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Review of Vitamin D trials - Grant Jan 2012

This web page consists of 3 sections

  1. Summary table of Vitamin D Clinical Trials ( in English)
  2. References for every entry in the summary table (that is, the references are a superset of the table)
  3. Abstracts include all but two of the entries in the summary table, as well as items not in the summary table


There are no hyperlinks between the table entries and the references, abstracts
If you want to get more information on an item in the table you will need to search for the name of one of the authors and find the correct year.
First: Highlight author
- FireFox: hit cntrl F (control + F key at the same time), then down arrow in lower left of screen
- Chrome (with efTwo add-on loaded) hit F2 key

CLICK HERE for Nov 2012 update

See also by Dr. Grant

- - - - - - - - - - - - - - - - - - - - - - - - - - -

William B. Grant, Ph.D.

Sunlight, Nutrition, and Health Research Center

P.O. Box 641603

San Francisco, CA 94164-1603, USA

www.sunarc.org

wbgrant@infionline.net


This is a preliminary summary of what has been demonstrated with vitamin D supplementation in randomized controlled trials (RCTs). If I’ve missed any important studies other than for falls and fractures, please let me know.


Since many early RCTs did not use more than 400 IU/d vitamin D3, they did not find any beneficial effects. The Institute of Medicine did not find any RCTs that they wanted to accept for any health outcome other than beneficial effects for bones [Chung, 2009, 2011; Ross, 2011].



Table 1. Summary of findings from RCTs with vitamin D

Outcome

Conditions

Finding

Reference

All cause mortality

Mean oral in take 528 IU/d

RR = 0.93 (95% CI, 0.87-0.99)

Autier and Gandini, 2007


daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention

(HR) = 0.93; 95% confidence interval (CI) = 0.85-1.02]

Avenell, epub

Atopic dermatitis



Sidbury, 2008

Bone loss in winter

oral cholecalciferol (500 IU/day) and calcium (500 mg/day) during the winter months

In the subjects receiving oral vitamin D3 and calcium, lumbar and femoral BMD increased significantly (lumbar spine: +0.8%, p = 0.04 versus year 1; femoral neck: +0.1%, p = 0.05 versus year 1), whereas controls continued to lose bone (intervention group versus control group: lumbar spine, p = 0.03; femoral neck, p = 0.05).

Meier, 2004

Cancer, All

1100 IU/d, 1450 mg/d calcium

When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group.

Lappe, 2007


daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention

cancer mortality (HR = 0.85; 95% CI = 0.68-1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92-1.25)

Avenell, epub

Breast, colorectal cancer

400 IU/d vitamin D3, 1500 mg/d or placebo

In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).

Bolland, 2011

Cardiometric

In meta-analyses of 10 trials

supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, -1.9 mm Hg [CI, -4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, -0.1 mm Hg [CI, -0.7 to 0.5 mm Hg]).

Pittas, 2010

Cardiovascular

Vitamin D supplementation during weight loss

more pronounced decrease occurred in the vitamin D group than in the placebo group in blood concentrations of parathyroid hormone (-26.5% compared with -18.7%; P = 0.014), triglycerides (-13.5% compared with +3.0%; P < 0.001), and the inflammation marker tumor necrosis factor-alpha (-10.2% compared with -3.2%; P = 0.049).

Zittermann, 2009

Cardiovascular disease event

Pooled study

.Results of secondary analyses in 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses (approximately 1000 IU/d) but not with calcium supplementation (pooled relative risk, 1.14 [CI, 0.92 to 1.41]), or a combination of vitamin D and calcium supplementation (pooled relative risk, 1.04 [CI, 0.92 to 1.18]) compared with placebo.

Wang, 2010

CVD survival


Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001).

Vacek, epub

Chronic kidney disease

Placebo or calcium (1,200 mg) and vitamin D(3) (800 IU) in fixed or separate combination.


Effect on parathyroid hormone

The proportion with a 30% or greater decrease in iPTH level at 6 months was 50% in all eGFR groups on treatment versus 6% to 9% for placebo (P < 0.001 for all). The effects of the intervention on iPTH levels did not differ according to baseline eGFR (interaction P > 0.1 for all times).

Kooienga, 2009


1000 IU/d vs. placebo

Mean 25(OH)D levels increased significantly higher in the treatment group (mean increase from baseline: 10.3+/-10.4 ng/mL vs. 0.8+/-6.8 ng/mL, p<0.0001).

Rucker, 2009

Depression

Cross-sectional study and randomized double blind controlled trial of 20,000 or 40,000 IU vitamin D per week versus placebo for 1 year.

In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after 1 year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium.

Jorde, 2008

Falls, fractures

700-1000 IU/d

Pooled RR = 0.81 (95% CI 0.71 to 0.92)

No effect for 400 IU/d

Bischoff-Ferrari, 2009b

Falls

Our study population consisted of 242 individuals recruited by advertisements and mailing lists (mean [ +/- SD] age, 77 +/- 4 years). All serum 25-hydroxyvitamin D (25[OH]D) levels were below 78 nmol/l. Individuals received in a double blinded fashion either 1000 mg of calcium or 1000 mg of calcium plus 800 IU of vitamin D per day over a treatment period of 12 months, which was followed by a treatment-free but still blinded observation period of 8 months.

Compared to calcium mono, supplementation with calcium plus vitamin D resulted in a significant decrease in the number of subjects with first falls of 27% at month 12 (RR = 0.73; CI = 0.54-0.96) and 39% at month 20 (RR = 0.61; CI = 0.34-0.76).

Concerning secondary endpoints, we observed significant improvements in quadriceps strength of 8%, a decrease in body sway of 28%, and a decrease in time needed to perform the TUG test of 11%.

Pfeifer, 2009

Non-vertebrate fractures

700-1000 IU/d

pooled RR was 0.80 (95% CI, 0.72-0.89;

Bischoff-Ferrari, 2009a

Gastric bypass

We evaluated three doses of vitamin D3 (800, 2,000, and 5,000 IU/day) in a prospective, randomized pilot trial of 45 patients undergoing Roux-en-Y gastric bypass.

At 12 months, the 800-, 2,000-, and 5,000-IU groups had a mean +/- SD increase in 25OHD of 27.5 +/- 40.0, 60.2 +/- 37.4, and 66.1 +/- 42.2 nmol/L, respectively (p = 0.09) with a maximum increase in each group of 87.4, 114.8, and 129.8 nmol/L. Forty-four percent, 78%, and 70% achieved 25OHD levels >or=75 nmol/L (p = 0.38).

Goldner, 2009

Glucose (fasting plasma) (FPG)

A total of 314 Caucasian adults without diabetes received either 500 mg calcium citrate and 700 IU vitamin D(3) or placebos daily for 3 years in a double-blind, randomized, controlled trial designed for bone-related outcomes.

Among participants with IFG at baseline, those who took combined calcium-vitamin D supplements had a lower rise in FPG at 3 years compared with those on placebo (0.02 mmol/l [0.4 mg/dl] vs. 0.34 mmol/l [6.1 mg/dl], respectively, P = 0.042) and a lower increase in HOMA-IR (0.05 vs. 0.91, P = 0.031).

Pitas, 2007

Haemodialysis

HD patients were included in this study if their serum 25(OH)D level was <75 mmol/L. Oral 25(OH)D(3) was administered daily at 10-30 microg/day based on the severity of the deficiency.

After 6 months of treatment [mean daily 25(OH)D(3): 16 +/- 5 microg/day], the serum 25(OH)D level increased (30 +/- 19 to 126 +/- 46 nmol/ L, P < 0.001), with 13% of patients in group 1, 57% in group 2 and 30% in group 3. The serum intact parathyroid hormone (iPTH) level decreased (235 +/- 186 to 189 +/- 137 pg/mL, P = 0.05), except in group 1. Bone alkaline phosphatase (BALP) showed a tendency to normalize (23 +/- 16 to 18.3 +/- 11 microg/L, P < 0.05), leading to a decrease in alfacalcidol administration from 66% to 43% (P < 0.05), except in group 1. The KDOQI targets achieved increased significantly for serum calcium (76% to 85%) and phosphate levels (66% to 77%) in all patients. The serum albumin level increased in all groups (34.6 +/- 4 to 36.8 +/- 4 g/L, P < 0.05), without any significant improvement in normalized protein catabolic rate (nPCR) or C-reactive proteins (CRP).

Jean, 2008

Heart failure, congestive

either 50 mug vitamin D(3)/d plus 500 mg Ca/d [D(+) group] or placebo plus 500 mg Ca/d [D(-) group] for 9 mo

Compared with baseline, parathyroid hormone was significantly lower and the antiinflammatory cytokine interleukin 10 was significantly higher in the D(+) group after 9 mo. The proinflammatory cytokine tumor necrosis factor alpha increased in the D(-) group but remained constant in the D(+) group. The survival rate did not differ significantly between the study groups during the follow-up period.

Schleithoff, 2006

Infectious diseases



Yamshchikov, 2009

Infections, symptomatic upper respiratory tract

50 microg vitamin D3 (2000 IU) daily or matching placebo for 12 weeks.

The mean 25-hydroxyvitamin D level at baseline was similar in both groups (64.3+/-25.4 nmol/l in the vitamin D group; 63.0+/-25.8 nmol/l in the placebo group; n.s.). After 12 weeks, 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group, whereas there was no change in vitamin D levels in the placebo group. There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter.

Li-Ng, 2009

Influenza

800 or 2000 IU/d

40 or 90% reduction

Aloia & Li-Ng, 2007

Influenza type A

1100 IU/d, no other oral intake

RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006

No effect for type B

Urashima, 2010

Insulin sensitivity

120,000 IU/fortnight

Seventy-one of the recruited subjects completed the study (35 in supplemented group, 36 in control group). There was an increase in oral glucose insulin sensitivity (OGIS) with supplementation by per protocol analysis (P = 0.038; intention-to-treat analysis P = 0.055). The age- and baseline 25-hydroxyvitamin D level-adjusted difference in change in OGIS was highly significant (mean difference 41.1 +/- 15.5; P = 0.01). No changes in secondary outcome measures (insulin secretion, basal indices of insulin sensitivity, blood pressure or lipid profile) were found with supplementation.

Nagpal, 2009


double-blind intervention administering 100 microg (4000 IU) vitamin D(3) (n 42) or placebo (n 39) daily for 6 months to South Asian women, aged 23-68 years, living in Auckland, New Zealand

Significant improvements were seen in insulin sensitivity and IR (P = 0.003 and 0.02, respectively), and fasting insulin decreased (P = 0.02) with supplementation compared with placebo.

Von hurst, 2010


participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D(3) or identical-looking placebo twice weekly for 6 months.

The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA(1c) and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups.

Grimnes, 2011


cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk.

The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change ± SE: 300 ± 130 compared with -126 ± 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 ± 39 compared with -36 ± 37 mU · L(-1) · min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 ± 0.03% compared with 0.14 ± 0.03%, respectively; P = 0.081).

Mitri, 2011

Muscle strength

6-month supplementation (December to May) of daily calcium plus monthly placebo (calcium/placebo group) or daily calcium plus oral cholecalciferol (150,000 IU once a month during the first 2 months, followed by 90,000 IU once a month for the last 4 months; calcium/vitamin D group)

SHF was increased in the calcium/vitamin D group by 16.4% (p = 0.0001) and SKE by 24.6% (p = 0.0007).

[strength of hip flexors (SHF) and knee extensors (SKE)]


Moreira-Pfrimer, 2009


800 or 1600 IU/d plus vibration

Same improvements with both doses

Verschueren, 2011

Musculoskeletal parameters

One hundred seventy-nine girls, ages 10-17 yr, were randomly assigned to receive weekly oral vitamin D doses of 1,400 IU (equivalent to 200 IU/d) or 14,000 IU (equivalent to 2,000 IU/d) in a double-blind, placebo-controlled, 1-yr protocol.

In the overall group of girls, lean mass increased significantly in both treatment groups (P < or = 0.05); bone area and total hip BMC increased in the high-dose group (P < 0.02). In premenarcheal girls, lean mass increased significantly in both treatment groups, and there were consistent trends for increments in BMD and/or BMC at several skeletal sites, reaching significance at lumbar spine BMD in the low-dose group and at the trochanter BMC in both treatment groups. There was no significant change in lean mass, BMD, or BMC in postmenarcheal girls.

El-Hajj, 2006

Multiple sclerosis

6000 IU/d vitamin D2 vs. 1000 IU/d vitamin D2

There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04).

Stein, 2011

Neuromuscular

8400 IU/week

significantly reduced sway compared with treatment with placebo (P = 0.047) in patients with elevated baseline sway but not in patients with normal baseline sway.

Lips, 2010

Physical performance


gait speed was higher among subjects supplemented with vitamin (whether trained or not) than in non-supplemented subjects (838+/-147 and 768+/-127 m/12 min, respectively, p=0.02).

Bunout, 2006

Pneumonia

Children, 100,000 IU once

Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02).

Manaseki-Holland, 2010


Oral vitamin D (1000 IU for <1 year and 2000 IU for >1 year) (n=100) or placebo (lactose) (n=100) once a day for 5 days, from enrolment.

Median duration (SE, 95% CI) of resolution of severe pneumonia was similar in the two groups [vitamin D: 72 (3.7, 64.7-79.3) hours; placebo: 64 (4.5, 55.2-72.8)hours]. Duration of hospitalization and time to resolution of tachypnea, chest retractions, and inability to feed were also comparable between the two groups.

Choudhary & Gupta, 2011

Pregnancy

4000 IU/d

No adverse effects on serum or urine calcium

Hollis, 2011

Stress fractures

Navy females, 800 IU/d, 2000 mg/d calcium

21% lower incidence

Lappe, 2008

Testosterone

Participants received either 83 μg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3).

Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group

Pilz, 2011

Tooth loss

Elderly, taking supplements or not

During the randomized trial, 11 of the 82 subjects (13%) taking supplements and 17 of the 63 subjects (27%) taking placebo lost one or more teeth (OR = 0.4; 95% CI: 0.2 to 0.9).

