Implications for 25-Hydroxyvitamin D testing of public health policies about the benefits and risks of Vitamin D fortification and supplementation

Figures & data

Table I. Clinical trials of vitamin D3 supplementation > 800 IU/day (> 20 μg/day) and the attributable benefits and risks.

Clinical trial	Study subjects	Treatment dose and duration	Primary outcome	Treatment effect (a secondary outcome if different from the primary one)	Type of control (double-blind unless stated otherwise)	Control treatment S-25(OH)D nmol/L mean (SD) or median (interquartile range)		Primary outcome improved with vitamin D	A secondary outcome improved	Adverse effect attributed to treatment
Aloia 2010 [6]	Men and women ages 20–80	4,000 IU/day for 4 months with or without 1,200 mg calcium	Characterize interaction of calcium and vitamin D on bone-turnover markers	No effect of vitamin D on PTH or bone turnover markers. Calcium alone lowered these.	Double placebo, without calcium or vitamin D	66 (24)	112 (30) (active D, placebo Ca group)	No	No	None
Amir 2010 [7]	Women with metastatic breast cancer	10,000 IU/day for 4 months	Overall pain scores	No effect on overall pain or bone turnover markers, but significantly fewer pain sites	Single-arm trial	70 (19–169)	162 (74–226)	No	Yes	None
Burton 2010 [8]	Patients with multiple sclerosis	Average 14,000 IU/day over 12 months (doses ranged up to 40,000 IU/day)	Safety and exploratory outcomes	Lower risk of progression of disability score	Open label untreated group (many took up to 4,000 IU/day vitamin D)	83 (27)	179 (76), at 12 months (varied through study)	NA since Phase 1–2 clinical trial.	Yes	None
El-Haj Fuleihan 2006 [9]	Pre-menarcheal girls	2,000 IU/day for 12 months	Bone density	Greater gains in hip and vertebral bone density, and lean body mass	Placebo	27 (15)	70 (23)	Yes	Yes	None
Hitz 2007 [10]	Hip-fracture patients	1,400 IU/day plus 1,200 mg calcium for 12 months	Bone density	Improved lumbar spine BMD	200 IU vitamin D only	53 (17)	82 (19)	Yes	No	None
Hitz 2007 [10]	Patients with lower-extremity fracture	1,400 IU/day plus 1,200 mg calcium for 12 months	Bone density	Improved lumbar spine BMD	200 IU vitamin D only	77 (18)	90 (24)	Yes	No	None
Jorde 2008 [11]	Adults wit BMI > 28	weekly 20,000 IU or 40,000 IU vs placebo for 1 yr	Weigh loss	Lower (improved] Beck Depression Index	placebo group	50.0 (20–100)	88 (51–162) and 112 (47–193)	NA	Yes	None
Jorde 2010 [12]	Same as above, Jorde 2008	Weekly 20,000 IU or 40,000 IU vs placebo for 1 yr	Cardiovascular and diabetes outcomes	No effect	Placebo group	60 (22)	101 (21) or 140 (34)	No	No	None
Lappe 2007 [13]	Women over age 65	1,100 IU/day, plus 1000 mg/day calcium, 4 yrs	Bone density	Lower rates of new cancer diagnosis	Placebo	71 (20)	96 (21)	NA	Yes	None
Martineau 2011 [14]	Tuberculosis		Time to sputum conversion					Yes (for a subgroup]	No	None
Mitri 2011 [15]	BMI 25–40 and glucose intolerance early diabetes	2,000 IU/d for 16 wk	Beta-cell function	Improved beta cell function	Double blind with or without calcium	46 (19)	77 (20)	Yes	No	None
Mocanu 2009 [16]	Nursing-home residents	5,000 IU/day for 12 months, single-arm study	Bone density	Increase in bone density at both in hip and vertebral spine	Baseline of same group	29 (20–36)	125 (104–150)	Yes	No	None
Nagpal 2009 [17]	Men, middle aged centrally obese	120,000 IU vit D3 every wk for 6 wks (8571 IU/d for 6 wk)	Insulin responsiveness	Improved oral glucose insulin sensitivity	Double-blind placebo	30 (13)	72 (27)	Yes	None	None
Nursyam 2006 [18]	Pulmonary tuberculosis patients	10,000 IU/day for 6 weeks	TB Sputum Clearance	Radiological improvement	Placebo group	Not measured	Not measured	Yes	Yes	None
Saunders 2010 [19]	Women > 70yr at risk of fracture	Once each year, a bolus dose of 500,000 IU for 4 yr	Falls and fractures both increased (worsened)	No secondary outcomes,	Double-blind placebo	49 (40–63)	49 (40–63)	No, greater falls and fractures intreated arm	None	Yes, increased falls and fracture
Smith 2009 [20]	Men and women through the South Pole winter	2,000 IU/day or 1,000 IU/day for 5 months	Effect on serum 25(OH]D	NA	Group receiving 400 IU/day	57 (18)	71 (23)	NA	NA	None
Stubbs 2010 [21]	End-stage renal disease	50,000 IU/wk for 8 wk but adjusted so 25(OH]D was 112–150 nM	Cytokine concentrations	Lower inflammatory cytokines	Single-arm trial	35	135	Yes		None
Urashima 2010 [22]	School children 6–15y	1,200 IU/day for 4 months through winter	Incidence of influenza A	Lower risk of influenza A and lower risk of asthma attacks	Placebo	Not measured	Not measured	Yes	Yes	None
Vieth 2004 [23]	Well thyroid clinic outpatients	4,000 IU/day for 3 months and 15 months	Wellbeing and mood in February	Wellbeing scores improved into winter	Lower dose group, 600 IU/d	79 (30)	112 (41)	Yes	No	None
von Hurst 2009 [24]	Insulin resistant Asian women	4,000 IU/day vs 600 IU/day for 6 months	Insulin responseiveness	Improved insulin responsiveness vs placebo	Placebo group	21 (11–40)	75 (50–84)	Yes	No	None

