Colecalciferol (vitamin D3)

Serious harms

Colecalciferol is vitamin D3, prescribed to prevent and treat vitamin D deficiency and alongside osteoporosis treatment ¹².

Condition	How often	Who is at risk	Source
Hypercalcaemia; if severe, arrhythmia, coma, death	Uncommon (1 in 1000 to 1 in 100); 9 of 102 on 10,000 IU daily against 0 of 109 on 400 IU over 3 years, all mild	Overdose; leukaemia, lymphoma, sarcoidosis; thiazide users	¹³⁴²
Irreversible kidney damage; soft-tissue calcification	Not quantified	Chronic overdose; impaired kidney function	¹²
Urinary tract stones	449 of 18,176 against 381 of 18,106 over 7 years (HR 1.17, 1.02 to 1.34)	Postmenopausal women taking calcium	⁵
Falls and fractures	500,000 IU yearly: falls 83.4 against 72.7, fractures 4.9 against 3.9 per 100 person-years (2256 women); 100,000 IU monthly against a standard dose: falls 1.47 against 0.63 per person-year (107 residents)	Women 70 or older; care residents	⁶⁷
Serious falls; falls with hospitalisation	7.5 against 4.1 and 4.8 against 2.0 per 100 person-years, pooled 1000 to 4000 against 200 IU daily (688 people); at 2000 IU, hospitalisation or death 33.6 against 12.1, arm stopped	70 or older, raised fall risk	⁸
Infantile hypercalcaemia with nephrocalcinosis	Estimated 1 in 32,465 births in Poland (CYP24A1 form)	Biallelic CYP24A1 or SLC34A1 loss	⁹
Infant overdose with coma, arrhythmia, permanent kidney impairment	Not quantified	Oversized droppers	¹⁰
Anaphylaxis; angio-oedema	Not quantified	Peanut or soya allergy (imported capsules); otherwise not stated	¹¹¹

In intoxication, 25-hydroxyvitamin D, or 25(OH)D, accumulates and parathyroid hormone (PTH) is suppressed; bone resorption and intestinal absorption raise calcium ¹². A UK label puts the adult intoxication threshold at 40,000 to 100,000 IU daily for 1 to 2 months; infants may react to far less ². Calcium normalises over weeks to months after stopping; soft-tissue damage may be permanent ²¹².

Other pathways it affects

Calcitriol acts in many tissues and directly or indirectly regulates about 3% of the genome ¹².

Tissue	Mechanism	Measured in people
Parathyroid glands	Calcitriol suppresses PTH transcription and parathyroid cell proliferation ¹⁸¹⁹	PTH 17.1 ng/L during hypercalciuria against 20.2 otherwise ¹²
Bone	With PTH, calcitriol activates osteoclasts ¹⁹	Radial density fell 3.5% on 10,000 IU daily against 1.2% on 400 IU over 3 years; estimated strength unchanged, relevance unclear ³¹²
Phosphate	Calcitriol stimulates FGF23, which suppresses CYP27B1 and induces CYP24A1; Fgf23-deficient mice have hyperphosphataemia ¹⁸	FGF23 not significantly changed by 2800 IU daily (181 adults, 8 weeks) ²⁰
Immune cells	In cells, calcitriol induces cathelicidin and impairs dendritic-cell maturation ¹⁸	Autoimmune disease 0.95% against 1.20% over 5.3 years (HR 0.78, 0.61 to 0.99); 0.85 (0.70 to 1.04) with later-confirmed cases ²¹¹⁴
Heart and vessels	Mice lacking the vitamin D receptor (VDR) or CYP27B1 have raised renin, hypertension and cardiac hypertrophy ¹⁸	Cardiovascular events not reduced in VITAL (HR 0.97) or ViDA (HR 1.02) ¹³²²
Fetus	High doses teratogenic in animals ¹	Up to 28,000 IU weekly in 1300 pregnancies: asymptomatic postpartum hypercalcaemia in 0.7% of women and of infants ²³

What it is for and how it works

Vitamin D is needed to absorb calcium from food ¹⁸.

Vitamin D3 400 IU daily prevents deficiency rickets in children, in which 25(OH)D is usually below 10 ng/mL ¹⁸. Liver CYP2R1 and kidney CYP27B1 hydroxylate colecalciferol to calcitriol, which binds VDR and increases intestinal TRPV6 and calbindin-D9k ²⁹¹⁸.

Vitamin D3 activation and inactivationEpidermis, liver endoplasmic reticulum and renal proximal tubule mitochondria

7-Dehydrocholesterol
several stepsUVB opens the B ring to previtamin D3, which isomerises thermally
Colecalciferol (vitamin D3)
Vitamin D 25-hydroxylase (CYP2R1)Microsomal enzyme of liver; the product binds vitamin D-binding protein
Calcifediol (25-hydroxyvitamin D3)
25-Hydroxyvitamin D 1α-hydroxylase (CYP27B1)Ferredoxin, Ferredoxin reductaseMitochondrial; PTH induces it, FGF23 and calcitriol suppress it
Calcitriol (1,25-dihydroxyvitamin D3)
Vitamin D 24-hydroxylase (CYP24A1)Sequential C-24 oxidations; calcitriol and FGF23 induce it, PTH suppresses it
Calcitroic acid

In the body

Colecalciferol is stored mainly in fat ¹².

The half-life of 25(OH)D is 13 to 15 days, of serum vitamin D3 about 24 hours ¹²³⁰. Thiazides reduce urinary calcium excretion and raise hypercalcaemia risk; vitamin D3 may increase digitalis toxicity ²¹.

Genetic variation

Some infants inherit defects that make preventive vitamin D raise blood calcium severely ⁹.

Biallelic loss of CYP24A1, which degrades calcitriol, or of SLC34A1, a renal phosphate transporter, causes this; in Poland, cases rose with prophylaxis of 300,000 units three times a year, and all 11 historical cases tested carried mutations ⁹.

Benefit against harm

Across 81 trials, vitamin D did not reduce fractures or falls ³¹.

Of those tested in VITAL, 12.7% had 25(OH)D below 20 ng/mL; in ViDA, 24.9% ¹³²².

Group	Benefit	Serious harm
Older adults, with calcium	Hip fracture 1 fewer per 1000 a year in the community (from 8), 9 fewer in institutions (from 54) ³²	Stones or kidney insufficiency 9 against 8 per 10,000 a year ³²
Adults 50 or older, 2000 IU daily, 5.3 years (25,871)	Cancer 793 against 824; fracture 769 against 782 ¹³³³	Hypercalcaemia and stones not significantly increased ¹³
25 trials, ages 0 to 95; data for 10,933 of 11,321	Respiratory infection NNT 33; NNT 4 below 25 nmol/L with daily or weekly doses ³⁴	Hypercalcaemia 21 of 3850, evenly distributed ³⁴

Without the medicine

Exercise prevents falls in older people living in the community ³⁸.

Falls were 0.77 times control (59 trials, 12,981 people), 195 fewer per 1000 a year; fall-related fractures RR 0.73 (low certainty) ³⁸. Sunlight makes vitamin D3 in skin; UVB intoxication has not been reported ¹⁹.

How the recommendations were set

Europe’s upper limit derives from the lowest dose that repeatedly raised urine calcium ¹².

EFSA divided 250 µg (10,000 IU) daily, with recurrent hypercalciuria in 11.3% against 4.0% on 10 µg, by 2.5, giving 100 µg daily ¹².

Stopping

After stopping, blood levels fall over weeks to months ¹²⁶.

Two years after VITAL ended, autoimmune disease no longer differed: 255 cases against 259 (HR 0.98) ¹⁴.

A prescription is changed together with the prescriber.