Krall, 2001

Tuberculosis

The subjects were randomised to receive vitamin D (0.25 mg/day) or placebo in a double blind method, during the 6th initial week of Tb treatment.

One hundred percent of the vitamin D group and only 76.7% of the placebo group had sputum conversion. This difference is statistically significant (p=0.002).


Nursyam, 2006


The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment.

Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]).

Wejse, 2009


A single oral dose of 2.5 mg (100,000 IU) vitamin D

significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses.

Martineau, 2011


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Lappe J, Cullen D, Haynatzki G, Recker R, Ahlf R, Thompson K. Calcium and vitamin d supplementation decreases incidence of stress fractures in female navy recruits. J Bone Miner Res. 2008 May;23(5):741-9.

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 Jun;85(6):1586-91.

Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, Berbari N. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009 Oct;137(10):1396-404.

Lips P, Binkley N, Pfeifer M, Recker R, Samanta S, Cohn DA, Chandler J, Rosenberg E, Papanicolaou DA. Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency. Am J Clin Nutr. 2010 Apr;91(4):985-91.

Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health. 2010 Oct;15(10):1148-55.

Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health. 2010 Oct;15(10):1148-55.

Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, Packe GE, Moore-Gillon JC, Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD, Woodward NJ, Venton TR, Barnes KE, Mullett CJ, Coussens AK, Rutterford CM, Mein CA, Davies GR, Wilkinson RJ, Nikolayevskyy V, Drobniewski FA, Eldridge SM, Griffiths CJ. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet. 2011 Jan 15;377(9761):242-50.

Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, Packe GE, Davidson RN, Eldridge SM, Maunsell ZJ, Rainbow SJ, Berry JL, Griffiths CJ. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med. 2007 Jul 15;176(2):208-13.

Meier C, Woitge HW, Witte K, Lemmer B, Seibel MJ. Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial. J Bone Miner Res. 2004 Aug;19(8):1221-30.

Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic β 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 Aug;94(2):486-94.

Moreira-Pfrimer LD, Pedrosa MA, Teixeira L, Lazaretti-Castro M. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial. Ann Nutr Metab. 2009;54(4):291-300.

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 Jan;26(1):19-27.

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 Jan-Mar;38(1):3-5.

Papaioannou A, Kennedy CC, Giangregorio L, Ioannidis G, Pritchard J, Hanley DA, Farrauto L, DeBeer J, Adachi JD. A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: no advantage of loading doses over daily supplementation. BMC Musculoskelet Disord. 2011 Jun 20;12:135.

Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2009 Feb;20(2):315-22.

Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2011 Mar;43(3):223-5.

Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010 Mar 2;152(5):307-14.

Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007 Apr;30(4):980-6.

Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. 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 Jan;96(1):53-8.

Rucker D, Tonelli M, Coles MG, Yoo S, Young K, McMahon AW. Vitamin D insufficiency and treatment with oral vitamin D3 in northern-dwelling patients with chronic kidney disease. J Nephrol. 2009 Jan-Feb;22(1):75-82.

Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006 Apr;83(4):754-9.

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 Sep;49(9):640-6.

Sidbury R, Sullivan AF, Thadhani RI, Camargo CA Jr. Randomized controlled trial of vitamin D supplementation for winter-related atopic dermatitis in Boston: a pilot study. Br J Dermatol. 2008 Jul;159(1):245-7.

Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR, Egan GF, Mitchell PJ, Harrison LC, Butzkueven H, Kilpatrick TJ. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011 Oct 25;77(17):1611-8.

Tang JY, Fu T, Leblanc E, Manson JE, Feldman D, Linos E, Vitolins MZ, Zeitouni NC, Larson J, Stefanick ML. Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial. J Clin Oncol. 2011 Aug 1;29(22):3078-84.

Toss G, Magnusson P. Is a daily supplementation with 40 microgram vitamin D(3) sufficient? A randomised controlled trial. Eur J Nutr. 2011 Nov 16. [Epub ahead of print]

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 May;91(5):1255-60.

Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D Deficiency and Supplementation and Relation to Cardiovascular Health. Am J Cardiol. 2011 Nov 7. [Epub ahead of print]

Verschueren SM, Bogaerts A, Delecluse C, Claessens AL, Haentjens P, Vanderschueren D, Boonen S. The effects of whole-body vibration training and vitamin D supplementation on muscle strength, muscle mass, and bone density in institutionalized elderly women: a 6-month randomized, controlled trial. J Bone Miner Res. 2011 Jan;26(1):42-9.

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. 2010 Feb;103(4):549-55.

Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010 Mar 2;152(5):315-23

Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL, Glerup H, Sodemann M. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2009 May 1;179(9):843-50.

Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract. 2009 Jul-Aug;15(5):438-49.

Zittermann A, Frisch S, Berthold HK, Götting C, Kuhn J, Kleesiek K, Stehle P, Koertke H, Koerfer R. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009 May;89(5):1321-7.

Abstracts

BMJ. 2009 Oct 1;339:b3692. doi: 10.1136/bmj.b3692.

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J.

Source

Centre on Aging and Mobility, University of Zurich, Switzerland. heike.bischoff@usz.ch

Abstract

OBJECTIVE:

To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals.

DATA SOURCES:

We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1alpha-hydroxyvitamin D(3) (1alpha-hydroxycalciferol) or 1,25-dihydroxyvitamin D(3) (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion.

RESULTS:

Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l v >or=60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94).

CONCLUSIONS:

Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.


J Bone Miner Res. 2011 Oct;26(10):2371-7. doi: 10.1002/jbmr.451.

High serum 25-hydroxyvitamin D is associated with a low incidence of stress fractures.

Burgi AA, Gorham ED, Garland CF, Mohr SB, Garland FC, Zeng K, Thompson K, Lappe JM.

Source

Department of Behavioral Sciences and Epidemiology, Naval Health Research Center, San Diego, CA, USA.

Abstract

Low serum 25-hydroxyvitamin D [25(OH)D] concentrations are associated with hip fractures, but the dose-response relationship of serum 25(OH)D with risk of stress fractures in young women is unknown. This nested case-control study in a cohort of female Navy recruits was designed to determine whether those with low prediagnostic serum 25(OH)D concentrations had greater risk of stress fracture. Sera were drawn in 2002-2009 from 600 women who were diagnosed subsequently with stress fracture of the tibia or fibula and 600 matched controls who did not experience a stress fracture. The 25(OH)D concentration was measured using the DiaSorin radioimmunoassay method. Controls were individually matched to cases on race (white, black, or other), length of service (±30 days), and day blood was drawn (±2 days). There was approximately half the risk of stress fracture in the top compared with the bottom quintile of serum 25(OH)D concentration (odds ratio [OR]=0.51, 95% CI 0.34-0.76, p0.01). The range of serum 25(OH)D in the lowest quintile was 1.5 to 19.7 (mean 13.9) ng/mL, whereas in the highest it was 39.9 to 112 (mean 49.7) ng/mL. It is concluded that there was a monotonic inverse dose-response gradient between serum 25(OH)D and risk of stress fracture. There was double the risk of stress fractures of the tibia and fibula in women with serum 25(OH)D concentrations of less than 20ng/mL compared to those with concentrations of 40ng/mL or greater. A target for prevention of stress fractures would be a serum 25(OH)D concentration of 40ng/mL or greater, achievable with 4000IU/d of vitamin D(3) supplementation.


Arch Intern Med. 2007 Sep 10;167(16):1730-7.

Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.

Autier P, Gandini S.

Source

International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon, France. autierp@iacr.fr

Abstract

BACKGROUND:

Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D(2)] or cholecalciferol [vitamin D(3)]) on any health condition.

METHODS:

The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library.

RESULTS:

We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention.

CONCLUSIONS:

Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings.


Am J Clin Nutr. 2009 May;89(5):1321-7. Epub 2009 Mar 25.

Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers.

Zittermann A, Frisch S, Berthold HK, Götting C, Kuhn J, Kleesiek K, Stehle P, Koertke H, Koerfer R.

Source

Klinik für Thorax- und Kardiovaskularchirurgie and Institut für Laboratoriums- und Transfusionsmedizin, Herzzentrum NRW, Ruhr Universität Bochum, Bad Oeynhausen, Germany. azittermann@hdz-nrw.de

Abstract

BACKGROUND:

High blood concentrations of parathyroid hormone and low concentrations of the vitamin D metabolites 25-hydroxyvitamin D [25(OH)D] and calcitriol are considered new cardiovascular disease risk markers. However, there is also evidence that calcitriol increases lipogenesis and decreases lipolysis.

OBJECTIVE:

We investigated the effect of vitamin D on weight loss and traditional and nontraditional cardiovascular disease risk markers in overweight subjects.

DESIGN:

Healthy overweight subjects (n = 200) with mean 25(OH)D concentrations of 30 nmol/L (12 ng/mL) received vitamin D (83 microg/d) or placebo in a double-blind manner for 12 mo while participating in a weight-reduction program.

RESULTS:

Weight loss was not affected significantly by vitamin D supplementation (-5.7 +/- 5.8 kg) or placebo (-6.4 +/- 5.6 kg). However, mean 25(OH)D and calcitriol concentrations increased by 55.5 nmol/L and 40.0 pmol/L, respectively, in the vitamin D group but by only 11.8 nmol/L and 9.3 pmol/L, respectively, in the placebo group (P < 0.001), whereas a more pronounced decrease occurred in the vitamin D group than in the placebo group in blood concentrations of parathyroid hormone (-26.5% compared with -18.7%; P = 0.014), triglycerides (-13.5% compared with +3.0%; P < 0.001), and the inflammation marker tumor necrosis factor-alpha (-10.2% compared with -3.2%; P = 0.049). The beneficial biochemical effects were independent of the loss in body weight, fat mass, and sex. However, compared with placebo, vitamin D supplementation also increased LDL-cholesterol concentrations (+5.4% compared with -2.5%; P < 0.001).

CONCLUSIONS:

The results indicate that a vitamin D supplement of 83 microg/d does not adversely affect weight loss and is able to significantly improve several cardiovascular disease risk markers in overweight subjects with inadequate vitamin D status participating in a weight-reduction program. This trial was registered at clinicaltrials.gov as NCT00493012.


J Bone Miner Res. 2008 May;23(5):741-9.

Calcium and vitamin d supplementation decreases incidence of stress fractures in female navy recruits.

Lappe J, Cullen D, Haynatzki G, Recker R, Ahlf R, Thompson K.

Source

Creighton University Osteoporosis Research Center, Omaha, Nebraska, USA.

Abstract

INTRODUCTION:

Stress fractures (SFx) are one of the most common and debilitating overuse injuries seen in military recruits, and they are also problematic for nonmilitary athletic populations. The goal of this randomized double-blind, placebo-controlled study was to determine whether a calcium and vitamin D intervention could reduce the incidence of SFx in female recruits during basic training.

MATERIALS AND METHODS:

We recruited 5201 female Navy recruit volunteers and randomized them to 2000 mg calcium and 800 IU vitamin D/d or placebo. SFx were ascertained when recruits reported to the Great Lakes clinic with symptoms. All SFx were confirmed with radiography or technetium scan according to the usual Navy protocol.

RESULTS:

A total of 309 subjects were diagnosed with a SFx resulting in an incidence of 5.9% per 8 wk. Using intention-to-treat analysis by including all enrolled subjects, we found that the calcium and vitamin D group had a 20% lower incidence of SFx than the control group (5.3% versus 6.6%, respectively, p = 0.0026 for Fisher's exact test). The per protocol analysis, including only the 3700 recruits who completed the study, found a 21% lower incidence of fractures in the supplemented versus the control group (6.8% versus 8.6%, respectively, p = 0.02 for Fisher's exact test).

CONCLUSIONS:

Generalizing the findings to the population of 14,416 women who entered basic training at the Great Lakes during the 24 mo of recruitment, calcium and vitamin D supplementation for the entire cohort would have prevented approximately 187 persons from fracturing. Such a decrease in SFx would be associated with a significant decrease in morbidity and financial costs.


Am J Clin Nutr. 2010 May;91(5):1255-60. Epub 2010 Mar 10.

Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.

Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H.

Source

Division of Molecular Epidemiology, Jikei University School of Medicine, Nishi-shimbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan. urashima@jikei.ac.jp

Abstract

BACKGROUND:

To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza.

OBJECTIVE:

We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren.

DESIGN:

From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D(3) supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen.

RESULTS:

Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3) compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006).

CONCLUSION:

This study suggests that vitamin D(3) supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373.


Ann Intern Med. 2011 Dec 20;155(12):827-38.

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.

Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA.

Source

Tufts Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, and Department of Medicine, Fujita Health University School of Medicine, Tsu, Japan.

Abstract

Background: Studies suggest that vitamin D supplementation may reduce cancer and fracture risks. Purpose: To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fractures in adults. Data Sources: English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011. Study Selection: Randomized, controlled trials (RCTs), prospective cohort studies, and nested case-control studies reporting incidence of or death from cancer and fracture outcomes. Data Extraction: Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus. Data Synthesis: 19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones. Limitations: Most trial participants were older (aged ≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders. Conclusion: Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer. Primary Funding Source: Agency for Healthcare Research and Quality.


Trop Med Int Health. 2010 Oct;15(10):1148-55. doi: 10.1111/j.1365-3156.2010.02578.x. Epub 2010 Aug 17.

Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.

Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G.

Source

Kabul Medical University, Kabul, Afghanistan.Aga Khan Health Services, Kabul, Afghanistan

Abstract

OBJECTIVES:

To determine whether (i) supplementation of oral 100,000 iu of vitamin D(3) (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes.

METHODS:

Double-blind individually randomised placebo-controlled trial in an inner-city hospital in Kabul, of 453 children aged 1-36 months, diagnosed with non-severe or severe pneumonia at the outpatient clinic. Children with rickets, other concurrent severe diseases, very severe pneumonia or wheeze, were excluded. Children were given vitamin D(3) or placebo drops additional to routine pneumonia treatment.

