. 2004;89–90(1–5):467–471.
• 3. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Washington, DC: National Academies Press; 2011.
• 4. McMillan A, Hicks J, Isabella C, Higa GM. A critical analysis of the (near) legendary status of vitamin D. Expert Rev Endocrinol Metab. 2012;7(1):103–119.
• 5. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline published correction appears in J Clin Endocrinol Metab. 2011;96(12):3908. J Clin Endocrinol Metab. 2011;96(7):1911–1930.
• 6. Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010;25(2):305–312.
• 7. Péréz-López FR, Brincat M, Erel CT, et al. EMAS position statement: vitamin D and postmenopausal health. Maturitas. 2012;71(1):83–88.
• 8. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: systematic review of health outcomes. Evidence Reports/Technology Assessments, no. 183. Rockville, Md.: Agency for Healthcare Research and Quality; 2009. http://www.ncbi.nlm.nih.gov/books/NBK32611/#ch3.s2. Accessed February 2, 2013.
• 9. Medical Services Commission. Vitamin D testing protocol. Victoria, British Columbia, Canada: British Columbia Medical Services Commission; October 1, 2010. http://www.ngc.gov/content.aspx?id=24511. Accessed December 17, 2011.
• 10. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S–1086S.
• 11. Prentice A. Vitamin D deficiency: a global perspective. Nutr Rev. 2008;66(10 suppl 2):S153–S164.
• 12. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827–838.

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See also Vitamin D Life

• To (Vitamin) D or Not to D - That Is the Question – Endocrinology conf. debate April 2013
• Should we be giving enhanced vitamin D intakes to all - Debate Dec 2011
• Low cost vitamin D Blood Tests
• All items in category Test for D 141 items
  Many on variation between tests: different days, different testing methods
• No vitamin D test needed before supplementing (typically) – April 2014