References

Regulator
Medicines and Healthcare products Regulatory Agency; Thornton & Ross Ltd (marketing authorisation holder). Fultium-D3 800 IU Capsules: summary of product characteristics MHRA Products, marketing authorisation PL 00240/0624; date of revision of the text 1 September 2026, 2026.
https://mhraproducts4853.blob.core.windows.net/docs/d536a204bd084be63dc38ae3d42a6bc86bfdf493
Funding and finding
Funding
not stated; UK product information carries no funding statement.
Finding
Indication: treatment and prophylaxis of vitamin D deficiency in adults and adolescents over 12 years with an identified risk; daily dose not to exceed 4000 IU. Contraindications: hypersensitivity, hypervitaminosis D, nephrolithiasis, nephrocalcinosis, conditions causing hypercalcaemia or hypercalciuria, severe renal impairment. Patients with pseudohypoparathyroidism, sarcoidosis, or taking thiazide diuretics or cardiac glycosides must be referred to their doctor; during long-term treatment serum calcium and renal function should be monitored, especially in elderly patients taking cardiac glycosides or diuretics and in patients prone to stone formation; the dose should be reduced or stopped if urinary calcium exceeds 300 mg (7.5 mmol) per 24 hours; serum calcium must be monitored at daily doses above 1000 IU. Undesirable effects: hypercalcaemia and hypercalciuria uncommon (more than 1/1000, less than 1/100); hypersensitivity reactions such as angio-oedema or laryngeal oedema, frequency not known. Overdose: hypercalcaemia can severely damage soft tissues and kidneys; symptoms include polyuria, nephrocalcinosis, renal calculi and in severe cases cardiac arrhythmias; extreme hypercalcaemia may result in coma and death; persistently high calcium may lead to irreversible renal damage and soft tissue calcification. Preclinical: high doses were teratogenic in animals; offspring of rabbits given high doses had lesions resembling supravalvular aortic stenosis.
Regulator
Medicines and Healthcare products Regulatory Agency; Consilient Health Limited (marketing authorisation holder). InVita D3 50,000 IU soft capsules: summary of product characteristics MHRA Products, marketing authorisation PL 24837/0074; date of revision of the text 21 July 2016, 2016.
https://mhraproducts4853.blob.core.windows.net/docs/25ff335eb5867479903f7012017ded419f0c5b6e
Funding and finding
Funding
not stated; UK product information carries no funding statement.
Finding
Indication: treatment of vitamin D3 deficiency; for deficiency below 25 nmol/L, 50,000 IU weekly for 6 to 8 weeks, then maintenance. Contraindications: hypercalcaemia or hypercalciuria, nephrolithiasis or nephrocalcinosis, serious renal impairment, hypervitaminosis D, pseudohypoparathyroidism, pregnancy, age under 18 years. Warnings: caution in renal impairment, with risk of soft tissue calcification; caution in sarcoidosis because of increased conversion to the active form; no clear evidence of causation between vitamin D3 and renal stones, but the risk is plausible, especially with calcium supplementation; a single annual oral bolus of 500,000 IU was reported to increase fractures in elderly subjects, with the greatest increase in the first 3 months after dosing. Interactions: thiazides reduce urinary calcium; vitamin D3 may increase the risk of digitalis toxicity (arrhythmia). Undesirable effects: hypercalcaemia and hypercalciuria uncommon (more than 1/1000, less than 1/100). Overdose: the threshold for intoxication is 40,000 to 100,000 IU daily for 1 to 2 months in adults with normal parathyroid function; infants and small children may react to far lower amounts; overdose causes hypercalcaemic syndrome with calcium deposits in kidneys (nephrolithiasis, nephrocalcinosis) and vessels; the often persisting and in some circumstances life-threatening hypercalcaemia takes several weeks to normalise after the preparation is stopped. Preclinical: prolonged hypercalcaemia caused calcification mainly in kidneys, heart, aorta, testes, thymus and intestinal mucosa.
Independent research
Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial JAMA, 2019.
doi:10.1001/jama.2019.11889 PubMed 31454046
Funding and finding
Registration
NCT01900860
Participants
311
Follow-up
3 years
Funding
Funding was provided by Pure North S'Energy Foundation in response to an investigator-initiated research grant proposal. Pure North S'Energy Foundation had no role in the design and conduct of the study, data collection, analysis, manuscript preparation or the decision to publish. Registry: lead sponsor University of Calgary; collaborator Pure North S'Energy Foundation.
In-kind support
Vitamin D3 drops (80, 800 or 2000 IU per drop) were provided and checked for quality by Ddrops Canada; finite element software was provided free of charge by Numerics88 Solutions, co-owned by an author.
Finding
Vitamin D3 400 IU (n=109), 4000 IU (n=100) or 10,000 IU (n=102) daily for 3 years; 287 (92%) completed. Serum 25-hydroxyvitamin D at baseline, 3 months and 3 years: 76.3, 76.7 and 77.4 nmol/L (400 IU); 81.3, 115.3 and 132.2 (4000 IU); 78.4, 188.0 and 144.4 (10,000 IU). Radial total volumetric BMD fell by 1.2%, 2.4% and 3.5%, and tibial by 0.4%, 1.0% and 1.7%, respectively; against 400 IU, radial differences were -3.9 mg HA/cm3 (95% CI -6.5 to -1.3) at 4000 IU and -7.5 (-10.1 to -5.0) at 10,000 IU, tibial -1.8 (-3.7 to 0.1) and -4.1 (-6.0 to -2.2). Failure load did not differ between groups. Participants with at least one episode of hypercalcaemia: 0 (400 IU), 4 (4%; 4000 IU), 9 (9%; 10,000 IU); hypercalciuria 19 (17%), 22 (22%), 34 (33%). Falls 4 (4%), 10 (10%), 5 (5%); low-trauma fractures 4, 3 and 5. Serious adverse events 16 (15%), 8 (8%), 14 (14%); one death (presumed myocardial infarction) in the 400 IU group. An erratum was published (JAMA 2019;322:1925).
Regulator
US Food and Drug Administration; Organon LLC (labeler). FOSAMAX PLUS D (alendronate sodium and cholecalciferol) tablets: full prescribing information DailyMed, US National Library of Medicine, set ID 10307e7e-9a84-4aa1-8c5c-4b209cffe4d1, version 10, effective 3 February 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/services/v2/spls/10307e7e-9a84-4aa1-8c5c-4b209cffe4d1.xml
Funding and finding
Funding
not stated; US prescribing information carries no funding statement.
Finding
The label has no boxed warning section. Section 5.2, cholecalciferol: the product alone should not be used to treat vitamin D deficiency, 'commonly defined as 25-hydroxyvitamin D level below 9 ng/mL'; vitamin D3 supplementation may worsen hypercalcemia and/or hypercalciuria in patients with diseases associated with unregulated overproduction of 1,25-dihydroxyvitamin D (for example leukemia, lymphoma, sarcoidosis), in whom urine and serum calcium should be monitored. Section 7: olestra, mineral oils, orlistat and bile acid sequestrants may impair absorption; anticonvulsants, cimetidine and thiazides may increase catabolism. Overdosage: signs of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness and lethargy; dialysis to remove vitamin D would not be beneficial. Animal data: high doses of vitamin D2 in pregnant rabbits caused abortions and fetal aortic stenosis, and in pregnant rats neonatal death and impaired osteogenesis. In a 24-week extension, the proportion with hypercalciuria did not differ between 2800 and 5600 IU weekly.
Independent research
Wallace RB, Wactawski-Wende J, O'Sullivan MJ, Larson JC, Cochrane B, Gass M, et al. Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements American Journal of Clinical Nutrition, 2011.
doi:10.3945/ajcn.110.003350 PubMed 21525191
Funding and finding
Registration
NCT00000611
Participants
36,282
Follow-up
mean 7.0 years (SD 1.4)
Funding
The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services (contracts listed). No statement on the role of the funder was found.