RESULTS:

Two hundred and twenty-four children received vitamin D(3;) and 229 received placebo. There was no significant difference in the mean number of days to recovery between the vitamin D(3) (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89; P = 0.17). The risk of a repeat episode of pneumonia within 90 days of supplementation was lower in the intervention (92/204; 45%) than the placebo group [122/211; (58%; relative risk 0.78; 95% CI 0.64, 0.94; P = 0.01]. Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02).

CONCLUSION:

A single high-dose oral vitamin D(3) supplementation to young children along with antibiotic treatment for pneumonia could reduce the occurrence of repeat episodes of pneumonia.


Ann Intern Med. 2010 Mar 2;152(5):307-14.

Systematic review: Vitamin D and cardiometabolic outcomes.

Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM.

Source

Tufts Medical Center and Friedman School of Nutrition Science and Policy, and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.

Abstract

BACKGROUND:

Vitamin D may modify risk for cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease).

PURPOSE:

To examine the association between vitamin D status, including the effect of vitamin D supplementation, and cardiometabolic outcomes in generally healthy adults.

DATA SOURCES:

English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Central Register of Controlled Trials (fourth quarter of 2009).

STUDY SELECTION:

11 reviewers screened citations to identify longitudinal cohort studies that reported associations between vitamin D status and cardiometabolic outcomes, including randomized trials of vitamin D supplementation.

DATA EXTRACTION:

5 independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus.

DATA SYNTHESIS:

13 observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in the highest versus the lowest vitamin D status groups. Eight trials found no effect of vitamin D supplementation on glycemia or incident diabetes. In meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk, 1.8 [95% CI, 1.3 to 2.4]). In meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, -1.9 mm Hg [CI, -4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, -0.1 mm Hg [CI, -0.7 to 0.5 mm Hg]). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes.

LIMITATIONS:

Studies included primarily white participants. Observational studies were heterogeneous. Several trials reported post hoc analyses.

CONCLUSION:

The association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at the dosages given.

PRIMARY FUNDING SOURCE:

National Institute of Diabetes and Digestive and Kidney Disease, the National Institutes of Health Office of Dietary Supplements, U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and Public Health Agency of Canada.


Arch Intern Med. 2009 Mar 23;169(6):551-61.

Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.

Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP, Henschkowski J.

Source

Centre on Aging and Mobility, University of Zurich, University Hospital, Switzerland. heike.bischoff@usz.ch

Abstract

BACKGROUND:

Antifracture efficacy with supplemental vitamin D has been questioned by recent trials.

METHODS:

We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial.

RESULTS:

The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation.

CONCLUSION:

Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.


J Clin Endocrinol Metab. 2011 Mar;96(3):E447-52. Epub 2010 Dec 22.

Vitamin D(3) is more potent than vitamin D(2) in humans.

Heaney RP, Recker RR, Grote J, Horst RL, Armas LA.

Source

Creighton University, 601 North 30th Street, Suite 4841, Omaha, Nebraska 68131, USA. rheaney@creighton.edu

Abstract

BACKGROUND:

Current unitage for the calciferols suggests that equimolar quantities of vitamins D(2) (D2) and D(3) (D3) are biologically equivalent. Published studies yield mixed results.

OBJECTIVE:

The aim of the study was to compare the potencies of D2 and D3.

DESIGN:

The trial used a single-blind, randomized design in 33 healthy adults. Calciferols were dosed at 50,000 IU/wk for 12 wk. Principal outcome variables were area under the curve for incremental total 25-hydroxyvitamin D [25(OH)D] and change in calciferol content of sc fat.

RESULTS:

Incremental mean (sd) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml (516) for the D2-treated group and 2136 (606) for the D3 (P < 0.001). Mean (sd) steady-state 25(OH)D increments showed similar differences: 24 ng/ml for D2 (10.3) and 45 ng/ml (16.2) for D3 (P <0.001). Subcutaneous fat content of D2 rose by 50 μg/kg in the D2-treated group, and D3 content rose by 104 μg/kg in the D3-treated group. Total calciferol in fat rose by only 33 ng/kg in the D2-treated, whereas it rose by 104 μg/kg in the D3-treated group. Extrapolating to total body fat D3, storage amounted to just 17% of the administered dose.

CONCLUSION:

D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2. For neither was there evidence of sequestration in fat, as had been postulated for doses in this range. Given its greater potency and lower cost, D3 should be the preferred treatment option when correcting vitamin D deficiency.


Am J Clin Nutr. 2006 Oct;84(4):694-7.

The case against ergocalciferol (vitamin D2) as a vitamin supplement.

Houghton LA, Vieth R.

Source

School of Nutrition and Dietetics, Acadia University, Wolfville, Canada. lisa.houghton@acadiau.ca

Abstract

Supplemental vitamin D is available in 2 distinct forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Pharmacopoeias have officially regarded these 2 forms as equivalent and interchangeable, yet this presumption of equivalence is based on studies of rickets prevention in infants conducted 70 y ago. The emergence of 25-hydroxyvitamin D as a measure of vitamin D status provides an objective, quantitative measure of the biological response to vitamin D administration. As a result, vitamin D3 has proven to be the more potent form of vitamin D in all primate species, including humans. Despite an emerging body of evidence suggesting several plausible explanations for the greater bioefficacy of vitamin D3, the form of vitamin D used in major preparations of prescriptions in North America is vitamin D2. The case that vitamin D2 should no longer be considered equivalent to vitamin D3 is based on differences in their efficacy at raising serum 25-hydroxyvitamin D, diminished binding of vitamin D2 metabolites to vitamin D binding protein in plasma, and a nonphysiologic metabolism and shorter shelf life of vitamin D2. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification.


Am J Clin Nutr. 2010 Apr;91(4):985-91. Epub 2010 Feb 3.

Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency.

Lips P, Binkley N, Pfeifer M, Recker R, Samanta S, Cohn DA, Chandler J, Rosenberg E, Papanicolaou DA.

Source

Department of Endocrinology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands. p.lips@vumc.nl

Abstract

BACKGROUND:

Vitamin D insufficiency, which is prevalent in older individuals, is associated with bone and muscle weakness and falls.

OBJECTIVE:

We examined the effects of a weekly dose of 8400 IU vitamin D(3) on postural stability, muscle strength, and safety.

DESIGN:

In this double-blind trial, subjects aged > or =70 y with serum 25-hydroxyvitamin D [25(OH)D] concentrations < or =20 but > or =6 ng/mL were randomly assigned to receive a weekly dose of 8400 IU vitamin D(3) (n = 114) or a placebo (n = 112). Mediolateral body sway with eyes open (assessed with the AccuSway(PLUS) platform; Advanced Medical Technology Inc, Watertown, MA) was the primary endpoint. Secondary endpoints included the short physical performance battery (SPPB) and serum 25(OH)D concentrations. An analysis of covariance model was used for treatment comparisons. Safety and tolerability were monitored.

RESULTS:

Serum 25(OH)D concentrations rose significantly (from 13.9 to 26.2 ng/mL, P < 0.001) in patients treated with 8400 IU vitamin D(3) but not in patients treated with the placebo. After 16 wk, neither mediolateral sway nor SPPB differed significantly between treatment groups. However, in the post hoc analysis of patients subgrouped by baseline sway (> or = 0.46 compared with <0.46 cm), treatment with 8400 IU vitamin D(3) significantly reduced sway compared with treatment with placebo (P = 0.047) in patients with elevated baseline sway but not in patients with normal baseline sway. Adverse experiences and incidences of hypercalcemia, hypercalciuria, and elevated creatinine were similar with both treatments. In patients treated with 8400 IU vitamin D(3), but not in placebo-treated patients, parathyroid hormone decreased significantly.

CONCLUSIONS:

Weekly treatment with 8400 IU vitamin D(3) raised 25(OH)D concentrations in elderly, vitamin D-insufficient individuals. Treatment with 8400 IU vitamin D(3) did not reduce mediolateral sway significantly compared with treatment with placebo in this population, although in post hoc analysis, treatment with 8400 IU vitamin D(3) reduced sway in the subgroup of patients who had elevated sway at baseline. Weekly treatment with 8400 IU vitamin D(3) was well tolerated. This trial was registered at clinicaltrials.gov as NCT00242476.


J Bone Miner Res. 2011 Jan;26(1):42-9.

The effects of whole-body vibration training and vitamin D supplementation on muscle strength, muscle mass, and bone density in institutionalized elderly women: a 6-month randomized, controlled trial.

Verschueren SM, Bogaerts A, Delecluse C, Claessens AL, Haentjens P, Vanderschueren D, Boonen S.

Source

Division of Musculoskeletal Rehabilitation, Department of Rehabilitation Sciences and, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium. sabine.verschueren@faber.kuleuven.be

Abstract

Sarcopenia and osteoporosis represent a growing public health problem. We studied the potential benefit of whole-body vibration (WBV) training given a conventional or a high dose of daily vitamin D supplementation in improving strength, muscle mass, and bone density in postmenopausal women. In a 2 × 2 factorial-design trial, 113 institutionalized elderly females aged over 70 years (mean age 79.6 years) were randomly assigned either to a WBV or a no-training group, receiving either a conventional dose (880 IU/day) or a high dose (1600 IU/day) of vitamin D(3). The primary aim was to determine the effects of 6 months of WBV and/or vitamin D supplementation on isometric and dynamic strength, leg muscle mass, and hip bone mineral density (BMD). Additionally, the increase in 25-hydroxyvitamin D [25(OH)D] levels between conventional and high-dose supplementation was compared. After 6 months of treatment, dynamic muscle strength, hip BMD, and vitamin D serum levels improved significantly in all groups, whereas isometric strength and muscle mass did not change. When compared with no training, the WBV program did not result in additional improvements. When compared with 880 IU, a high dose of 1600 IU of vitamin D did result in higher serum vitamin D levels but did not result in additional improvements. In institutionalized women older than 70 years, the WBV training protocol tested is not more efficient in enhancing muscle mass, strength, and hip BMD compared with vitamin D supplementation. A higher dose of 1600 IU of vitamin D does not provide additional musculoskeletal benefit in this population compared with conventional doses.


Ann Nutr Metab. 2009;54(4):291-300. Epub 2009 Aug 31.

Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial.

Moreira-Pfrimer LD, Pedrosa MA, Teixeira L, Lazaretti-Castro M.

Source

Division of Endocrinology, School of Medicine, Federal University of São Paulo/UNIFESP, São Paulo, Brazil. lindapfrimer@hotmail.com

Abstract

AIMS:

To investigate the effects of a 6-month supplementation with calcium and cholecalciferol on biochemical parameters and muscle strength of institutionalized elderly.

METHODS:

This prospective, double-blind, placebo-controlled, randomized trial included Brazilian institutionalized people > or =60 years of age receiving a 6-month supplementation (December to May) of daily calcium plus monthly placebo (calcium/placebo group) or daily calcium plus oral cholecalciferol (150,000 IU once a month during the first 2 months, followed by 90,000 IU once a month for the last 4 months; calcium/vitamin D group). Fasting blood samples for 25(OH)D, PTH and calcium determination were collected (n = 56) and muscle tests were performed (n = 46) to measure the strength of hip flexors (SHF) and knee extensors (SKE) before (baseline) and after the 6-month intervention (6 months).

RESULTS:

Due to seasonal variations, serum 25(OH)D significantly enhanced in both groups after treatment, but the calcium/vitamin D group had significantly higher 25 (OH)D levels than the calcium/placebo group (84 vs. 33%, respectively; p < 0.0001). No cases of hypercalcemia were observed. While the calcium/placebo group showed no improvement in SHF and SKE at 6 months (p = 0.93 and p = 0.61, respectively), SHF was increased in the calcium/vitamin D group by 16.4% (p = 0.0001) and SKE by 24.6% (p = 0.0007).

CONCLUSIONS:

The suggested cholecalciferol supplementation was safe and efficient in enhancing 25(OH)D levels and lower limb muscle strength in the elderly, in the absence of any regular physical exercise practice.


Exp Gerontol. 2006 Aug;41(8):746-52. Epub 2006 Jun 22.

Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects.

Bunout D, Barrera G, Leiva L, Gattas V, de la Maza MP, Avendaño M, Hirsch S.

Source

INTA, University of Chile, Santiago, Chile. dbunout@inta.cl

Abstract

The aim was to assess the effects of resistance training and vitamin D supplementation on physical performance of healthy elderly subjects. Ninety-six subjects, aged 70 years or more with 25 OH vitamin D levels of 16 ng/ml or less, were randomized to a resistance training or control group. Trained and control groups were further randomized to receive in a double blind fashion, vitamin D 400 IU plus 800 mg of calcium per day or calcium alone. Subjects were followed for nine months. Serum 25 OH vitamin D increased from 12.4+/-2.2 to 25.8+/-6.5 ng/ml among subjects supplemented with vitamin D. Trained subjects had significant improvements in quadriceps muscle strength, the short physical performance test and timed up and go. The latter improved more in trained subjects supplemented with vitamin D. At the end of the follow up, gait speed was higher among subjects supplemented with vitamin (whether trained or not) than in non-supplemented subjects (838+/-147 and 768+/-127 m/12 min, respectively, p=0.02). Romberg ratio was lower among supplemented controls than non-supplemented trained subjects (128+/-40% and 144+/-37%, respectively, p=0.05). In conclusion, vitamin D supplementation improved gait speed and body sway, and training improved muscle strength.


Cancer Prev Res (Phila). 2009 Mar;2(3):213-23. Epub 2009 Mar 3.

Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial.

Fedirko V, Bostick RM, Flanders WD, Long Q, Shaukat A, Rutherford RE, Daniel CR, Cohen V, Dash C.

Source

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.

Abstract

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop "treatable" biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.


Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2933-41. Epub 2009 Oct 27.

Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial.

Fedirko V, Bostick RM, Flanders WD, Long Q, Sidelnikov E, Shaukat A, Daniel CR, Rutherford RE, Woodard JJ.

Source

Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

Abstract

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.


Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):280-91.

Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.