Figure 1. Vitamin D intake from food alone (Top panel) and from food plus dietary supplements (Bottom panel) in Canada. These data on vitamin D consumption in Canada, which has relatively high levels of food fortification (Top) and consumption of vitamin supplements (Bottom, which shows the total of food plus supplements) shows that most of the population does not attain the RDA intake for vitamin D. These data were obtained from the Canadian Community Health Survey - HS - 2004 - Cycle 2.2, which collected information from over 35,000 respondents of all ages from across Canada residing in private households [27]. The dashed line in each panel indicates the adult RDA (600 IU/day; 15 μg/day) according to the IOM, and that the median intakes are consistently well below the RDA for all segments of the population.

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Burton JM, Kimball S, Vieth R . A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74:1852–9.

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El-Hajj Fuleihan G, Nabulsi M, Tamim H . Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab 2006;91:405–12.

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Hitz MF, Jensen JE, Eskildsen PC. Bone mineral density and bone markers in patients with a recent low-energy fracture: effect of 1 y of treatment with calcium and vitamin D. Am J Clin Nutr 2007;86:251–9.

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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;264:599–609.

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Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol 2010;171:903–8.

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Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586–91.

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Martineau AR, Timms PM, Bothamley GH . High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011;377:242–50.

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Mitri J, wson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 2011;94:486–94.

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Mocanu V, Stitt PA, Costan AR . Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving. Am J Clin Nutr 2009;89:1132–7.

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Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med 2009;26:19–27.

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Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 2006;38:3–5.

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Sanders KM, Stuart AL, Williamson EJ . Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303: 1815–22.

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Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during Antarctic winter. Am J Clin Nutr 2009;89:1092–8.

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Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 2010;21:353–61.

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Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010;91:1255–60.

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Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 μg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J 2004;3:8.

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von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr 2009;1–7.

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