In-kind support
Both active and placebo pills were provided by GlaxoSmithKline (Philadelphia, PA).
Finding
Calcium carbonate 500 mg plus vitamin D3 200 IU twice daily (1000 mg calcium and 400 IU vitamin D3 per day) against matching placebo: self-reported, clinically diagnosed urinary tract stones in 449 women in the active group against 381 in the placebo group (hazard ratio 1.17, 95% CI 1.02 to 1.34); the Methods give 18,176 women in the active group and 18,106 in the placebo group, and the tables reverse these two numbers. Neither total calcium intake nor calcium supplement use at baseline was associated with stone risk; results were similar when participants below 80% adherence were censored.
Independent research
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial JAMA, 2010.
doi:10.1001/jama.2010.594 PubMed 20460620
Funding and finding
Registration
ACTRN12605000658617; ISRCTN83409867
Participants
2,256
Follow-up
3 to 5 years
Funding
The study was supported by project grant No. 251682 from the National Health and Medical Research Council and by the Australian Government Department of Health and Ageing. The funding organizations were independent of the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
In-kind support
Study medication was supplied by PSM Healthcare, Auckland, New Zealand.
Finding
Cholecalciferol 500,000 IU once a year in autumn or winter versus placebo for 3 to 5 years: falls 83.4 versus 72.7 per 100 person-years (incidence rate ratio 1.15, 95% CI 1.02 to 1.30); fractures 171 versus 135, 4.9 versus 3.9 per 100 person-years (rate ratio 1.26, 1.00 to 1.59). In a substudy, serum 25-hydroxyvitamin D rose to about 120 nmol/l at 1 month after dosing, was about 90 nmol/l at 3 months and remained higher than placebo at 12 months.
Independent research
Ginde AA, Blatchford P, Breese K, Zarrabi L, Linnebur SA, Wallace JI, et al. High-Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long-Term Care Residents: A Randomized Clinical Trial Journal of the American Geriatrics Society, 2017.
doi:10.1111/jgs.14679 PubMed 27861708
Funding and finding
Participants
107
Follow-up
12 months
Funding
Beeson Career Development Award (NIH/NIA K23AG040708), NIH/NCATS Colorado CTSA grant UL1TR001082 and the American Geriatrics Society Jahnigen Career Development Scholars Award. The sponsors had no role in the design, methods, subject recruitment, data collection, analysis, interpretation or presentation of the paper.
In-kind support
Study drugs were provided by Pencol Compounding Pharmacy (Denver, CO).
Finding
High dose, monthly vitamin D3 100,000 IU (n=55), against standard dose (n=52): monthly placebo for residents taking 400 to 1000 IU/day as usual care, or monthly 12,000 IU for those taking less than 400 IU/day, for 12 months. Mean trough 25-hydroxyvitamin D 32 against 25.1 ng/mL. Acute respiratory infection 0.67 against 1.11 per person-year, incidence rate ratio 0.60 (95% CI 0.38 to 0.94). Falls were more common with the high dose: 1.47 against 0.63 per person-year, IRR 2.33 (1.49 to 3.63). Fractures 0.10 against 0.19 per person-year, IRR 0.56 (0.18 to 1.71). No hypercalcaemia or kidney stones occurred in either group.
Independent research
Appel LJ, Michos ED, Mitchell CM, Blackford AL, Sternberg AL, Miller ER 3rd, et al. The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults: A Response-Adaptive, Randomized Clinical Trial Annals of Internal Medicine, 2021.
doi:10.7326/M20-3812 PubMed 33284677
Funding and finding
Registration
NCT02166333
Participants
688
Follow-up
median 21.7 months; follow-up ended 31 May 2019
Funding
This trial was funded by the National Institute on Aging (U01AG047837) with support from the Office of Dietary Supplements, the Mid-Atlantic Nutrition Obesity Research Center (P30DK072488) and the Johns Hopkins Institute for Clinical and Translational Research (UL1TR003098). The NIA had no role in the collection, analysis and interpretation of data, the preparation, review and approval of the manuscript, or the decision to submit; a role in design is not addressed.
In-kind support
Vitamin D pills were manufactured by Continental Vitamin Company (Vernon, CA) and purchased by the trial.
Finding
Dose-finding stage (514 participants: 256 at 200 IU/day, 121 at 1000, 68 at 2000, 69 at 4000) followed by comparison of the best dose with 200 IU/day; the control group received 200 IU/day, not placebo. The data and safety monitoring board stopped the 2000 IU/day dose partly because of a higher rate of hospitalisation or death than at 200 IU/day (33.6 against 12.1 per 100 person-years; HR 2.69, 95% CI 1.50 to 4.82) and the 4000 IU/day dose because of higher rates of the primary outcome (HR 1.13, 0.80 to 1.61) and of hospitalisation or death (HR 1.68, 0.86 to 3.27). Primary outcome, first fall or death over 2 years, 1000 IU/day (n=308, observation limited to time on 1000 IU/day) against 200 IU/day (n=339): HR 0.94 (0.76 to 1.15); in the same comparison, serious fall HR 1.87 (1.03 to 3.41) and fall with hospitalisation HR 2.48 (1.13 to 5.46). Sensitivity analysis of all randomised participants, pooled 1000 to 4000 IU/day (n=349) against 200 IU/day (n=339): first fall HR 1.05 (0.87 to 1.27); first serious fall 37 events (7.5 per 100 person-years) against 20 (4.1), HR 1.85 (1.07 to 3.19); first fall with hospitalisation 24 (4.8 per 100 person-years) against 10 (2.0), HR 2.39 (1.14 to 5.00). Kidney, bladder or ureteral stones 4 against 4 events (1000 against 200 IU/day); hypercalcaemia 1 event in the pooled higher doses against 0.
Independent research
Pronicka E, Ciara E, Halat P, Janiec A, Wójcik M, Rowińska E, et al. Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases Journal of Applied Genetics, 2017.
doi:10.1007/s13353-017-0397-2 PubMed 28470390
Funding and finding
Participants
11
Funding
This study was supported by projects NSC 2014/15/B/NZ5/03541 (National Science Centre) and CMHI 180/09 (The Children's Memorial Health Institute grant). No statement on the role of the funders was found.
Finding
Idiopathic infantile hypercalcaemia presents with severe hypercalcaemia, failure to thrive, vomiting, dehydration and nephrocalcinosis; periodic rises in incidence in the UK in the 1950s and in Poland and Germany in the twentieth century followed rickets over-prophylaxis, in Poland with 'periodic' doses of 300,000 units three times a year, when at least 36 affected infants were treated at the authors' centre; some needed several months of hospital treatment. All 11 historical cases carried mutations, 9 in CYP24A1 and 2 in SLC34A1, biallelic in all but one. From the frequency of the recurrent CYP24A1 p.R396W allele, incidence in Poland is estimated at 1 in 32,465 births. The authors suggest molecular testing for both genes in each case of idiopathic hypercalcaemia or hypercalciuria in children and adults.
Regulator
US Food and Drug Administration; signed by Joshua M. Sharfstein, Principal Deputy Commissioner of Food and Drugs. FDA Letter to Industry Concerning Liquid Vitamin D Dietary Supplements US Food and Drug Administration, Dietary Supplements Guidance Documents and Regulatory Information, June 2010 (archived FDA page, last updated 26 November 2014), 2010.
http://wayback.archive-it.org/7993/20170722024258/https:/www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm215527.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