Fedirko V, Bostick RM, Long Q, Flanders WD, McCullough ML, Sidelnikov E, Daniel CR, Rutherford RE, Shaukat A.

Source

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.

Abstract

The exact antineoplastic effects of calcium and vitamin D(3) in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3) on a marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D(3) versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D(3) groups, respectively, but not in the calcium plus vitamin D(3) group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D(3) may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D(3) as chemopreventive agents against colorectal neoplasms.


Cancer Res. 2011 Jan 15;71(2):413-23. Epub 2010 Nov 17.

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.

Ahearn TU, McCullough ML, Flanders WD, Long Q, Sidelnikov E, Fedirko V, Daniel CR, Rutherford RE, Shaukat A, Bostick RM.

Source

Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Winship Cancer Institute, Emory University, Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia 30322, USA.

Abstract

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.


Neurology. 2011 Oct 25;77(17):1611-8.

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR, Egan GF, Mitchell PJ, Harrison LC, Butzkueven H, Kilpatrick TJ.

Source

Department of Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia. Mark.Stein@mh.org.au

Abstract

OBJECTIVE:

Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS.

METHODS:

Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses.

RESULTS:

Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04).

CONCLUSION:

We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation.

CLASSIFICATION OF EVIDENCE:

This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.


Cancer Prev Res (Phila). 2011 Oct;4(10):1645-54. Epub 2011 Jun 30.

Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial.

Hopkins MH, Owen J, Ahearn T, Fedirko V, Flanders WD, Jones DP, Bostick RM.

Source

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.

Abstract

Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for developing colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92) of 2 g/d calcium and/or 800 IU/d vitamin D(3) supplementation versus placebo over 6 months. Plasma concentrations of proinflammatory markers [C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-1β, and IL-8] and an anti-inflammatory marker (IL-10) were measured using ELISAs. After 6 months of treatment, in the vitamin D(3) supplementation group, CRP decreased 32% overall (P = 0.11), 37% in men (P = 0.05), and 41% among non-nonsteroidal anti-inflammatory drug (NSAID) users (P = 0.05) relative to placebo. In the vitamin D(3) supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (P = 0.003) in the vitamin D(3) treatment group overall, 83% (P = 0.01) among men, and 48% among non-NSAID users (P = 0.01). There was no evidence of synergy between vitamin D(3) and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D(3) or calcium supplementation alone and support further investigation of vitamin D(3) as a chemopreventive agent against inflammation and colorectal neoplasms.


Diabet Med. 2009 Jan;26(1):19-27.

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.

Nagpal J, Pande JN, Bhartia A.

Source

Sitaram Bhartia Institute of Science and Research, New Delhi, India.

Abstract

AIM:

To determine the short-term effect of vitamin D(3) supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men.

SUBJECTS AND METHODS:

A double-blind randomized controlled trial was conducted at a tertiary care facility in which 100 male volunteers aged > or = 35 years received three doses of vitamin D(3) (120,000 IU each; supplemented group) fortnightly or placebo (control group). Hepatic fasting insulin sensitivity [homeostasis model assessment (HOMA), quantitative insulin-sensitivity check index, HOMA-2], postprandial insulin sensitivity [oral glucose insulin sensitivity (OGIS)], insulin secretion (HOMA%B, HOMA2-%B), lipid profile and blood pressure were measured at baseline and at 6 weeks' follow-up.

RESULTS:

Seventy-one of the recruited subjects completed the study (35 in supplemented group, 36 in control group). There was an increase in OGIS with supplementation by per protocol analysis (P = 0.038; intention-to-treat analysis P = 0.055). The age- and baseline 25-hydroxyvitamin D level-adjusted difference in change in OGIS was highly significant (mean difference 41.1 +/- 15.5; P = 0.01). No changes in secondary outcome measures (insulin secretion, basal indices of insulin sensitivity, blood pressure or lipid profile) were found with supplementation.

CONCLUSION:

The trial indicates that vitamin D(3) supplementation improves postprandial insulin sensitivity (OGIS) in apparently healthy men likely to have insulin resistance (centrally obese but non-diabetic).


Endocr Pract. 2009 Jul-Aug;15(5):438-49.

Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials.

Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR, Tangpricha V.

Source

Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30030, USA. AYAMSHC@emory.edu

Abstract

OBJECTIVE:

To review the existing human controlled intervention studies of vitamin D as adjunctive therapy in settings of infection and provide recommendations for design and implementation of future studies in this field on the basis of the evidence reviewed.

METHODS:

We conducted a systematic review of randomized controlled clinical trials that studied vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948 through 2009 were identified through search terms in PubMed and Ovid MEDLINE.

RESULTS:

Thirteen published controlled trials were identified by our search criteria. Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient demographics, sample size, and vitamin D intervention strategies. Serious adverse events attributable to vitamin D supplementation were rare across all studies. On the basis of studies reviewed to date, the strongest evidence supports further research into adjunctive vitamin D therapy for tuberculosis, influenza, and viral upper respiratory tract illnesses. In the selected studies, certain aspects of study design are highlighted to help guide future clinical research in the field.

CONCLUSION:

More rigorously designed clinical trials are needed for further evaluation of the relationship between vitamin D status and the immune response to infection as well as for delineation of necessary changes in clinical practice and medical care of patients with vitamin D deficiency in infectious disease settings.


Am J Respir Crit Care Med. 2007 Jul 15;176(2):208-13. Epub 2007 Apr 26.

A single dose of vitamin D enhances immunity to mycobacteria.

Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, Packe GE, Davidson RN, Eldridge SM, Maunsell ZJ, Rainbow SJ, Berry JL, Griffiths CJ.

Source

Centre for Health Sciences, Queen Mary's School of Medicine and Dentistry, Barts and The London, and Department of Clinical Biochemistry, North West London Hospitals NHS Trust, Northwick Park Hospital, Harrow, E1 2AT, UK. a.martineau@qmul.ac.uk

Abstract

RATIONALE:

Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed.

OBJECTIVES:

To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status.

METHODS:

A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.

MEASUREMENTS AND MAIN RESULTS:

The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion.

CONCLUSIONS:

A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).


Am J Kidney Dis. 2009 Mar;53(3):408-16. Epub 2009 Jan 29.

The effect of combined calcium and vitamin D3 supplementation on serum intact parathyroid hormone in moderate CKD.

Kooienga L, Fried L, Scragg R, Kendrick J, Smits G, Chonchol M.

Source

Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, CO 80262, USA.

Abstract

BACKGROUND:

Studies addressing the effects of vitamin D(3) supplementation on secondary hyperparathyroidism in patients with moderate chronic kidney disease are scarce.

STUDY DESIGN:

Post hoc analysis of the randomized clinical trial Vitamin D, Calcium, Lyon Study II (DECALYOS II) to assess effects according to baseline estimated glomerular filtration rate (eGFR).

SETTING & PARTICIPANTS:

Multicenter, randomized, double-blinded, placebo-controlled study of 639 elderly women randomly assigned to calcium-vitamin D(3) fixed combination; calcium plus vitamin D(3) separate combination, or placebo.

INTERVENTIONS:

Placebo or calcium (1,200 mg) and vitamin D(3) (800 IU) in fixed or separate combination.

OUTCOMES & MEASUREMENTS:

Proportion of participants with a mean decrease in intact parathyroid hormone (iPTH) level of 30% or greater. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and categorized as 60 or greater, 45 to 59, and less than 45 mL/min/1.73 m(2).

RESULTS:

610 participants had an eGFR at baseline: 288 (47.2%), 222 (36.4%), and 100 (16.4%) were in each decreasing eGFR category. Across decreasing eGFR groups, 88%, 86%, and 89% had 25-hydroxyvitamin D (25[OH]D) levels less than 15 ng/mL at baseline. On treatment, similar improvements in the proportion of participants achieving 25(OH)D levels greater than 30 ng/mL at 6 months were seen in all kidney function groups (43%, 49%, and 41%, respectively). Active regimens versus placebo increased mean 25(OH)D levels from baseline in all eGFR groups at all times (P < 0.001 for all). The proportion with a 30% or greater decrease in iPTH level at 6 months was 50% in all eGFR groups on treatment versus 6% to 9% for placebo (P < 0.001 for all). The effects of the intervention on iPTH levels did not differ according to baseline eGFR (interaction P > 0.1 for all times).

LIMITATIONS:

This study included only elderly white women.

CONCLUSION:

Vitamin D(3) was effective in increasing 25(OH)D and decreasing iPTH levels in patients with moderate chronic kidney disease.


J Nephrol. 2009 Jan-Feb;22(1):75-82.

Vitamin D insufficiency and treatment with oral vitamin D3 in northern-dwelling patients with chronic kidney disease.

Rucker D, Tonelli M, Coles MG, Yoo S, Young K, McMahon AW.

Source

Department of Medicine, Division of General Internal Medicine, University of Alberta, University of Alberta Hospital, Edmonton, Alberta, Canada.

Abstract

BACKGROUND:

Vitamin D insufficiency is common in people living at northern latitudes and those with chronic kidney disease (CKD). We studied persons with both of these risk factors to determine the prevalence of vitamin D insufficiency and whether serum 25-hydroxyvitamin D (25(OH)D) levels were affected by oral vitamin D3 supplementation.

METHODS:

This was a prospective controlled trial of 128 patients with stage 3-5 non-dialysis dependent CKD. Patients were assigned to the intervention (oral vitamin D3 1,000 IU/day) in a 1:1 ratio at the discretion of the attending dietitian. Serum biochemical markers were measured at baseline (May-July) and after 3 months of follow-up. There were 63 control and 65 intervention subjects.

RESULTS:

Mean 25(OH)D levels increased significantly higher in the treatment group (mean increase from baseline: 10.3+/-10.4 ng/mL vs. 0.8+/-6.8 ng/mL, p<0.0001). This difference remained significant after adjustment for differing baseline characteristics between groups (p<0.0001). Treatment with oral vitamin D3 reduced vitamin D insufficiency by 37%, as compared with a 2% increase in prevalence among the control group (p<0.0001). Considering the entire study population, 93% of patients had levels less than <30 ng/mL at least once during the study.

CONCLUSION:

Vitamin D insufficiency is highly prevalent in northern-dwelling patients with stage 3-5 CKD, and is moderated by oral supplementation with 1,000 IU of vitamin D3 daily.


Eur J Clin Nutr. 1995 Sep;49(9):640-6.

Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults.

Scragg R, Khaw KT, Murphy S.

Source

Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, UK.

Abstract

OBJECTIVE:

A possible role for vitamin D deficiency in contributing to the winter increase in cardiovascular disease mortality was investigated by testing the effect of vitamin D supplementation on blood pressure and other cardiovascular risk factors during winter.

DESIGN:

Randomised double-blind trial of vitamin D supplementation in winter.

SUBJECTS:

Men and women, mean age 70 years (range 63-76) recruited from general practitioner age-sex registers in Cambridge (UK).

INTERVENTION:

95 people received a single oral dose of 2.5 mg cholecalciferol and 94 received the placebo at baseline interviews during December 1991. Follow-up assessment was 5 weeks later during January 1992.

RESULTS:

Comparing follow-up with baseline assessment, serum 25-hydroxyvitamin D increased in the treated group and decreased slightly in the placebo group [mean (s.d.) change: 7.2 (+/- 3.8) vs -1.4 (+/- 1.1) ng/ml, P = 0.0001]; while parathyroid hormone decreased in the treated, and increased in the placebo, group [-0.27 (+/- 0.78) vs 0.13 (+/- 0.75) pmol/l, P = 0.0004]. However, the mean change in blood pressure was similar in both groups: systolic -5 (+/- 13) vs -5 (+/- 16) mmHg, P = 0.81; diastolic -1 (+/- 9) vs -1 (+/- 9), P = 0.92; as was the mean change in serum cholesterol [-0.07 (+/- 0.52) vs -0.05 (+/- 0.60) mmol/l, P = 0.81]. In contrast, the mean change in radial pulse was significantly decreased in the treated group compared with placebo [-2 (+/- 9) vs 1 (+/- 7) beats per min, P = 0.030].

CONCLUSIONS:

The failure of vitamin D supplementation to change blood pressure or serum cholesterol suggests that the winter increase in these factors is not caused by decreased vitamin D levels.


Acta Med Indones. 2006 Jan-Mar;38(1):3-5.

The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.

Nursyam EW, Amin Z, Rumende CM.

Source

Departement of Internal Medicine, Faculty of Medicine, University of Indonesia-dr.Cipto Mangunkusumo Hospital, Jakarta.

Abstract

AIM:

to compare the vitamin D group of pulmonary tuberculosis patients with a placebo group in terms of clinical improvement, nutritional status, sputum conversion, and radiological improvement.

METHODS:

sixty seven tuberculosis patient visiting the Pulmonary Clinic, of Cipto Mangunkusumo Hospital, Jakarta, from January 1st to August 31st, 2001 were included in this study. The subjects were randomised to receive vitamin D (0.25 mg/day) or placebo in a double blind method, during the 6th initial week of Tb treatment. The rate of sputum conversion, complete blood counts, blood chemistry as well as radiologic examination were evaluated.

RESULTS:

there were more male patients than females (39:28), 78.7% were in the productive age group, 71.6% had low nutritional status, 62.4% with low education level, and 67.2% with low income. One hundred percent of the vitamin D group and only 76.7% of the placebo group had sputum conversion. This difference is statistically significant (p=0.002).

CONCLUSION:

the sputum conversion had no correlation with the hemoglobin level, blood clotting time, calcium level, lymphocyte count, age, sex, and nutritional status. There were more subjects with radiological improvement in the vitamin D group.


Epidemiol Infect. 2009 Oct;137(10):1396-404. Epub 2009 Mar 19.

A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.

Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, Berbari N.

Source

Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA.

