Clinical Review

How much vitamin D should you recommend to your nonpregnant patients?

OBG Manag. 2011 July;23(7):44-53

	Hear Dr. Szmuilowicz discuss treatment recommendations

References

1. Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: National Academies Press; 2011.

2. Ross AC, Manson JE, Abrams SA, 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.

3. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364(3):248-254.

4. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21(7):1151-1154.

5. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.

6. Sai AJ, Walters RW, Fang X, Gallagher JC. Relationship between vitamin D parathyroid hormone, and bone health. J Clin Endocrinol Metab. 2011;96(3):E436-446.

7. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr. 2008;88(2):558S-564S.

8. Jackson RD, LaCroix AZ, Gass M, et al. Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.

9. Papadimitropoulos E, Wells G, Shea B, et al. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):560-569.

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. Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008;149(4):242-250.

12. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep). 2009;(183):1-420.

13. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer—ready for prime time? N Engl J Med. 2011;364(15):1385-1387.

14. Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77(12):903-910.

15. The Forum at Harvard School of Public Health. Boosting Vitamin D: Not enough or too much? The Andelot Series on Current Science Controversies. http://www.hsph.harvard.edu/forum/boosting-vitamin-d-not-enough-or-too-much.cfm. Published March 29 2011. Accessed April 22, 2011.

16. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab. 2011;96(4):981-988.

17. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96(3):E447-452.

18. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93(3):677-681.

19. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington DC: National Osteoporosis Foundation; 2010. http://www.nof.org/professionals/clinical-guidelines. Accessed June 7, 2011.

20. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.

21. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):81-93.

22. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629-1637.

How should vitamin D insufficiency be defined?

Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.

Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.³ Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,^3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.

The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.^1,3

The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,^4,5 although this threshold has varied substantially across studies.⁶

How prevalent is vitamin D insufficiency?

Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20Â ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.⁷

The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20Â ng/mL.

The data on vitamin D insufficiency and skeletal health

Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.

Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.⁸ However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,⁹ nonvertebral,¹⁰ and hip fractures.¹⁰

Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:

A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.¹¹
A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.¹²

After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.

TABLE 2

Calcium and vitamin D dietary reference intakes for adults, by life stage

Life stage (gender)	Calcium		Vitamin D
Life stage (gender)	RDA (mg/d)	Tolerable upper intake level (mg/d)*	RDA (IU/d)	Serum 25OHD level (ng/mL) (corresponding to the RDA)^†	Tolerable upper intake level (IU/d)*
19–50 yr (male and female)	1,000	2,500	600	20	4,000
51–70 yr (male)	1,000	2,000	600	20	4,000
51–70 yr (female)	1,200	2,000	600	20	4,000
71+ yr (male and female)	1,200	2,000	800	20	4,000
Adapted from: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab. 2011;96(1):53–58. RDA = Recommended Dietary Allowance, 25OHD=25-hydroxyvitamin D * The tolerable upper intake level is the threshold above which is a risk of adverse events. The upper intake level is not intended to be a target intake. There is no consistent evidence of greater benefit at intake levels above the RDA. The serum 25OHD level corresponding to the upper intake level is 50 ng/mL. ^† Measures of the serum 25OHD level corresponding to the RDA and covering the requirements of at least 97.5% of the population.

The data on vitamin D insufficiency and nonskeletal outcomes

Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.³ However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.¹³ Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.¹⁴