FDA was concerned that some liquid vitamin D products for infants are sold with droppers that can hold considerably more liquid vitamin D than an infant should receive, so that caregivers could give an unsafe dose by mistake. The letter describes vitamin D toxicity: initial symptoms usually associated with high serum calcium include weakness, fatigue, lassitude, headache, nausea, vomiting and diarrhoea; mental status changes and coma may develop; cardiac arrhythmias may ensue; renal function may be affected early; prolonged hypercalcaemia can lead to soft tissue deposition of calcium, favoured in the kidney; osteomalacia may occur; if caught early, treatment may completely reverse the symptoms, but residual sequelae may include permanent renal impairment and osteoporosis. The letter text carries no date; the FDA guidance index lists it as June 2010. FDA recommended that droppers be clearly and accurately marked at 400 units and that droppers for infant products hold no more than 400 units.
Regulator
Medicines and Healthcare products Regulatory Agency. Unlicensed imported vitamin D (colecalciferol) capsules: potential peanut oil and soya oil allergens MHRA Drug Safety Update, volume 5, issue 8, March 2012: S2 (republished on GOV.UK 11 December 2014), 2012.
https://www.gov.uk/drug-safety-update/unlicensed-imported-vitamin-d-colecalciferol-capsules-potential-peanut-oil-and-soya-oil-allergens
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Vigantoletten and Dekristol colecalciferol capsules, unlicensed in the UK and imported in German-language packaging for individual patients, contain soya oil and arachis (peanut) oil respectively, which is unlikely to be evident to non-German speakers; imported Osto D2 and Drisdol capsules may pose a similar risk. Allergy to soya oil or arachis oil may lead to severe allergic reactions, including anaphylaxis; these products are contraindicated in patients with relevant allergies, and doctors and pharmacists should ask about allergies before supply.
Regulator
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch-Ernst KI, et al. Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate EFSA Journal, 2023.
doi:10.2903/j.efsa.2023.8145 PubMed 37560437
Funding and finding
Funding
European Food Safety Authority, on requests from the European Commission. Preparatory systematic reviews were contracted by EFSA (OC/EFSA/NUTRI/2021/01) to the University of Helsinki with the University of Oslo.
Finding
Tolerable upper intake level 100 µg vitamin D per day for adults, including pregnant and lactating women, and for adolescents aged 11 to 17 years; 50 µg per day for children aged 1 to 10 years. Critical endpoint persistent hypercalciuria; LOAEL 250 µg per day from two randomised trials, uncertainty factor 2.5. 1 µg equals 40 IU; VITAL used 50 µg per day. Evidence tables record each included study's funding as public, private, mixed or unclear.
Independent research
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease New England Journal of Medicine, 2019.
doi:10.1056/NEJMoa1809944 PubMed 30415629
Funding and finding
Registration
NCT01169259
Participants
25,871
Follow-up
median 5.3 years
Funding
NIH grants U01 CA138962 and R01 CA138962, with support from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke and National Center for Complementary and Integrative Health. The NIH sponsors had a collaborative role in design, conduct and interpretation; final decisions, data collection, management, analysis, review and approval of the manuscript and the decision to submit rested with the investigators.
In-kind support
Pharmavite LLC donated vitamin D3, matching placebo and calendar packaging; Pronova BioPharma and BASF donated Omacor fish oil; Quest Diagnostics measured serum 25-hydroxyvitamin D at no cost.
Finding
Vitamin D3 2000 IU per day versus placebo: invasive cancer in 793 of 12,927 versus 824 of 12,944 (HR 0.96, 95% CI 0.88 to 1.06); major cardiovascular events in 396 versus 409 (HR 0.97, 0.85 to 1.12); median 5.3 years.
Independent research
Costenbader KH, Cook NR, Lee IM, Hahn J, Walter J, Bubes V, et al. Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial Arthritis & Rheumatology, 2024.
doi:10.1002/art.42811 PubMed 38272846
Funding and finding
Registration
NCT01351805; NCT01169259
Participants
25,871
Follow-up
5.3-year randomised period plus 2 years of observational follow-up in 21,592 participants (83.5%)
Funding
Supported by the NIH (grants R01-AR-059086, K24-AR-066109, U01-CA-138962, R01-CA-138962 and R01-AT-011729). No statement on the role of the funder was found.
In-kind support
The vitamin D pill and its matching placebo were prepared by Pharmavite LLC; the n-3 fatty acid pill and its placebo by Pronova BioPharma.
Finding
With two more years of observation after the trial, confirmed autoimmune disease occurred in 255 participants originally randomised to vitamin D3 2000 IU/day against 259 randomised to its placebo, HR 0.98 (95% CI 0.83 to 1.17) at 7 years. Of newly confirmed cases, 65 had onset during the randomised period; including them changed the randomised-period result for vitamin D to HR 0.85 (0.70 to 1.04). The authors conclude that the protective effects of vitamin D dissipated two years after trial termination; psoriasis was the only disease with a sustained, significant reduction (HR 0.61, 0.38 to 0.98).
Independent research
Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes New England Journal of Medicine, 2019.
doi:10.1056/NEJMoa1900906 PubMed 31173679
Funding and finding
Registration
NCT01942694
Participants
2,423
Follow-up
median 2.5 years
Funding
Planning: NIDDK planning grant U34DK091958 and the NIDDK Intramural Research Program. Conduct: NIDDK and the NIH Office of Dietary Supplements through cooperative agreement U01DK098245, which makes the NIDDK project scientist a member of the D2d Research Group; secondary funding from the American Diabetes Association (1-14-D2d-01). The protocol was designed by the planning committee and the primary sponsor (NIDDK) without input from manufacturers; the coordinating-centre statistical team analysed the data.
In-kind support
Trial pills were purchased from an independent nutritional-supplement manufacturer with no association with members of the research group.
Finding
Vitamin D3 4000 IU/day (n=1211) against placebo (n=1212): diabetes in 293 against 323 participants (9.39 against 10.66 per 100 person-years), HR 0.88 (95% CI 0.75 to 1.04). Mean 25-hydroxyvitamin D 27.7 ng/ml at baseline and 54.3 ng/ml at 24 months with vitamin D, 28.8 ng/ml with placebo. Post hoc, baseline 25-hydroxyvitamin D below 12 ng/ml (103 participants): HR 0.38 (0.18 to 0.80); 12 ng/ml or higher (2319): HR 0.92 (0.78 to 1.08). Protocol-specified adverse events, participants with at least one: hypercalcaemia 5 against 3; nephrolithiasis (participant-reported) 24 against 20; serious adverse events 173 against 153; deaths 5 against 5. 24-hour urine calcium was not measured.
Independent research
Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA Jr, et al. Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial The Lancet Diabetes & Endocrinology, 2017.
doi:10.1016/S2213-8587(17)30103-1 PubMed 28461159
Funding and finding
Registration
ACTRN12611000402943
Participants
5,108
Follow-up
mean treatment duration 3.4 years (range 2.5 to 4.2)
Funding
Funding statement of the published structured abstract: Health Research Council of New Zealand and Accident Compensation Corporation of New Zealand. The full text was not accessible; the role of the funders in this report was not read. In the primary ViDA report the same funders had no role in design, conduct, analysis or publication. Registry ACTRN12611000402943: funding sources Health Research Council of New Zealand and Accident Compensation Commission (government bodies); primary sponsor University of Auckland; secondary sponsor Carlos A. Camargo Jr (individual); no other collaborators.
Finding
Colecalciferol 200,000 IU initially, then 100,000 IU monthly, against placebo: at least one fall in 1312 of 2539 (52%) against 1326 of 2517 (53%), adjusted HR 0.99 (95% CI 0.92 to 1.07); non-vertebral fractures in 156 of 2558 (6%) against 136 of 2550 (5%), adjusted HR 1.19 (0.94 to 1.50). Falls were a post-hoc outcome; fractures a secondary outcome.