Abstract

Vitamin D has been shown to be an important immune system regulator. Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections (URIs). To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms, 162 adults were randomized to receive 50 microg vitamin D3 (2000 IU) daily or matching placebo for 12 weeks. A bi-weekly questionnaire was used to record the incidence and severity of URI symptoms. There was no difference in the incidence of URIs between the vitamin D and placebo groups (48 URIs vs. 50 URIs, respectively, P=0.57). There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [5.4+/-4.8 days vs. 5.3+/-3.1 days, respectively, P=0.86 (95% CI for the difference in duration -1.8 to 2.1)]. The mean 25-hydroxyvitamin D level at baseline was similar in both groups (64.3+/-25.4 nmol/l in the vitamin D group; 63.0+/-25.8 nmol/l in the placebo group; n.s.). After 12 weeks, 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group, whereas there was no change in vitamin D levels in the placebo group. There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter. Further studies are needed to determine the role of vitamin D in infection.


Lancet. 2011 Jan 15;377(9761):242-50. Epub 2011 Jan 5.

High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.

Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, Packe GE, Moore-Gillon JC, Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD, Woodward NJ, Venton TR, Barnes KE, Mullett CJ, Coussens AK, Rutterford CM, Mein CA, Davies GR, Wilkinson RJ, Nikolayevskyy V, Drobniewski FA, Eldridge SM, Griffiths CJ.

Source

Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK. a.martineau@qmul.ac.uk

Abstract

BACKGROUND:

Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent.

METHODS:

We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068.

FINDINGS:

126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001).

INTERPRETATION:

Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism.


Am J Med. 2001 Oct 15;111(6):452-6.

Calcium and vitamin D supplements reduce tooth loss in the elderly.

Krall EA, Wehler C, Garcia RI, Harris SS, Dawson-Hughes B.

Source

Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine, 715 Albany Street, Boston, MA O2118, USA.

Abstract

PURPOSE:

Oral bone and tooth loss are correlated with bone loss at nonoral sites. Calcium and vitamin D supplementation slow the rate of bone loss from various skeletal sites, but it is not known if intake of these nutrients affects oral bone and, in turn, tooth retention.

SUBJECTS AND METHODS:

Tooth loss was examined in 145 healthy subjects aged 65 years and older who completed a 3-year, randomized, placebo-controlled trial of the effect of calcium and vitamin D supplementation on bone loss from the hip, as well as a 2-year follow-up study after discontinuation of study supplements. Teeth were counted at 18 months and 5 years. A comprehensive oral examination at 5 years included assessment of caries, oral hygiene, and periodontal disease. The odds ratio (OR) and 95% confidence interval (CI) of tooth loss were estimated by stepwise multivariate logistic regression. Initial age (mean +/- SD) of subjects was 71 +/- 5 years, and the number of teeth remaining was 22 +/- 7.

RESULTS:

During the randomized trial, 11 of the 82 subjects (13%) taking supplements and 17 of the 63 subjects (27%) taking placebo lost one or more teeth (OR = 0.4; 95% CI: 0.2 to 0.9). During the 2-year follow-up period, 31 of the 77 subjects (40%) with total calcium intake of at least 1000 mg per day lost one or more teeth compared with 40 of the 68 subjects (59%) who consumed less (OR = 0.5; 95% CI: 0.2 to 0.9).

CONCLUSION:

These findings suggest that intake levels of calcium and vitamin D aimed at preventing osteoporosis have a beneficial effect on tooth retention.


Nephrol Dial Transplant. 2008 Nov;23(11):3670-6. Epub 2008 Jun 24.

Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers.

Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C.

Source

Centre de Rein Artificiel, 42 avenue du 8 mai 1945, 69160, Tassin la Demi-lune, France. guillaume-jean-crat@wanadoo.fr

Abstract

BACKGROUND:

Vitamin D deficiency is frequently observed in end-stage renal disease (ESRD) patients; however, the effects of vitamin D supplementation have rarely been reported. We aimed to assess the effects of daily 25(OH)D(3) supplementation on mineral metabolism, bone markers and Kidney Disease Outcomes Quality Initiative (KDOQI) targets in haemodialysis (HD) patients for a period of 6 months.

METHODS:

HD patients were included in this study if their serum 25(OH)D level was <75 mmol/L. Oral 25(OH)D(3) was administered daily at 10-30 microg/day based on the severity of the deficiency. Characteristics of the patients were compared from the baseline to 6 months on the basis of their response to 25(OH)D(3) administration and the patients were divided into three groups. Patients who showed partial response [serum 25(OH)D <75 nmol/L] were placed in group 1, those who showed normal response [serum 25(OH)D ranging from 75 to 150 nmol/L] were placed in group 2 and those who showed excessive response [serum 25(OH)D >150 nmol/L] were placed in group 3.

RESULTS:

Of the 253 HD patients, 225 (89%) showed vitamin D insufficiency or deficiency, 172 were included in the study and 149 patients completed the study. After 6 months of treatment [mean daily 25(OH)D(3): 16 +/- 5 microg/day], the serum 25(OH)D level increased (30 +/- 19 to 126 +/- 46 nmol/ L, P < 0.001), with 13% of patients in group 1, 57% in group 2 and 30% in group 3. The serum intact parathyroid hormone (iPTH) level decreased (235 +/- 186 to 189 +/- 137 pg/mL, P = 0.05), except in group 1. Bone alkaline phosphatase (BALP) showed a tendency to normalize (23 +/- 16 to 18.3 +/- 11 microg/L, P < 0.05), leading to a decrease in alfacalcidol administration from 66% to 43% (P < 0.05), except in group 1. The KDOQI targets achieved increased significantly for serum calcium (76% to 85%) and phosphate levels (66% to 77%) in all patients. The serum albumin level increased in all groups (34.6 +/- 4 to 36.8 +/- 4 g/L, P < 0.05), without any significant improvement in normalized protein catabolic rate (nPCR) or C-reactive proteins (CRP).

CONCLUSION:

With a daily dose ranging from 10 to 30 microg, daily oral 25(OH)D(3) supplementation corrects most vitamin D deficiencies or insufficiencies in HD patients, without any evident toxicity. The main effects observed included correction of excessive bone turnover, despite less alfacalcidol administration, increase in serum albumin level and increase in the percentage of patients with serum calcium and phosphorus levels within the recommendation of the KDOQI guidelines.


J Intern Med. 2008 Dec;264(6):599-609. Epub 2008 Sep 10.

Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial.

Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K.

Source

Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway. rolf.jorde@unn.no

Abstract

OBJECTIVES:

The objective of the present study was to examine the cross-sectional relation between serum 25-hydroxyvitamin D [25-(OH) D] levels and depression in overweight and obese subjects and to assess the effect of vitamin D supplementation on depressive symptoms.

DESIGN:

Cross-sectional study and randomized double blind controlled trial of 20,000 or 40,000 IU vitamin D per week versus placebo for 1 year.

SETTING:

A total of 441 subjects (body mass index 28-47 kg m(-2), 159 men and 282 women, aged 21-70 years) recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway.

MAIN OUTCOME MEASURES:

Beck Depression Inventory (BDI) score with subscales 1-13 and 14-21.

RESULTS:

Subjects with serum 25(OH)D levels < 40 nmol L(-1) scored significantly higher (more depressive traits) than those with serum 25(OH)D levels > or = 40 nmol L(-1) on the BDI total [6.0 (0-23) versus 4.5 (0-28) (median and range)] and the BDI subscale 1-13 [2.0 (0-15) versus 1.0 (0-29.5)] (P < 0.05). In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after 1 year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium.

CONCLUSIONS:

It appears to be a relation between serum levels of 25(OH)D and symptoms of depression. Supplementation with high doses of vitamin D seems to ameliorate these symptoms indicating a possible causal relationship.


Obes Surg. 2009 Feb;19(2):173-9. Epub 2008 Sep 16.

Finding the optimal dose of vitamin D following Roux-en-Y gastric bypass: a prospective, randomized pilot clinical trial.

Goldner WS, Stoner JA, Lyden E, Thompson J, Taylor K, Larson L, Erickson J, McBride C.

Source

Section of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-3020, USA. wgoldner@unmc.edu

Abstract

BACKGROUND:

Vitamin D deficiency is common following bariatric surgery and is due to a combination of baseline deficiency and postoperative malabsorption. There are few prospective studies evaluating the appropriate dose of vitamin D to prevent and treat vitamin D deficiency following bariatric surgery.

METHODS:

We evaluated three doses of vitamin D3 (800, 2,000, and 5,000 IU/day) in a prospective, randomized pilot trial of 45 patients undergoing Roux-en-Y gastric bypass. Serum 25 hydroxy Vitamin D (25OHD), intact PTH (iPTH), calcium, and urine calcium/creatinine ratios were measured at 6, 12, and 24 months postoperatively. Due to a high dropout rate at 24 months, we focus on the 12-month data.

RESULTS:

At 12 months, the 800-, 2,000-, and 5,000-IU groups had a mean +/- SD increase in 25OHD of 27.5 +/- 40.0, 60.2 +/- 37.4, and 66.1 +/- 42.2 nmol/L, respectively (p = 0.09) with a maximum increase in each group of 87.4, 114.8, and 129.8 nmol/L. Forty-four percent, 78%, and 70% achieved 25OHD levels >or=75 nmol/L (p = 0.38). Results for the 6- and 24-month time points were similar to the 12-month results. Mean weight loss at 24 months of the study was not different among groups (p = 0.52). Serum calcium did not change significantly, and there were no cases of hypercalcemia or sustained hypercalciuria.

CONCLUSIONS:

Higher doses of vitamin D supplementation trend towards higher levels of 25OHD. Vitamin D replacement as high as 5,000 IU /day is safe and necessary in many patients to treat vitamin D deficiency following Roux-en-Y gastric bypass yet is still suboptimal in others.


Osteoporos Int. 2009 Feb;20(2):315-22. Epub 2008 Jul 16.

Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.

Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H.

Source

Institute of Clinical Osteology Gustav Pommer and Clinic Der Fürstenhof, Bad Pyrmont, Germany. iko_pyrmont@t-online.de

Abstract

In 242 community-dwelling seniors, supplementation with either 1000 mg of calcium or 1000 mg of calcium plus vitamin D resulted in a decrease in the number of subjects with first falls of 27% at month 12 and 39% at month 20. Additionally, parameters of muscle function improved significantly.

INTRODUCTION:

The efficacy of vitamin D and calcium supplementation on risk of falling in the elderly is discussed controversially. Randomized controlled trials using falls as primary outcome are needed. We investigated long-term effects of calcium and vitamin D on falls and parameters of muscle function in community-dwelling elderly women and men.

METHODS:

Our study population consisted of 242 individuals recruited by advertisements and mailing lists (mean [ +/- SD] age, 77 +/- 4 years). All serum 25-hydroxyvitamin D (25[OH]D) levels were below 78 nmol/l. Individuals received in a double blinded fashion either 1000 mg of calcium or 1000 mg of calcium plus 800 IU of vitamin D per day over a treatment period of 12 months, which was followed by a treatment-free but still blinded observation period of 8 months. Falls were documented using diaries. The study took place in Bad Pyrmont, Germany (latitude 52 degrees ) and Graz, Austria (latitude 46 degrees ).

RESULTS:

Compared to calcium mono, supplementation with calcium plus vitamin D resulted in a significant decrease in the number of subjects with first falls of 27% at month 12 (RR = 0.73; CI = 0.54-0.96) and 39% at month 20 (RR = 0.61; CI = 0.34-0.76). Concerning secondary endpoints, we observed significant improvements in quadriceps strength of 8%, a decrease in body sway of 28%, and a decrease in time needed to perform the TUG test of 11%.

DISCUSSION:

Combined calcium and vitamin D supplementation proved superior to calcium alone in reducing the number of falls and improving muscle function in community-dwelling older individuals.


Age Ageing. 2007 Sep;36(5):507-13. Epub 2007 Jul 26.

Does vitamin D stop inpatients falling? A randomised controlled trial.

Burleigh E, McColl J, Potter J.

Source

Department of Medicine for the Elderly, Mansionhouse Unit, Victoria Infirmary, 21 Mansionhouse Road, Glasgow, G41 3DX, UK. Liz.Burleigh@sgh.scot.nhs.uk

Abstract

BACKGROUND:

Vitamin D deficiency is common in older people and may increase risk of falls and fracture. Hospital inpatients are at particular risk of falling. Previous studies suggest that vitamin D improves neuromuscular function and reduces falls.

OBJECTIVE:

To determine whether routine supplementation with vitamin D plus calcium reduces numbers of fallers and falls in a cohort of hospital admissions while they are inpatients.

DESIGN:

Randomised, double-blind, controlled study. Participants: two hundred and five acute admissions >65 years to a geriatric medical unit.

METHODS:

Patients were randomised to intervention of daily vitamin D 800 iu plus calcium 1,200 mg or control group of daily calcium 1,200 mg, until discharge or death.

RESULTS:

Baseline characteristics were similar in both groups with a median age 84 years and a median length of stay = 30 days (IQR 14.75-71.00). In a pre-selected sub-group (54/205 participants), median admission vitamin D level = 22.00 nmol/l (IQR 15.00-30.50). This did not significantly increase in the treatment versus control group. Median study drug adherence = 88%, with no significant difference between study groups (Mann-Whitney: P = 0.711). Although there were fewer fallers in the vitamin D cohort, this did not reach statistical significance (vitamin D: calcium = 36:45 fallers; RR 0.82 (CI 0.59-1.16). Neither the mean number of falls (vitamin D: calcium = 1.040:1.155; Mann-Whitney P = 0.435) or time to first fall (Log-rank test P = 0.377) differed between groups.

CONCLUSIONS:

In a population of geriatric hospital inpatients, vitamin D did not reduce the number of fallers. Routine supplementation cannot be recommended to reduce falls in this group.


Age Ageing. 2004 Nov;33(6):589-95.

Vitamin D supplementation improves neuromuscular function in older people who fall.

Dhesi JK, Jackson SH, Bearne LM, Moniz C, Hurley MV, Swift CG, Allain TJ.

Source

Elderly Day Hospital, Thomas Guy House, Guys Hospital, St Thomas Street, London, UK. jugdeep.dhesi@gsst.nhs.uk

Abstract

BACKGROUND:

vitamin D supplementation reduces the incidence of fractures in older adults. This may be partly mediated by effects of vitamin D on neuromuscular function.

OBJECTIVE:

to determine the effects of vitamin D supplementation on aspects of neuromuscular function known to be risk factors for falls and fractures.

DESIGN:

randomised, double-blind, placebo-controlled study.

SETTING:

falls clinic taking referrals from general practitioners and accident and emergency department.

SUBJECTS:

139 ambulatory subjects (>/=65 years) with a history of falls and 25-hydroxyvitamin D (25OHD)

OUTCOME MEASURES:

assessments including biochemistry, postural sway, choice reaction time (CRT), aggregate functional performance time (AFPT), and quadriceps strength were carried out at baseline and 6 months post-intervention.

RESULTS:

baseline characteristics were comparable between both groups. 25OHD in the treatment group increased significantly at 6 months. AFPT deteriorated in the control group and improved in the intervention group, representing a significant difference between groups (+6.6 s versus -2.0 s, t = 2.80, P < 0.05). Similar changes were observed for CRT (-0.06 s versus +0.41 s, t = -2.52, P < 0.01) and postural sway (+0.0025 versus -0.0138, t = 2.35, P < 0.02). There was no significant difference in muscle strength change between groups (-10 N versus -2 N, t = -1.26, ns). A significant correlation between change in AFPT and change in 25OHD levels was observed (r = 0.19, P = 0.03). There was no significant difference in the number of falls (0.39 versus 0.24, t = 1.08, P = 0.28) or fallers (14 versus 11, P = 0.52) between two groups.

CONCLUSIONS:

vitamin D supplementation, in fallers with vitamin D insufficiency, has a significant beneficial effect on functional performance, reaction time and balance, but not muscle strength. This suggests that vitamin D supplementation improves neuromuscular or neuroprotective function, which may in part explain the mechanism whereby vitamin D reduces falls and fractures.


Am J Respir Crit Care Med. 2009 May 1;179(9):843-50. Epub 2009 Jan 29.

Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.

Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL, Glerup H, Sodemann M.

Source

Infectious Disease Research Unit, Aarhus University Hospital, Skejby, Brendstrupgaardsvej, 8200 Aarhus N, Denmark. wejse@dadlnet.dk

Abstract

RATIONALE:

Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis.

OBJECTIVES:

To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality.

METHODS:

We conducted a randomized, double-blind, placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month follow-up. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment.

MEASUREMENTS AND MAIN RESULTS:

The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-1+2.

CONCLUSIONS:

Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN35212132).


Diabetes Care. 2007 Apr;30(4):980-6. Epub 2007 Feb 2.

The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults.

Pittas AG, Harris SS, Stark PC, Dawson-Hughes B.

Source

Department of Endocrinology, Diabetes, and Metabolism, Tufts-New England Medical Center, Boston, MA 02111, USA. apittas@tufts-nemc.org

Abstract

OBJECTIVE:

We sought to compare the effects of combined calcium and vitamin D supplementation versus placebo on blood glucose and markers of inflammation in nondiabetic adults aged > or =65 years.

RESEARCH DESIGN AND METHODS:

A total of 314 Caucasian adults without diabetes received either 500 mg calcium citrate and 700 IU vitamin D(3) or placebos daily for 3 years in a double-blind, randomized, controlled trial designed for bone-related outcomes. In a post hoc analysis, fasting plasma glucose (FPG), insulin sensitivity (estimated by homeostasis model assessment of insulin resistance [HOMA-IR]), plasma C-reactive protein, and interleukin-6, were measured at baseline and 3 years.

RESULTS:

The effects of combined calcium-vitamin D supplementation on 3-year change in FPG depended on baseline FPG (P = 0.02 for interaction). Therefore, we conducted analyses separately in participants with normal fasting glucose (NFG) (FPG <5.6 mmol/l, n = 222) and impaired fasting glucose (IFG) (FPG 5.6-6.9 mmol/l, n = 92) at baseline. Among participants with IFG at baseline, those who took combined calcium-vitamin D supplements had a lower rise in FPG at 3 years compared with those on placebo (0.02 mmol/l [0.4 mg/dl] vs. 0.34 mmol/l [6.1 mg/dl], respectively, P = 0.042) and a lower increase in HOMA-IR (0.05 vs. 0.91, P = 0.031). In the NFG subgroup, there was no difference in the change in FPG or HOMA-IR between the two treatment arms. There were no differences in C-reactive protein or interleukin-6 between the two treatment arms in either subgroup.

CONCLUSIONS:

In healthy, older adults with IFG, supplementation with calcium and vitamin D may attenuate increases in glycemia and insulin resistance that occur over time. However, our findings should be considered hypothesis generating and need to be confirmed in randomized trials specifically designed for the outcomes of interest.


Ann Intern Med. 2010 Mar 2;152(5):315-23.

Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events.

Wang L, Manson JE, Song Y, Sesso HD.

Source

Brigham and Women's Hospital and Harvard School of Public Health, Boston, Massachusetts 02215, USA. luwang@rics.bwh.harvard.edu

Abstract

BACKGROUND:

Vitamin D and calcium may affect the cardiovascular system independently and interactively.

PURPOSE:

To assess whether vitamin D and calcium supplements reduce the risk for cardiovascular events in adults.

DATA SOURCES:

Studies published in English from 1966 to July 2009 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.

STUDY SELECTION:

Two investigators independently selected 17 prospective studies and randomized trials that examined vitamin D supplementation, calcium supplementation, or both and subsequent cardiovascular events.

DATA EXTRACTION:

Three investigators extracted and checked data about study designs, participants, exposures or interventions, outcomes, and data quality.

DATA SYNTHESIS:

Five prospective studies of patients receiving dialysis and 1 study involving a general population showed consistent reductions in cardiovascular disease (CVD) mortality among adults who received vitamin D supplements. Four prospective studies of initially healthy persons found no differences in incidence of CVD between calcium supplement recipients and nonrecipients. Results of secondary analyses in 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses (approximately 1000 IU/d) but not with calcium supplementation (pooled relative risk, 1.14 [CI, 0.92 to 1.41]), or a combination of vitamin D and calcium supplementation (pooled relative risk, 1.04 [CI, 0.92 to 1.18]) compared with placebo.

LIMITATIONS:

Only articles published in English that reported cardiovascular event outcomes were included. The small number of studies, the lack of trials designed specifically to assess primary effects on cardiovascular outcomes, and important between-study heterogeneity preclude definitive conclusions.

CONCLUSION:

Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects. Further research is needed to elucidate the role of these supplements in CVD prevention.


Arch Intern Med. 2005 Jul 25;165(14):1618-23.

A randomized controlled trial of vitamin D3 supplementation in African American women.

Aloia JF, Talwar SA, Pollack S, Yeh J.

Source

Department of Medicine, Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY 11501, USA. jaloia@winthrop.org

Abstract

BACKGROUND:

We conducted a randomized, placebo-controlled, double-blind trial to test the hypothesis that vitamin D(3) supplementation would prevent bone loss in calcium-replete, African American postmenopausal women.

METHODS:

Two hundred eight healthy black postmenopausal women, 50 to 75 years of age, were assigned to receive either placebo or 20 microg/d (800 IU) of vitamin D(3). Calcium supplements were provided to ensure a total calcium intake of 1200 to 1500 mg/d. After 2 years, the vitamin D(3) dose was increased to 50 microg/d (2000 IU) in the active group, and the study continued for an additional year. Bone mineral density (BMD) was measured every 6 months. Markers of bone turnover, vitamin D metabolites, and parathyroid hormone (PTH) levels were measured in serum.

RESULTS:

There were no significant differences in BMD between the active and control groups throughout the study. There was also no relationship between serum 25-hydroxyvitamin D levels attained and rates of bone loss. There was an increase in BMD of the total body, hip, and radius at 1 year in both groups. Over the 3 years, BMD declined at these sites by 0.26% to 0.55% per year. The BMD of the lumbar spine increased slightly in the placebo and active groups. There were no persistent changes in serum PTH levels or the markers of bone turnover, although there was a transient decline in PTH in both groups at 3 months. No significant adverse events were attributed to vitamin D supplementation.

CONCLUSIONS:

There was no observed effect of vitamin D(3) supplementation on bone loss or bone turnover markers in calcium-replete, postmenopausal African American women. Further studies are needed to determine if these findings are applicable to women of other ethnic groups.


J Bone Miner Res. 2004 Aug;19(8):1221-30. Epub 2004 May 24.

Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial.

Meier C, Woitge HW, Witte K, Lemmer B, Seibel MJ.

Source

Bone Research Program, ANZAC Research Institute, University Sydney, Concord, New South Wales, Australia.

Abstract

Bone metabolism follows a seasonal pattern with high bone turnover and bone loss during the winter. In a randomized, open-label 2-year sequential follow-up study of 55 healthy adults, we found that supplementation with oral vitamin D3 and calcium during winter abolished seasonal changes in calciotropic hormones and markers of bone turnover and led to an increase in BMD. Supplementation with oral vitamin D3 and calcium during the winter months seems to counteract the effects of seasonal changes in vitamin D and thus may be beneficial as a primary prevention strategy for age-related bone loss.

INTRODUCTION:

Bone metabolism follows a seasonal pattern characterized by high bone turnover and bone loss during winter. We investigated whether wintertime supplementation with oral vitamin D3 and calcium had beneficial effects on the circannual changes in bone turnover and bone mass.

MATERIALS AND METHODS:

This prospective study comprised an initial observation period of 12 months ("year 1"), followed by an intervention during parts of year 2. Fifty-five healthy subjects living in southwestern Germany (latitude, 49.5 degrees N) were randomized into two groups: 30 subjects were assigned to the treatment group and received oral cholecalciferol (500 IU/day) and calcium (500 mg/day) during the winter months of year 2 (October-April), while 25 subjects assigned to the control group obtained no supplements. Primary endpoints were changes in calciotropic hormones [serum 25(OH)D, 1,25(OH)2D, and parathyroid hormone], markers of bone formation (serum bone-specific alkaline phosphatase) and of bone resorption (urinary pyridinoline and deoxypyridinoline), and changes in lumbar spine and femoral neck BMD.

RESULTS:

Forty-three subjects completed the study. During year 1, calciotropic hormones, markers of bone turnover, and BMD varied by season in both groups. During the winter months of year 1, bone turnover was significantly accelerated, and lumbar spine and femoral BMD declined by 0.3-0.9%. In year 2, seasonal changes in calciotropic hormones and markers of bone turnover were either reversed or abolished in the intervention group while unchanged in the control cohort. In the subjects receiving oral vitamin D3 and calcium, lumbar and femoral BMD increased significantly (lumbar spine: +0.8%, p = 0.04 versus year 1; femoral neck: +0.1%, p = 0.05 versus year 1), whereas controls continued to lose bone (intervention group versus control group: lumbar spine, p = 0.03; femoral neck, p = 0.05).

CONCLUSIONS:

Supplementation with oral vitamin D3 and calcium during winter prevents seasonal changes in bone turnover and bone loss in healthy adults. It seems conceivable that annually recurring cycles of low vitamin D and mild secondary hyperparathyroidism during the winter months contributes, at least in part and over many years, to age-related bone loss. Supplementation with low-dose oral vitamin D3 and calcium during winter may be an efficient and inexpensive strategy for the primary prevention of bone loss in northern latitudes.


Am J Clin Nutr. 2006 Apr;83(4):754-9.

Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.

Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R.

Source

Institute of Nutrition and Food Science, University of Bonn, Bonn, Germany.

Abstract

BACKGROUND:

Elevated circulating concentrations of proinflammatory cytokines may contribute to the pathogenesis of congestive heart failure (CHF). In vitro studies suggest that vitamin D suppresses proinflammatory cytokines and increases antiinflammatory cytokines.

OBJECTIVE:

We evaluated the effect of vitamin D supplementation on the survival rate and different biochemical variables in patients with CHF.

DESIGN:

One hundred twenty-three patients randomly received either 50 mug vitamin D(3)/d plus 500 mg Ca/d [D(+) group] or placebo plus 500 mg Ca/d [D(-) group] for 9 mo. Biochemical variables were assessed at baseline and after 9 mo. The survival rate was calculated for a follow-up period of 15 mo.

RESULTS:

Ninety-three patients completed the study. Significant treatment effects were observed on logarithmic-transformed serum concentrations of 25-hydroxyvitamin D (P = 0.001), parathyroid hormone (P = 0.007), tumor necrosis factor alpha (P = 0.006), and interleukin 10 (P = 0.042). 25-Hydroxyvitamin D increased by 26.8 ng/mL in the D(+) group but increased only by 3.6 ng/mL in the D(-) group. Compared with baseline, parathyroid hormone was significantly lower and the antiinflammatory cytokine interleukin 10 was significantly higher in the D(+) group after 9 mo. The proinflammatory cytokine tumor necrosis factor alpha increased in the D(-) group but remained constant in the D(+) group. The survival rate did not differ significantly between the study groups during the follow-up period.

CONCLUSIONS:

Vitamin D(3) reduces the inflammatory milieu in CHF patients and might serve as a new antiinflammatory agent for the future treatment of the disease. Our data provide evidence for the involvement of an impaired vitamin D-parathyroid hormone axis in the progression of CHF.


J Clin Endocrinol Metab. 2006 Feb;91(2):405-12. Epub 2005 Nov 8.

Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial.

El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, Choucair M, Arabi A, Vieth R.

Source

Calcium Metabolism and Osteoporosis Program, American University of Beirut-Medical Center, Bliss Street, 113-6044 Beirut, Lebanon. gf01@aub.edu.lb

Abstract

BACKGROUND:

Despite the high prevalence of hypovitaminosis D in children and adolescents worldwide, the impact of vitamin D deficiency on skeletal health is unclear.

METHODS:

One hundred seventy-nine girls, ages 10-17 yr, were randomly assigned to receive weekly oral vitamin D doses of 1,400 IU (equivalent to 200 IU/d) or 14,000 IU (equivalent to 2,000 IU/d) in a double-blind, placebo-controlled, 1-yr protocol. Areal bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip, forearm, total body, and body composition were measured at baseline and 1 yr. Serum calcium, phosphorus, alkaline phosphatase, and vitamin D metabolites were measured during the study.