Industry-funded
Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, et al. Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial JAMA Internal Medicine, 2016.
doi:10.1001/jamainternmed.2015.7148 PubMed 26747333
Funding and finding
Registration
NCT01017354
Participants
200
Follow-up
12 months
Funding
The primary funding sources for this trial were professorship grant PP00B-114864 from the Swiss National Science Foundation and The VELUX Foundations. Supplementary funding was provided by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Monthly vitamin D3 24,000 IU (control), 60,000 IU, or 24,000 IU plus calcifediol 300 µg for one year. Lower extremity function did not differ between groups (P=0.26). Incidence of falls: 66.9% (95% CI 54.4% to 77.5%) with 60,000 IU and 66.1% (53.5% to 76.8%) with 24,000 IU plus calcifediol, against 47.9% (35.8% to 60.3%) with 24,000 IU (P=0.048); mean number of falls 1.47, 1.24 and 0.94 (P=0.09).
Independent research
Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects Physiological Reviews, 2016.
doi:10.1152/physrev.00014.2015 PubMed 26681795
Funding and finding
Funding
S. Christakos receives funding from National Institutes of Health Grants AG044552, AI100379, and DK38961-22. A. Verstuyf is funded by Fund for Scientific Research-Flanders (FWO) Grant G.OA17.14N and by KU Leuven Grant GOA/14/010. G. Carmeliet is funded by Grant FWO G.0573.13. No statement on the role of the funders was found.
Finding
Review. In children with severe vitamin D deficiency, serum 25-hydroxyvitamin D is usually below 10 ng/ml, the threshold for control of intestinal calcium absorption; below it, serum 1,25-dihydroxyvitamin D and intestinal calcium absorption fall. Daily intake of 400 IU vitamin D3 is sufficient to prevent this type of rickets in children. Rickets and osteomalacia in humans and mice lacking VDR or CYP27B1 are rescued when calcium absorption is ensured. VDR functions as an obligate heterodimer with RXR. 1,25-Dihydroxyvitamin D3 increases the apical calcium channel TRPV6 and calbindin-D9k in the intestine and suppresses transcription of the PTH gene. The renal proximal tubule is the major site of 1,25-dihydroxyvitamin D3 synthesis by CYP27B1, which PTH upregulates and FGF23 and 1,25-dihydroxyvitamin D3 downregulate.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Dietary reference values for vitamin D EFSA Journal, 2016.
doi:10.2903/j.efsa.2016.4547
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01230); adopted 29 June 2016. Preparatory meta-regression data came from a review undertaken for EFSA by an external contractor (Brouwer-Brolsma et al., 2016).
Finding
Average requirements and population reference intakes could not be derived; a serum 25-hydroxyvitamin D of 50 nmol/L was chosen as the target value for all population groups and adequate intakes set at 15 µg/day for adults and children aged 1 to 17 years and 10 µg/day for infants aged 7 to 11 months, from a meta-regression of 83 trial arms (35 studies) conducted under minimal cutaneous synthesis; with cutaneous synthesis the dietary requirement is lower or may be zero. Skin synthesis depends on latitude, season, ozone and cloud, surface reflection, time outdoors, sunscreen, clothing, skin colour and age; the 'vitamin D winter' runs November to February in Rome (41.9°N), October to April in Berlin and Amsterdam (about 52.5°N) and early October to mid-March in Tromsø (69.4°N). Synthesis is lower in dark than in light skin and decreases with age. UV-B photodegrades previtamin D3 and vitamin D3 to inert isomers, which prevents toxicity from prolonged sun exposure; vitamin D intoxication by UV-B has not been reported. 25-hydroxyvitamin D has a mean half-life of about 13 to 15 days; in the kidney 1,25-dihydroxyvitamin D stimulates PTH-dependent tubular calcium reabsorption, and it suppresses PTH gene expression and parathyroid cell proliferation.
Independent research
Trummer C, Schwetz V, Pandis M, Grübler MR, Verheyen N, Gaksch M, et al. Effects of vitamin D supplementation on FGF23: a randomized-controlled trial European Journal of Nutrition, 2019.
doi:10.1007/s00394-018-1672-7 PubMed 29602956
Funding and finding
Participants
181
Follow-up
8 weeks
Funding
The Styrian Vitamin D Hypertension Trial was supported by funding from the Austrian National Bank (Jubilaeumsfond projects 13878 and 13905); open access funding by the Medical University of Graz. No statement on the role of the funder was found.
In-kind support
Fresenius Kabi provided the study medication (Oleovit D3); BIOMEDICA Medizinprodukte supplied FGF23 assay kits; BioPersMed (publicly funded COMET K-project) provided analysis equipment.
Finding
Vitamin D3 2800 IU/day against placebo for 8 weeks raised 25-hydroxyvitamin D by 11.1 ng/mL (95% CI 8.9 to 13.3). Effect on C-terminal FGF23 in the whole cohort: 0.374 pmol/L (-0.024 to 0.772), P=0.065. In subgroups with baseline 25-hydroxyvitamin D below 20 ng/mL (n=70) and below 16 ng/mL (n=40), FGF23 rose by 0.973 pmol/L (reported 95% CI -0.032 to 1.979, P=0.019) and 0.593 pmol/L (0.076 to 1.109, P=0.022).
Independent research
Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial BMJ, 2022.
doi:10.1136/bmj-2021-066452 PubMed 35082139
Funding and finding
Registration
NCT01169259; NCT01351805
Participants
25,871
Follow-up
median 5.3 years
Funding
This study was funded by the National Institutes of Health grants R01 AR059086, U01 CA138962 and R01 CA138962. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.
In-kind support
The vitamin D pill and its matching placebo were prepared by Pharmavite LLC; the omega 3 fatty acid pill and its placebo by Pronova BioPharma.
Finding
Vitamin D3 2000 IU/day against placebo: confirmed autoimmune disease in 123 of 12,927 against 155 of 12,944 participants, HR 0.78 (95% CI 0.61 to 0.99); confirmed plus probable 210 against 247, HR 0.85 (0.70 to 1.02); excluding the first two years, HR 0.61 (0.43 to 0.86). Benefit varied with body mass index (P for interaction 0.02): HR 0.62 (0.42 to 0.93) below 25 kg/m2, 0.92 (0.61 to 1.38) at 25 to 30 and 0.88 (0.54 to 1.44) at 30 or more. Potential side effects were collected by questionnaire.
Independent research
Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial JAMA Cardiology, 2017.
doi:10.1001/jamacardio.2017.0175 PubMed 28384800
Funding and finding
Registration
ACTRN12611000402943
Participants
5,108
Follow-up
median 3.3 years
Funding
Supported by grant 10/400 from the Health Research Council of New Zealand and by the Accident Compensation Corporation of New Zealand. The funders had no role in the design and conduct of the study, data handling, manuscript preparation or the decision to submit.
In-kind support
Vitamin D3 and placebo soft-gel capsules from Tishcon Corporation; whether purchased or donated was not read.
Finding
Vitamin D3 200,000 IU initially, then 100,000 IU monthly (n=2558), against placebo (n=2550): cardiovascular disease in 303 (11.8%) against 293 (11.5%), HR 1.02 (95% CI 0.87 to 1.20). In participants with baseline 25-hydroxyvitamin D below 20 ng/mL: 80 (13.1%) against 88 (13.4%), HR 1.00 (0.74 to 1.35). Deaths 65 against 58. One person developed hypercalcaemia, from primary hyperparathyroidism.
Independent research
Roth DE, Morris SK, Zlotkin S, Gernand AD, Ahmed T, Shanta SS, et al. Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth New England Journal of Medicine, 2018.
doi:10.1056/NEJMoa1800927 PubMed 30089075
Funding and finding
Registration
NCT01924013
Participants
1,300
Follow-up
from 17 to 24 weeks of gestation to 1 year of infant age
Funding
Funded by the Bill and Melinda Gates Foundation (OPP1066764). The trial funder had no role in trial design, data collection, analysis or interpretation of the results.
In-kind support
Vitamin D3 and placebo tablets were manufactured by the Toronto Institute for Pharmaceutical Technology.
Finding
Five groups: placebo; 4200, 16,800 or 28,000 IU/week prenatally with placebo postpartum; or 28,000 IU/week prenatally and for 26 weeks postpartum. Among 1164 infants assessed at one year (90% of 1300 pregnancies), length-for-age z-scores did not differ (-0.93, -1.11, -0.97, -1.06 and -0.94; P=0.23), nor did other anthropometric measures, birth outcomes or morbidity. Confirmed hypercalcaemia, all asymptomatic, occurred in no women prenatally, 8 women (0.7%) postpartum (5 in the prenatal-and-postpartum group) and 6 infants (0.7%), without significant differences between groups; the risk of possible maternal hypercalciuria at delivery rose with dose; no women had urinary tract stones. A correction notice was published in 2021 (N Engl J Med 385:1728).
Funding unknown
Wang Y, DeLuca HF. Is the vitamin D receptor found in muscle? Endocrinology, 2011.
doi:10.1210/en.2010-1109 PubMed 21190957
Funding and finding
Funding
not stated in the abstract; the full text was not accessible (paywall), so the funding statement was not read.
Finding
Abstract: most available antibodies against the vitamin D receptor detect proteins other than the receptor and may give false-positive results. With antibodies that detect no protein in tissues of vitamin D receptor null mice, a specific immunohistochemical assay found the receptor undetectable in skeletal, cardiac and smooth muscle, suggesting that the action of vitamin D on muscle is indirect or does not involve the known receptor.
Independent research
Girgis CM, Mokbel N, Cha KM, Houweling PJ, Abboud M, Fraser DR, et al. The Vitamin D Receptor (VDR) Is Expressed in Skeletal Muscle of Male Mice and Modulates 25-Hydroxyvitamin D (25OHD) Uptake in Myofibers Endocrinology, 2014.
doi:10.1210/en.2014-1016 PubMed 24949660
Funding and finding
Funding
Postgraduate scholar awards (Australian Postgraduate Award) from the University of Sydney; Joseph Thornton Tweddle Research Scholarship 2014 (Royal Australasian College of Physicians); J.E.G. and R.J.C.-B. are supported by the National Health and Medical Research Council.
Finding
Mouse and cell study. The authors describe the presence of VDR in skeletal muscle as controversial. VDR transcript and protein (VDR-D6 antibody, validated by absent signal in knockout tissue) were detected in murine quadriceps; Western blot detection required hyperosmolar lysis buffer; levels were low compared with duodenum and fell with age. C2C12 and primary myotubes increased VDR and CYP24A1 after 1,25-dihydroxyvitamin D, and primary myotubes expressed functional CYP27B1. 1,25-dihydroxyvitamin D increased uptake of tritiated 25-hydroxyvitamin D3 in myofibers from wild-type but not VDR knockout mice.
Independent research
Billington EO, Burt LA, Plett R, Rose MS, Boyd SK, Hanley DA. Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial Osteoporosis International, 2020.
doi:10.1007/s00198-020-05500-2 PubMed 32556518
Funding and finding
Registration
NCT01900860
Participants
302
Follow-up
3 years
Funding
The full text was not accessible. Registry: lead sponsor University of Calgary; collaborator Pure North S'Energy Foundation. The primary trial report states that funding came from Pure North S'Energy Foundation, which had no role in design, conduct, analysis or publication.
In-kind support
Primary report: vitamin D3 drops provided by Ddrops Canada.
Finding
Vitamin D3 400 (n=105), 4000 (n=96) or 10,000 IU/day (n=101) for 3 years; tibial artery calcification measured by HR-pQCT at baseline, 6, 12, 24 and 36 months. At baseline 85 participants (28%) had calcification, mean 2.8 mg hydroxyapatite (95% CI 1.7 to 3.9), which increased by 0.020 mgHA per month (0.012 to 0.029) with no treatment-group effect (P=0.645 for interaction); no participant developed new arterial calcification.
Independent research
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis BMJ, 2011.
doi:10.1136/bmj.d2040 PubMed 21505219
Funding and finding
Participants
28,072
Funding
Funded by the Health Research Council of New Zealand and the University of Auckland School of Medicine Foundation. AA is funded by a Career Scientist award of the Chief Scientist Office of the Scottish Government Health Directorates. No statement on the role of the funders was found.
Finding
In the 16,718 WHI women (46%) not taking personal calcium supplements at randomisation, hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22; in women taking them, risk was unaltered. Meta-analysis of three placebo-controlled trials of calcium with vitamin D: myocardial infarction RR 1.21 (95% CI 1.01 to 1.44), stroke 1.20 (1.00 to 1.43), myocardial infarction or stroke 1.16 (1.02 to 1.32). Calcium or calcium with vitamin D, trial-level data for 28,072 participants: myocardial infarction RR 1.24 (1.07 to 1.45), myocardial infarction or stroke 1.15 (1.03 to 1.27), death 1.04 (0.95 to 1.13). Patient-level analysis: number needed to treat for five years to cause one myocardial infarction 240, one stroke 283, one myocardial infarction or stroke 178; to prevent one fracture 302.
Regulator
Medicines and Healthcare products Regulatory Agency. Calcium and vitamin D: no prescribing changes MHRA Drug Safety Update, volume 5, issue 3, October 2011: H1 (republished on GOV.UK 11 December 2014), 2011.
https://www.gov.uk/drug-safety-update/calcium-and-vitamin-d-no-prescribing-changes
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Review of Bolland et al. (BMJ 2011) reanalysis of WHI: in women not self-medicating with calcium at baseline, clinical myocardial infarction 209 events with calcium plus vitamin D against 168 with placebo (3.5 against 2.9 per 1000 patient-years; HR 1.22, 95% CI 1.00 to 1.50), with all-cause mortality not increased (HR 0.99, 0.86 to 1.14); in women self-medicating with calcium, mortality was lower with calcium plus vitamin D (HR 0.84, 0.73 to 0.97). The Commission on Human Medicines advised that the data did not provide convincing evidence of increased cardiovascular risk, citing borderline significance, exclusion of more than half of WHI participants from the meta-analysis, differing endpoints, multiple testing and possible misclassification of gastrointestinal symptoms, and recommended studying calcium and vitamin D separately. Prescribers should weigh benefits and risks individually.
Independent research
Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase Proceedings of the National Academy of Sciences of the United States of America, 2004.
doi:10.1073/pnas.0402490101 PubMed 15128933
Funding and finding
Funding
Robert A. Welch Foundation Grants I-0971 and I-1275; National Institutes of Health Grants HL 20948, GM 08014 and DK 56603; and the Howard Hughes Medical Institute.
Finding
Synthesis of active vitamin D requires 25-hydroxylation in the liver and 1α-hydroxylation in the kidney, the latter by the mitochondrial enzyme CYP27B1. A patient with low circulating 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency was homozygous for a transition in exon 2 of CYP2R1 on chromosome 11p15.2 that substitutes proline for a conserved leucine at residue 99 and eliminated vitamin D 25-hydroxylase activity. One of 50 Nigerian control subjects was heterozygous for the same L99P change.
Regulator
European Medicines Agency, Committee for Medicinal Products for Human Use. Fosavance (alendronic acid/colecalciferol) tablets: summary of product characteristics, EPAR product information European Medicines Agency; marketing authorisation EU/1/05/310, first authorised 24 August 2005, renewed 24 April 2015; product information document of 10 February 2026, 2026.
https://www.ema.europa.eu/en/documents/product-information/fosavance-epar-product-information_en.pdf
Funding and finding
Funding
not stated; EU product information carries no funding statement.