RESULTS:

In the overall group of girls, lean mass increased significantly in both treatment groups (P < or = 0.05); bone area and total hip BMC increased in the high-dose group (P < 0.02). In premenarcheal girls, lean mass increased significantly in both treatment groups, and there were consistent trends for increments in BMD and/or BMC at several skeletal sites, reaching significance at lumbar spine BMD in the low-dose group and at the trochanter BMC in both treatment groups. There was no significant change in lean mass, BMD, or BMC in postmenarcheal girls.

CONCLUSIONS:

Vitamin D replacement had a positive impact on musculoskeletal parameters in girls, especially during the premenarcheal period.


BMJ. 2011 May 31;342:d2975. doi: 10.1136/bmj.d2975.

Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India up to age 6 months: randomised controlled trial.

Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, Filteau S.

Source

Institute of Home Economics, Delhi University, F-4 Haus Khas Enclave, New Delhi 110016, India. geetatrilokkumar@gmail.com

Abstract

OBJECTIVE:

To investigate whether vitamin D supplementation can decrease the mortality and morbidity of low birthweight infants in low income countries.

DESIGN:

Randomised controlled trial.

SETTING:

Large government hospital in New Delhi, India.

PARTICIPANTS:

2079 low birthweight infants born at term (>37 weeks' gestation).

MAIN OUTCOME MEASURES:

Primary outcome was admission to hospital or death during the first six months of life. Main secondary outcome was growth.

INTERVENTIONS:

Weekly vitamin D supplements for six months at a dose of one recommended nutrient intake per day (35 µg/week). Infants were visited weekly at home for observed supplementation and were brought to the clinic monthly for clinical examination and anthropometric measurements.

RESULTS:

Between group differences were not significant for death or hospital admissions (92 among 1039 infants in the vitamin D group v 99 among 1040 infants in the placebo group; adjusted rate ratio 0.93, 95% confidence interval 0.68 to 1.29; P = 0.68), or referral to the outpatient clinic for moderate morbidity. Vitamin D supplementation resulted in better vitamin D status as assessed by plasma calcidiol levels at six months. In adjusted analyses, vitamin D treatment significantly increased standard deviation (z) scores at six months for weight, length, and arm circumference and decreased the proportion of children with stunted growth (length for age z score ≤ 2) or with arm circumference z scores of 2 or less.

CONCLUSION:

A weekly dose of vitamin D resulted in better vitamin D status and benefited the classic vitamin D function of bone growth but did not decrease the incidence of severe morbidity or death among young low birthweight infants. Trial registration ClinicalTrials.gov NCT00415402.


BMC Musculoskelet Disord. 2011 Jun 20;12:135.

A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: no advantage of loading doses over daily supplementation.

Papaioannou A, Kennedy CC, Giangregorio L, Ioannidis G, Pritchard J, Hanley DA, Farrauto L, DeBeer J, Adachi JD.

Source

McMaster University, HHSC, St. Peter's Hospital Juravinski Research Centre, 88 Maplewood Avenue Hamilton, ON L8M 1W9, Canada. papaioannou@hhsc.ca

Abstract

BACKGROUND:

There remains uncertainty regarding the appropriate therapeutic management of hip fracture patients. The primary aim of our study was to examine whether large loading doses in addition to daily vitamin D offered any advantage over a simple daily low-dose vitamin D regimen for increasing vitamin D levels.

METHODS:

In this randomized controlled study, patients over age 50 with an acute fragility hip fracture were enrolled from two hospital sites in Ontario, Canada. Participants were randomized to one of three loading dose groups: placebo; 50,000 IU vitamin D2; or 100,000 IU D2. Following a placebo/loading dose, all patients received a daily tablet of 1,000 IU vitamin D3 for 90 days. Serum 25-hydroxy vitamin D (25-OHD) was measured at baseline, discharge from acute care (approximately 4-weeks), and 3-months.

RESULTS:

Sixty-five patients were enrolled in the study (44% male). An immediate rise in 25-OHD occurred in the 100,000 group, however there were no significant differences in 25-OHD between the placebo, 50,000 and 100,000 loading dose groups after 4-weeks (69.3, 84.5, 75.6 nmol/L, p = 0.15) and 3-months (86.7, 84.2, 73.3 nmol/L, p = 0.09), respectively. At the end of the study, approximately 75% of the placebo and 50,000 groups had reached the target therapeutic range (75 nmol/L), and 44% of the 100,000 group.

CONCLUSIONS:

In correcting vitamin D insufficiency/deficiency in elderly patients with hip fracture, our findings suggest that starting with a lower daily dose of Vitamin D3 achieved similar results as providing an additional large loading dose of Vitamin D2. At the end of the study, all three groups were equally effective in attaining improvement in 25-OHD levels. Given that a daily dose of 1,000 IU vitamin D3 (with or without a loading dose) resulted in at least 25% of patients having suboptimal vitamin D status, patients with acute hip fracture may benefit from a higher daily dose of vitamin D.


Am J Clin Nutr. 2011 Aug;94(2):486-94. Epub 2011 Jun 29.

Effects of vitamin D and calcium supplementation on pancreatic β 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.

Mitri J, Dawson-Hughes B, Hu FB, Pittas AG.

Source

Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, Boston, MA 02111, USA.

Abstract

BACKGROUND:

A suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking.

OBJECTIVE:

We determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes.

DESIGN:

Ninety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic β cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia.

RESULTS:

Participants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D × calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change ± SE: 300 ± 130 compared with -126 ± 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 ± 39 compared with -36 ± 37 mU · L(-1) · min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 ± 0.03% compared with 0.14 ± 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium.

CONCLUSION:

In adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved β cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.


J Clin Oncol. 2011 Aug 1;29(22):3078-84. Epub 2011 Jun 27.

Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial.

Tang JY, Fu T, Leblanc E, Manson JE, Feldman D, Linos E, Vitolins MZ, Zeitouni NC, Larson J, Stefanick ML.

Source

Department of Dermatology, Stanford University School of Medicine, 450 Broadway, Pavilion C, MC 5334, Redwood City, CA, USA. tangy@stanford.edu

Abstract

PURPOSE:

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.

METHODS:

Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.

RESULTS:

Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.

CONCLUSION:

Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.


Cochrane Database Syst Rev. 2011 Jul 6;(7):CD007470.

Vitamin D supplementation for prevention of mortality in adults.

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C.

Source

Department of Internal Medicine - Gastroenterology and Hepatology, Medical Faculty, University of Nis, Zorana Djindjica 81, Nis, Serbia, 18000.

Abstract

BACKGROUND:

The available evidence on vitamin D and mortality is inconclusive.

OBJECTIVES:

To assess the beneficial and harmful effects of vitamin D for prevention of mortality in adults.

SEARCH STRATEGY:

We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science (to January 2011). We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials.

SELECTION CRITERIA:

We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention. Vitamin D could have been administered as supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).

DATA COLLECTION AND ANALYSIS:

Six authors extracted data independently. Random-effects and fixed-effect model meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RR). To account for trials with zero events, meta-analyses of dichotomous data were repeated using risk differences (RD) and empirical continuity corrections. Risk of bias was considered in order to minimise risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors.

MAIN RESULTS:

Fifty randomised trials with 94,148 participants provided data for the mortality analyses. Most trials included elderly women (older than 70 years). Vitamin D was administered for a median of two years. More than one half of the trials had a low risk of bias. Overall, vitamin D decreased mortality (RR 0.97, 95% confidence interval (CI) 0.94 to 1.00, I(2) = 0%). When the different forms of vitamin D were assessed separately, only vitamin D(3) decreased mortality significantly (RR 0.94, 95% CI 0.91 to 0.98, I(2) = 0%; 74,789 participants, 32 trials) whereas vitamin D(2), alfacalcidol, or calcitriol did not. Trial sequential analysis supported our finding regarding vitamin D(3), corresponding to 161 individuals treated to prevent one additional death. Vitamin D(3) combined with calcium increased the risk of nephrolithiasis (RR 1.17, 95% CI 1.02 to 1.34, I(2) = 0%). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18, 95% CI 1.17 to 8.68, I(2) = 17%). Data on health-related quality of life and health economics were inconclusive.

AUTHORS' CONCLUSIONS:

Vitamin D in the form of vitamin D(3) seems to decrease mortality in predominantly elderly women who are mainly in institutions and dependent care. Vitamin D(2), alfacalcidol, and calcitriol had no statistically significant effect on mortality. Vitamin D(3) combined with calcium significantly increased nephrolithiasis. Both alfacalcidol and calcitriol significantly increased hypercalcaemia.


Diabetes. 2011 Nov;60(11):2748-57. Epub 2011 Sep 12.

Vitamin D, insulin secretion, sensitivity, and lipids: results from a case-control study and a randomized controlled trial using hyperglycemic clamp technique.

Grimnes G, Figenschau Y, Almås B, Jorde R.

Source

Tromsø Endocrine Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway. guri.grimnes@unn.no

Abstract

OBJECTIVE:

Vitamin D deficiency is associated with an unfavorable metabolic profile in observational studies. The intention was to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels.

RESEARCH DESIGN AND METHODS:

Participants were recruited from a population-based study (the Tromsø Study) based on their serum 25(OH)D measurements. A 3-h hyperglycemic clamp was performed, and the participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D(3) or identical-looking placebo twice weekly for 6 months. A final hyperglycemic clamp was then performed.

RESULTS:

The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA(1c) and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups.

CONCLUSIONS:

Vitamin D supplementation to apparently healthy subjects with insufficient serum 25(OH)D levels does not improve insulin sensitivity or secretion or serum lipid profile.


J Bone Miner Res. 2011 Sep 28. doi: 10.1002/jbmr.524. [Epub ahead of print]

Effects of three monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility and muscle strength in older postmenopausal women: a randomised controlled trial.

Glendenning P, Zhu K, Inderjeeth C, Howat P, Lewis JR, Prince RL.

Source

School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia.

Abstract

Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3 monthly vitamin D therapy on falls, muscle strength and mobility, we conducted a nine-month randomised, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n=353) or an identical placebo (n=333). All participants were advised to increase dietary calcium intake. Falls data were collected three monthly. At baseline, 3, 6 and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7±4.1 years. The average serum 25OHD value at baseline was 65.8±22.7 nmol/L. By three, six and nine months after supplementation, 25OHD levels of the vitamin D group were approximately 15 nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864±412mg/day) and 9 months (855±357mg/day). Faller rates in the two groups did not differ: vitamin D group 102/353(29%); placebo group 89/333(27%). At 9 months, compared to placebo or baseline, muscle strength and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered three monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures. © 2011 American Society for Bone and Mineral Research.


PLoS One. 2011;6(11):e25966. Epub 2011 Nov 4.

Effects of vitamin d supplementation on cognitive and emotional functioning in young adults - a randomised controlled trial.

Dean AJ, Bellgrove MA, Hall T, Phan WM, Eyles DW, Kvaskoff D, McGrath JJ.

Source

Queensland Brain Institute, The University of Queensland, St Lucia, Australia.

Abstract

BACKGROUND:

Epidemiological research links vitamin D status to various brain-related outcomes. However, few trials examine whether supplementation can improve such outcomes and none have examined effects on cognition. This study examined whether Vitamin D supplementation led to improvements in diverse measures of cognitive and emotional functioning, and hypothesised that supplementation would lead to improvements in these outcomes compared to placebo.

METHODS/PRINCIPAL FINDINGS:

Healthy young adults were recruited to a parallel-arm, double-blind trial conducted at The University of Queensland. Participants were randomly allocated to receive Vitamin D (one capsule daily, containing 5000 IU cholecalciferol) or identical placebo capsule for six weeks. All participants and outcome assessors were blinded to group assignment. Primary outcome measures assessed at baseline and 6 weeks were working memory, response inhibition and cognitive flexibility. Secondary outcomes were: hallucination-proneness, psychotic-like experiences, and ratings of depression, anxiety and anger. 128 participants were recruited, randomised and included in primary analyses (vitamin D n = 63; placebo n = 65). Despite significant increases in vitamin D status in the active group, no significant changes were observed in working memory (F = 1.09; p = 0.30), response inhibition (F = 0.82; p = 0.37), cognitive flexibility (F = 1.37; p = 0.24) or secondary outcomes. No serious adverse effects were reported.

CONCLUSIONS:

Our findings indicate that vitamin D supplementation does not influence cognitive or emotional functioning in healthy young adults. Future controlled trials in targeted populations of interest are required to determine whether supplementation can improve functioning in these domains. Australian and New Zealand Clinical Trials Registry; ACTRN12610000318088.


Indian Pediatr. 2011 Aug 15. pii: S097475591100214-1. [Epub ahead of print]

Vitamin D Supplementation for Severe Pneumonia A Randomized Controlled Trial.

Choudhary N, Gupta P.

Source

Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, India. Correspondence to: Dr Nidhi Choudhary, Block ED, 72A, Pitampura, Delhi 110 034, India, nidhi_mamc2001@yahoo.co.in.

Abstract

OBJECTIVE:

To determine the role of oral vitamin D supplementation for resolution of severe pneumonia in under-five children.

DESIGN:

Randomized double blind placebo-controlled trial.

SETTING:

Inpatients from a tertiary care hospital.

PARTICIPANTS:

Two hundred children [mean (SD) age: 13.9 (11.7) months; boys: 120] between 2 months to 5 years with severe pneumonia. Pneumonia was diagnosed in the presence of fever, cough, tachypnea (as per WHO cutoffs) and crepitations. Children with pneumonia and chest indrawing or at least one of the danger sign (inability to feed, lethargy, cyanosis) were diagnosed as having severe pneumonia. The two groups were comparable for baseline characteristics including age, anthropometry, socio-demographic profile and clinical and laboratory parameters.