Finding
Colecalciferol component (2800 or 5600 IU weekly): vitamin D3 may increase the magnitude of hypercalcaemia and/or hypercalciuria when given to patients with diseases associated with unregulated overproduction of calcitriol (for example leukaemia, lymphoma, sarcoidosis); urine and serum calcium should be monitored in these patients. The content of vitamin D is not suitable for correction of vitamin D deficiency. Anticonvulsants, cimetidine and thiazides may increase the catabolism of vitamin D. Overdose section: vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at doses below 10,000 IU/day. Pharmacokinetics: the mean serum half-life of vitamin D3 after a 2800 IU dose is about 24 hours; after radioactive vitamin D3, urinary excretion was 2.4% at 48 hours and faecal excretion 4.9% at 4 days, almost exclusively as metabolites.
Independent research
Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis The Lancet Diabetes & Endocrinology, 2018.
doi:10.1016/S2213-8587(18)30265-1 PubMed 30293909
Funding and finding
Participants
53,537
Funding
Accepted manuscript: Funding support from the Health Research Council of New Zealand. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The HRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Vitamin D had no effect on total fracture (36 trials, 44,790 participants; RR 1.00, 95% CI 0.93 to 1.07), hip fracture (20 trials, 36,655; RR 1.11, 0.97 to 1.26) or falls (37 trials, 34,144; RR 0.97, 0.93 to 1.02); results were similar in trials of high against low doses and with doses above 800 IU per day. No clinically relevant differences in bone mineral density (-0.16% to 0.76% over 1 to 5 years). Trial sequential analysis placed total fracture and falls within the futility boundary for relative risk reductions of 15%, 10% and 7.5%; for hip fracture, uncertainty remains as to whether vitamin D might increase risk. The authors conclude there is little justification to use vitamin D supplements to maintain or improve musculoskeletal health.
Independent research
Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men Cochrane Database of Systematic Reviews, 2014.
doi:10.1002/14651858.CD000227.pub4 PubMed 24729336
Funding and finding
Participants
91,791
Funding
Internal: Health Services Research Unit, University of Aberdeen; computing, administration and library services. External: Chief Scientist Office, Scottish Government Health Directorates (part funding of salary, AA). No statement on the role of the funders was found.
Finding
Vitamin D alone: hip fracture RR 1.12 (95% CI 0.98 to 1.29; 11 trials, 27,693 participants), any new fracture RR 1.03 (0.96 to 1.11; 15 trials, 28,271). Vitamin D plus calcium: hip fracture RR 0.84 (0.74 to 0.96; 9 trials, 49,853), equal to 1 fewer hip fracture per 1000 older adults per year in the community (estimated 8 per 1000 per year) and 9 fewer per 1000 per year in institutions (estimated 54 per 1000 per year); any fracture RR 0.95 (0.90 to 0.99). Adverse effects: hypercalcaemia, usually mild (2.6 to 2.8 mmol/L), RR 2.28 (1.57 to 3.31; 21 trials, 17,124), for calcitriol RR 4.41 (2.14 to 9.09); gastrointestinal symptoms RR 1.04 (1.00 to 1.08); renal disease RR 1.16 (1.02 to 1.33; 11 trials, 46,548). For vitamin D plus calcium, renal calculi or insufficiency 9 against 8 per 10,000 per year (RR 1.17, 1.03 to 1.34; 2 trials, 39,552), data dominated by the 7-year WHI trial. Mortality RR 0.97 (0.93 to 1.01; 29 trials, 71,032).
Independent research
LeBoff MS, Chou SH, Ratliff KA, Cook NR, Khurana B, Kim E, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults New England Journal of Medicine, 2022.
doi:10.1056/NEJMoa2202106 PubMed 35939577
Funding and finding
Registration
NCT01704859
Participants
25,871
Follow-up
median 5.3 years
Funding
Grants R01 AR060574, R01 AR070854 and R01 AR059775 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The VITAL parent trial is supported by grants U01 CA138962, R01 CA138962 and R01 AT011729 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke and the National Center for Complementary and Integrative Health. The study was designed by the first and last authors, and the manuscript was written by the first author.
In-kind support
Quest Diagnostics measured serum 25-hydroxyvitamin D; the paper names Omacor (Pronova BioPharma and BASF) as the n-3 fatty acid agent. The VITAL parent publication records the study agents as donated by Pharmavite, Pronova BioPharma and BASF.
Finding
Vitamin D3 2000 IU per day versus placebo: first fracture in 769 of 12,927 versus 782 of 12,944 participants (HR 0.98, 95% CI 0.89 to 1.08); nonvertebral HR 0.97 (0.87 to 1.07); hip HR 1.01 (0.70 to 1.47); median 5.3 years. In a post hoc analysis, 401 participants with baseline 25-hydroxyvitamin D below 12 ng/ml showed no benefit. The introduction states that other societies or foundations recommend at least 800 to 2000 IU per day for adults aged 50 years or older to attain 25-hydroxyvitamin D of at least 30 ng/ml.
Independent research
Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ, 2017.
doi:10.1136/bmj.i6583 PubMed 28202713
Funding and finding
Participants
10,933
Follow-up
trial duration 7 weeks to 1.5 years
Funding
Supported by a grant from the National Institute for Health Research (NIHR) under its Health Technology Assessment programme (reference 13/03/25). The NIHR was not involved in the study design, the collection, analysis or interpretation of data, the writing of the report or the decision to submit.
Finding
At least one acute respiratory tract infection: adjusted OR 0.88 (95% CI 0.81 to 0.96), number needed to treat 33; daily or weekly dosing without boluses OR 0.81 (0.72 to 0.91; 5133 participants), regimens with at least one bolus of 30,000 IU or more OR 0.97 (0.86 to 1.10; 5800), P for interaction 0.05. Among those dosed daily or weekly, baseline 25-hydroxyvitamin D below 25 nmol/L: OR 0.30 (0.17 to 0.53), NNT 4 (234 participants, 6 trials); 25 nmol/L or higher: OR 0.75 (0.60 to 0.95), NNT 15 (1603 participants). Bolus dosing gave no protection even below 25 nmol/L (OR 0.82, 0.51 to 1.33). Serious adverse events OR 0.98 (0.80 to 1.20); hypercalcaemia in 21 of 3850 (0.5%) and renal stones in 6 of 3841 (0.2%), evenly distributed between arms.
Expert consensus
US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement JAMA, 2018.
doi:10.1001/jama.2018.3185 PubMed 29677309
Funding and finding
Funding
The USPSTF is an independent, voluntary body; the US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support its operations.
Finding
Recommends against daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium for primary prevention of fractures in community-dwelling postmenopausal women (D); evidence insufficient for higher doses in postmenopausal women and for men and premenopausal women (I). Harm: adequate evidence that vitamin D with calcium increases kidney stones, judged small; in WHI, 1 urinary tract stone was diagnosed for every 273 women supplemented over 7 years; pooled vitamin D plus calcium for 4 to 7 years, absolute risk difference 0.33% (95% CI 0.06% to 0.60%), RR 1.18 (1.04 to 1.35). Released 17 April 2018; the USPSTF web page marks the topic as being updated.
Independent research
Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults Cochrane Database of Systematic Reviews, 2014.
doi:10.1002/14651858.CD007470.pub3 PubMed 24414552
Funding and finding
Participants
95,286
Follow-up
weighted mean 4.4 years of vitamin D administration
Funding
Internal: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Denmark. External: Ministry of Science, Republic of Serbia. No statement on the role of the funders was found.
Finding
All forms of vitamin D: deaths 5,920 of 47,472 (12.5%) against 6,077 of 47,814 (12.7%), RR 0.97 (95% CI 0.94 to 0.99); more than 8% of participants dropped out, and worst-best and best-worst case analyses showed that vitamin D could be associated with a dramatic increase or decrease in mortality. Vitamin D3: 4,153 of 37,817 (11.0%) against 4,340 of 38,110 (11.4%), RR 0.94 (0.91 to 0.98; 38 trials), about 150 people treated for 5 years per death prevented; vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. No significant subgroup differences, including baseline 25-hydroxyvitamin D below against at or above 20 ng/mL, ambulatory against institutionalised, and with or without calcium. Vitamin D3 decreased cancer mortality, RR 0.88 (0.78 to 0.98; 4 trials, 44,492). Vitamin D3 combined with calcium increased nephrolithiasis, RR 1.17 (1.02 to 1.34; 4 trials, 42,876). Alfacalcidol and calcitriol increased hypercalcaemia, RR 3.18 (1.17 to 8.68; 3 trials, 710).
Independent research
Neale RE, Baxter C, Romero BD, McLeod DSA, English DR, Armstrong BK, et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality The Lancet Diabetes & Endocrinology, 2022.
doi:10.1016/S2213-8587(21)00345-4 PubMed 35026158
Funding and finding
Registration
ACTRN12613000743763
Participants
21,315
Follow-up
median 5.7 years; 5 years of intervention
Funding
Summary of the publication: 'The D-Health Trial is funded by National Health and Medical Research Council.' Registry: National Health and Medical Research Council Project Grant 1046681; primary sponsor QIMR Berghofer Medical Research Institute (government body); secondary sponsor none. The full-text statement on the role of the funder was not read (publisher page inaccessible).
Finding
Vitamin D3 60,000 IU per month versus placebo: 562 deaths (5.3%) versus 538 (5.1%), HR 1.04 (95% CI 0.93 to 1.18); cancer mortality HR 1.15 (0.96 to 1.39), and 1.24 (1.01 to 1.54) in an exploratory analysis excluding the first 2 years; mean serum 25-hydroxyvitamin D during follow-up 115 versus 77 nmol/l; median follow-up 5.7 years.
Independent research
Sherrington C, Fairhall NJ, Wallbank GK, Tiedemann A, Michaleff ZA, Howard K, et al. Exercise for preventing falls in older people living in the community Cochrane Database of Systematic Reviews, 2019.
doi:10.1002/14651858.CD012424.pub2 PubMed 30703272
Funding and finding
Participants
23,407
Funding
Partly funded by the National Institute for Health Research (NIHR) via Cochrane Infrastructure funding, with additional funding via the NIHR Cochrane Reviews of NICE Priority scheme (NIHR127512). No statement on the role of the funder beyond the authors' responsibility for the views expressed was found.
Finding
Exercise against control (81 trials, 19,684 participants): rate of falls RaR 0.77 (95% CI 0.71 to 0.83; 59 trials, 12,981; high certainty), 195 fewer falls per 1000 people over one year from an illustrative 850; people with one or more falls RR 0.85 (0.81 to 0.89; 63 trials, 13,518; high certainty), 72 fewer fallers per 1000 from 480; fall-related fractures RR 0.73 (0.56 to 0.95; 10 trials, 4047; low certainty); falls requiring medical attention RR 0.61 (0.47 to 0.79; low certainty). Balance and functional exercises reduced the rate of falls by 24% and Tai Chi by 19%.
Expert consensus
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know Journal of Clinical Endocrinology and Metabolism, 2011.
doi:10.1210/jc.2010-2704 PubMed 21118827
Funding and finding
Funding
Institute of Medicine committee assembled at the request of agencies of the US and Canadian governments.
Finding
Recommended Dietary Allowance of vitamin D 600 IU per day for ages 1 to 70 years and 800 IU per day from 71 years, corresponding to serum 25-hydroxyvitamin D of at least 20 ng/ml (50 nmol/l); tolerable upper intake level 4000 IU per day from 9 years. Evidence on cancer, cardiovascular disease, diabetes and autoimmune disorders was judged inconsistent, inconclusive as to causality and insufficient to set requirements.
Expert consensus
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline Journal of Clinical Endocrinology and Metabolism, 2011.
doi:10.1210/jc.2011-0385 PubMed 21646368
Funding and finding
Funding
Developed under The Endocrine Society's Clinical Guidelines Subcommittee; the abstract states that the Task Force received no corporate funding or remuneration.
Finding
Vitamin D deficiency defined as 25-hydroxyvitamin D below 20 ng/ml (50 nmol/liter) and insufficiency as 21 to 29 ng/ml (the nmol/liter range is printed as '525-725'). Screening recommended for individuals at risk, not for the population. Adults aged 50 to 70 and over 70 years require at least 600 and 800 IU/day; to raise the blood level of 25-hydroxyvitamin D above 30 ng/ml may require at least 1500 to 2000 IU/day of supplemental vitamin D.
Expert consensus
Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, et al. IOM committee members respond to Endocrine Society vitamin D guideline Journal of Clinical Endocrinology and Metabolism, 2012.
doi:10.1210/jc.2011-2218 PubMed 22442278
Funding and finding
Funding
The authors worked independently and voluntarily to develop the manuscript; no funding sources were used.
Finding
Members of the 2011 IOM committee disagree that serum 25-hydroxyvitamin D of 30 ng/ml or higher is needed, finding no bone-health benefit above about 20 ng/ml, and disagree that all persons below 20 ng/ml are deficient. They state that 16 ng/ml (40 nmol/liter) meets the needs of about half the population and that 20 ng/ml assures bone health in practically all persons (97.5%); using 20 ng/ml as a cutoff inflates the number of persons deemed deficient. They argue that the guideline incorrectly characterises several large subgroups as at risk and lacks evidence of benefit from high intakes.
Expert consensus
Demay MB, Pittas AG, Bikle DD, Diab DL, Kiely ME, Lazaretti-Castro M, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology and Metabolism, 2024.
doi:10.1210/clinem/dgae290 PubMed 38828931
Funding and finding
Funding
Funding for the development of this guideline was provided by The Endocrine Society. No other entity provided financial support.
Finding
Suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years, adults aged 75 years or older, pregnancy, and high-risk prediabetes; suggests against supplementation beyond the Dietary Reference Intake in adults under 50 and against routine supplementation beyond it at 50 to 74 years; suggests against routine 25-hydroxyvitamin D testing in these groups; for adults 50 years or older with an indication, suggests daily lower-dose instead of non-daily higher-dose vitamin D. The Endocrine Society no longer endorses the target 25-hydroxyvitamin D level of 30 ng/mL (75 nmol/L) or specific levels to define vitamin D sufficiency.
Independent research
Baram L, Dai Z, McDonald S, Bero LA. Disclosure of funding sources and conflicts of interest in evidence underpinning vitamin D and calcium recommendations in bone health guidelines Public Health Nutrition, 2022.
doi:10.1017/S1368980022000246 PubMed 35067274
Funding and finding
Funding
This work was funded by Australian National Health and Medical Research Council project grant APP1139997 (Bero). The funding source played no role in the conceptualisation, design, analytical methods, data interpretation, reporting of the manuscript or publication decisions.
Finding
Of 156 cited articles, 120 (77%) disclosed a funding source and 43 (28%) declared at least one author conflict of interest; 49 (31%) had no conflict-of-interest declaration of any sort. Commercially funded articles tended to reach conclusions favourable to vitamin D or calcium more often than articles with non-commercial or no funding (RR 1.32, 95% CI 0.94 to 1.87; P=0.16). Articles with missing or unclear conflict-of-interest disclosure were more likely to have favourable conclusions than those with a disclosure statement (RR 1.56, 1.05 to 2.31; P=0.017).

Updated 2026-10-22