INTERVENTION:

Oral vitamin D (1000 IU for <1 year and 2000 IU for >1 year) (n=100) or placebo (lactose) (n=100) once a day for 5 days, from enrolment. Both the groups received antibiotics as per the Indian Academy of Pediatrics guidelines, and supportive care (oxygen, intravenous fluids and monitoring).

OUTCOME VARIABLES:

Primary: time to resolution of severe pneumonia. SECONDARY: duration of hospitalization and time to resolution of tachypnea, chest retractions and inability to feed.

RESULTS:

Median duration (SE, 95% CI) of resolution of severe pneumonia was similar in the two groups [vitamin D: 72 (3.7, 64.7-79.3) hours; placebo: 64 (4.5, 55.2-72.8)hours]. Duration of hospitalization and time to resolution of tachypnea, chest retractions, and inability to feed were also comparable between the two groups.

CONCLUSION:

Short-term supplementation with oral vitamin D (1000-2000 IU per day for 5 days) has no beneficial effect on resolution of severe pneumonia in under-five children. Further studies needs to be conducted with higher dose of Vitamin D or longer duration of supplementation to corroborate these findings.


Eur J Nutr. 2011 Nov 16. [Epub ahead of print]

Is a daily supplementation with 40 microgram vitamin D(3) sufficient? A randomised controlled trial.

Toss G, Magnusson P.

Source

Department of Endocrinology and Gastroenterology, County Council of Östergötland, SE-581 85, Linköping, Sweden.

Abstract

PURPOSE:

The effect of 40 μg (1,600 IU) per day of vitamin D(3) on serum 25-hydroxyvitamin D (25(OH)D) and markers of bone and mineral metabolism was evaluated.

METHODS:

This intervention study was designed as a double-blind randomised controlled trial. Forty-five community-dwelling subjects (32 females), age 55-84 years, at 58° North latitude were supplemented for 1 year with 40 μg vitamin D(3) plus 1,000 mg calcium per day, or with 1,000 mg calcium per day for controls. Safety parameters and 25(OH)D, intact parathyroid hormone (PTH), ionized calcium, bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase isoform 5b (TRACP5b) were measured over the study period.

RESULTS:

All subjects supplemented with vitamin D(3) reached a 25(OH)D level above 50 nmol/L. Mean (SD) serum 25(OH)D increased from 50.4 (13.5) nmol/L to 84.2 (17.5) nmol/L, range 55.0-125.0 nmol/L in the vitamin D(3) supplemented group and the corresponding levels for the control group were 47.3 (14.1) nmol/L and 45.7 (13.4) nmol/L, range 26.0-73.0 nmol/L. No serious adverse event was recorded and the highest 25(OH)D level reached, 125.0 nmol/L, is well below toxic levels. BALP and TRACP5b did not change significantly over the study period.

CONCLUSIONS:

This trial suggests that a daily supplementation with 40 μg vitamin D(3) is sufficient to secure a 25(OH)D level of 50 nmol/L. No side effects were observed in the study group.


J Clin Endocrinol Metab. 2011 Nov 23. [Epub ahead of print]

Long-Term Follow-Up for Mortality and Cancer in a Randomized Placebo-Controlled Trial of Vitamin D3 and/or Calcium (RECORD Trial).

Avenell A, Maclennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, Grant AM, Campbell MK, Anderson FH, Cooper C, Francis RM, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA; the RECORD Trial Group.

Source

Health Services Research Unit (A.A., G.S.M., D.J.J., G.C.M., A.M.M., P.R.P., A.M.G., M.K.C.), University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; Geriatric Medicine (F.H.A.), Developmental Origins of Health and Disease, Research Division, and Medical Research Council Lifecourse Epidemiology Unit (C.C.), University of Southampton, Southampton SO16 6YD, and Institute of Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom; Institute for Ageing and Health (R.M.F.), Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom; Hull York Medical School (W.J.G.), University of Hull, Hull HU6 7RX, United Kingdom; Royal Infirmary of Edinburgh (C.M.R.), Edinburgh EH3 9HB, United Kingdom; York Trials Unit (D.J.T.), University of York, York YO10 5DD, United Kingdom; and Medical and Surgical Sciences (W.A.W.), University of Nottingham, Nottingham NG7 2UH, United Kingdom.

Abstract

Context:Vitamin D or calcium supplementation may have effects on vascular disease and cancer.Objective:Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people.Design and Setting:The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom.Participants:Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture.

Interventions:Participants were randomly allocated to daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention.Main Outcome Measures:All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated.

Results:In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85-1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79-1.05), cancer mortality (HR = 0.85; 95% CI = 0.68-1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92-1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94-1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92-1.24), cancer mortality (HR = 1.13; 95% CI = 0.91-1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91-1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant.

Conclusions:Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence.


Am J Cardiol. 2011 Nov 7. [Epub ahead of print]

Vitamin D Deficiency and Supplementation and Relation to Cardiovascular Health.

Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA.

Source

Mid America Cardiology, Division of Cardiovascular Medicine, University of Kansas Medical Center and Hospital, Kansas City, Kansas.

Abstract

Recent evidence supports an association between vitamin D deficiency and hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease, and heart failure. The effect of vitamin D supplementation, however, has not been well studied. We examined the associations between vitamin D deficiency, vitamin D supplementation, and patient outcomes in a large cohort. Serum vitamin D measurements for 5 years and 8 months from a large academic institution were matched to patient demographic, physiologic, and disease variables. The vitamin D levels were analyzed as a continuous variable and as normal (≥30 ng/ml) or deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate analysis, survival analysis, and Cox proportional hazard modeling were performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were women (n = 7,758), and the average body mass index was 30 ± 8 kg/m(2). The mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients, 3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were deficient. Vitamin D deficiency was associated with several cardiovascular-related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001). In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency.


Am J Clin Nutr. 2011 Oct;94(4):1144-9. Epub 2011 Aug 31.

Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.

Bolland MJ, Grey A, Gamble GD, Reid IR.

Source

Department of Medicine, University of Auckland, New Zealand. m.bolland@auckland.ac.nz

Abstract

BACKGROUND:

Frequent use of personal, nonprotocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D (CaD) on cardiovascular risk in the Women's Health Initiative (WHI).

OBJECTIVE:

We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study (WHI CaD) by using the WHI limited-access clinical trials data set.

DESIGN:

The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community-dwelling, postmenopausal women. The incidence of total cancer (excluding nonmelanoma skin cancers), breast and colorectal cancers, hip and total fracture, and mortality was assessed by using Cox proportional hazards models.

RESULTS:

In the WHI CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).

CONCLUSIONS:

For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality. The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements. The WHI CaD trial is registered at clinicaltrials.gov as NCT00000611.


Am J Clin Nutr. 2007 Jun;85(6):1586-91.

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.

Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.

Source

Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA. jmlappe@creighton.edu

Erratum in

  • Am J Clin Nutr. 2008 Mar;87(3):794.

Abstract

BACKGROUND:

Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking.

OBJECTIVE:

The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types.

DESIGN:

This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo.

RESULTS:

When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk.

CONCLUSIONS:

Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.


Trop Med Int Health. 2010 Oct;15(10):1148-55. doi: 10.1111/j.1365-3156.2010.02578.x. Epub 2010 Aug 17.

Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.

Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G.

Source

Aga Khan Health Services, Kabul, Afghanistan Kabul Medical University, Kabul, Afghanistan.

Abstract

OBJECTIVES:

To determine whether (i) supplementation of oral 100,000 iu of vitamin D(3) (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes.

METHODS:

Double-blind individually randomised placebo-controlled trial in an inner-city hospital in Kabul, of 453 children aged 1-36 months, diagnosed with non-severe or severe pneumonia at the outpatient clinic. Children with rickets, other concurrent severe diseases, very severe pneumonia or wheeze, were excluded. Children were given vitamin D(3) or placebo drops additional to routine pneumonia treatment.

RESULTS:

Two hundred and twenty-four children received vitamin D(3;) and 229 received placebo. There was no significant difference in the mean number of days to recovery between the vitamin D(3) (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89; P = 0.17). The risk of a repeat episode of pneumonia within 90 days of supplementation was lower in the intervention (92/204; 45%) than the placebo group [122/211; (58%; relative risk 0.78; 95% CI 0.64, 0.94; P = 0.01]. Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02).

CONCLUSION:

A single high-dose oral vitamin D(3) supplementation to young children along with antibiotic treatment for pneumonia could reduce the occurrence of repeat episodes of pneumonia.


JAMA. 2005 May 11;293(18):2257-64.

Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.

Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B.

Source

Department of Nutrition, Harvard School of Public Health, Boston, Mass 02115, USA. hbischof@hsph.harvard.edu

Abstract

CONTEXT:

The role and dose of oral vitamin D supplementation in nonvertebral fracture prevention have not been well established.

OBJECTIVE:

To estimate the effectiveness of vitamin D supplementation in preventing hip and nonvertebral fractures in older persons.

DATA SOURCES:

A systematic review of English and non-English articles using MEDLINE and the Cochrane Controlled Trials Register (1960-2005), and EMBASE (1991-2005). Additional studies were identified by contacting clinical experts and searching bibliographies and abstracts presented at the American Society for Bone and Mineral Research (1995-2004). Search terms included randomized controlled trial (RCT), controlled clinical trial, random allocation, double-blind method, cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, fractures, humans, elderly, falls, and bone density.

STUDY SELECTION:

Only double-blind RCTs of oral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementation or placebo in older persons (> or =60 years) that examined hip or nonvertebral fractures were included.

DATA EXTRACTION:

Independent extraction of articles by 2 authors using predefined data fields, including study quality indicators.

DATA SYNTHESIS:

All pooled analyses were based on random-effects models. Five RCTs for hip fracture (n = 9294) and 7 RCTs for nonvertebral fracture risk (n = 9820) met our inclusion criteria. All trials used cholecalciferol. Heterogeneity among studies for both hip and nonvertebral fracture prevention was observed, which disappeared after pooling RCTs with low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d), separately. A vitamin D dose of 700 to 800 IU/d reduced the relative risk (RR) of hip fracture by 26% (3 RCTs with 5572 persons; pooled RR, 0.74; 95% confidence interval [CI], 0.61-0.88) and any nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR, 0.77; 95% CI, 0.68-0.87) vs calcium or placebo. No significant benefit was observed for RCTs with 400 IU/d vitamin D (2 RCTs with 3722 persons; pooled RR for hip fracture, 1.15; 95% CI, 0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI, 0.86-1.24).

CONCLUSIONS:

Oral vitamin D supplementation between 700 to 800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention.


Horm Metab Res. 2011 Mar;43(3):223-5. Epub 2010 Dec 10.

Effect of vitamin D supplementation on testosterone levels in men.

Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A.

Source

Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria.

Abstract

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 μg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3). Initial 25(OH)D concentrations were in the deficiency range (< 50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.


Br J Nutr. 2010 Feb;103(4):549-55. Epub 2009 Sep 28.

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.

von Hurst PR, Stonehouse W, Coad J.

Source

Institute of Food, Nutrition and Human Health, Massey University, Private Bag 102 904, North Shore Mail Centre, Auckland, New Zealand. p.r.vonhurst@massey.ac.nz

Abstract

Low serum 25-hydroxyvitamin D (25(OH)D) has been shown to correlate with increased risk of type 2 diabetes. Small, observational studies suggest an action for vitamin D in improving insulin sensitivity and/or insulin secretion. The objective of the present study was to investigate the effect of improved vitamin D status on insulin resistance (IR), utilising randomised, controlled, double-blind intervention administering 100 microg (4000 IU) vitamin D(3) (n 42) or placebo (n 39) daily for 6 months to South Asian women, aged 23-68 years, living in Auckland, New Zealand. Subjects were insulin resistant - homeostasis model assessment 1 (HOMA1)>1.93 and had serum 25(OH)D concentration < 50 nmol/l. Exclusion criteria included diabetes medication and vitamin D supplementation >25 microg (1000 IU)/d. The HOMA2 computer model was used to calculate outcomes. Median (25th, 75th percentiles) serum 25(OH)D(3) increased significantly from 21 (11, 40) to 75 (55, 84) nmol/l with supplementation. Significant improvements were seen in insulin sensitivity and IR (P = 0.003 and 0.02, respectively), and fasting insulin decreased (P = 0.02) with supplementation compared with placebo. There was no change in C-peptide with supplementation. IR was most improved when endpoint serum 25(OH)D reached > or = 80 nmol/l. Secondary outcome variables (lipid profile and high sensitivity C-reactive protein) were not affected by supplementation. In conclusion, improving vitamin D status in insulin resistant women resulted in improved IR and sensitivity, but no change in insulin secretion. Optimal vitamin D concentrations for reducing IR were shown to be 80-119 nmol/l, providing further evidence for an increase in the recommended adequate levels. Registered Trial No. ACTRN12607000642482.


Osteoporos Int. 2010 Jul;21(7):1121-32. Epub 2009 Dec 3.

Benefit-risk assessment of vitamin D supplementation.

Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC.

Source

Centre on Aging and Mobility, Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich, Gloriastrasse 25, 8091, Zurich, Switzerland. Heike.Bischoff@usz.ch

Abstract

Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D.

INTRODUCTION:

This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk.

METHODS AND RESULTS:

Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk.

CONCLUSION:

Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.


J Bone Miner Res. 2011 Oct;26(10):2341-57. doi: 10.1002/jbmr.463.

Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness.

Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL.

Source

Division of Neonatology and Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC 29425, USA. hollisb@musc.edu

Abstract

The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000IU of vitamin D(3) per day until delivery. The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p<0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000-IU group (p<0.0001). The relative risk (RR) for achieving a concentration of 80nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups (RR=1.52, 95% CI 1.24-1.86), the 4000- and the 400-IU groups (RR=1.60, 95% CI 1.32-1.95) but not between the 4000- and. 2000-IU groups (RR=1.06, 95% CI 0.93-1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3) concentrations throughout pregnancy (p<0.0001), with maximal production of 1,25(OH)(2)D(3) in all strata in the 4000-IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans.


Review of Vitamin D trials - Grant Jan 2012        
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