Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines - CADTH RAPID RESPONSE REPORT: SUMMARY OF ABSTRACTS
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CADTH RAPID RESPONSE REPORT: SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines Service Line: Rapid Response Service Version: 1.0 Publication Date: June 07, 2018 Report Length: 22 Pages
Authors: Casey Gray, Robin Featherstone
Cite As: Calcium and v itamin D supplementation f or adults: saf ety and guidelines. Ottawa: CADTH; 2018 Jun. (CADTH rapid response report: summary of
abstracts).
Acknowledgments:
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SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 2Research Questions
1. What is the clinical evidence for the safety of calcium and vitamin D supplementation i n
adults?
2. What are the evidence-based guidelines regarding the use of calcium and vitamin D
supplements in the general adult population?
Key Findings
Thirteen systematic reviews (seven with meta-analyses), 30 randomized controlled trials ,
and seven evidence based guidelines were identified regarding calcium and vitamin D
supplementation in adults.
Methods
A limited literature search was conducted on key resources including PubMed, The
Cochrane Library, University of York Centre for Reviews and Dissemination (CRD)
databases, Canadian and major international health technology agencies and guideline
developers, as well as a focused Internet search. Methodological filters were applied to limit
retrieval to adverse events studies and guidelines. Where possible, retrieval was limited to
the human population. The search was also limited to English language documents
published between January 1, 2013 and May 25, 2018. Internet links were provided, where
available.
Selection Criteria
One reviewer screened citations and selected studies based on the inclusion criteria
presented in Table 1.
Table 1: Selection Criteria
Population Adults ages 18 to 65
Interventions Combination calcium and vitamin D supplements – any strength, any combination dosage;
Calcium alone (any dosage);
Vitamin D alone (any dosage)
Comparators Q1: No supplementation; placebo; dietary control group; any comparator group
Q2: No comparator
Outcomes Q1: Safety, harms (some possible harms - kidney stones, GI complications);
Patient related outcomes (adherence, discontinuation, patient satisfaction/annoyance with taking
supplements)
Q2: Guidelines, recommendations
Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-
randomized studies (safety only), evidence-based guidelines
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 3Results
Rapid Response reports are organized so that the higher quality evidence is presented first.
Therefore, health technology assessment reports, systematic reviews, and meta -analyses
are presented first. These are followed by randomized controlled trials, non-randomized
studies, and evidence-based guidelines; however, due to the volume of systematic reviews,
meta-analyses, and randomized controlled trials, non-randomized studies were not included
in this report.
Thirteen systematic reviews (seven with meta-analyses), 30 randomized controlled trials,
and seven evidence based guidelines were identified regarding calcium and vitamin D
supplementation in adults. No relevant health technology assessments were identified.
Additional references of potential interest are provided in the appendix.
Overall Summary of Findings
Thirteen systematic reviews 1-13 (seven with meta-analyses1-5,9,12), and 30 randomized
controlled trials,14-43 were identified regarding the safety of calcium and vitamin D
supplementation in adults. Detailed study characteristics are provided in Table 2.
Ten systematic reviews were identified regarding vitamin D supplementation. 1,3,5-8, 10-13
Generally, there were no differences between vitamin D supplementation and comparator
regarding adverse effects, whereas three studies reported elevated risks of at least one
adverse event.3,6,13 Similarly, twenty one randomized studies consistently showed
favourable safety profiles for vitamin D supplementation. 15-16,20-22,25-28,31-40,42-43
The authors of two systematic reviews examined calcium supplementation and observed no
increased risk or dose-response relationship with adverse events,2,9 other than an
increased incidence of hypercalcemia with calcium in one study. 9 Three RCTs and two
randomized cross -over trials showed mixed favourable and unfavourable effects of calcium
supplementation.14,17,19,23,29 Calcium supplementation did not cause adverse effects in three
randomized studies,14,17,24 however, one study showed higher risk of hypercalcuria with a
high dose, but not lower calcium doses compared with placebo, 19 and a second study
showed increased serum cholesterol concentrations and carotid intima-media thickness for
postmenopausal, but not premenopausal women with dyslipidemia. 29
In two systematic reviews , combined vitamin D and calcium supplementation were
examined and no difference from comparator or dose response relationship with adverse
events was observed.2,4 Four randomized studies examined combined calcium and vitamin
D supplementation with mixed findings.18,24,30,41 There were adverse effects reported in the
intervention group for one study that were unrelated to the vitamin D dose. 18 A second
randomized study showed unclear effects on morbidity and mortality, 30 and a third showed
similar distribution of adverse events compared with placebo. 41 The fourth study reported
on adherence and indicated that there was no difference between low dose and high dose
calcium supplementation.24
Seven evidence based guidelines 44-50 were identified regarding the use of calcium and
vitamin D supplements in the general adult population. The guidelines and position
statements provide various recommendations regarding clinically effective and safe doses
of vitamin D and calcium. Detailed recommendations are provided in Table 3.
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 4Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
Systematic Reviews and Meta-Analyses
General Population
Malihi, 2017 1 Long term vitamin No supplement or All AEs No difference between groups for any
D2 or D3 placebo Non-calcemic AEs outcome
Withdrawal rates
Chung, 2016 2 Calcium; Placebo or no CVD events No difference in RCTs for calcium or
calcium + comparator CVD related mortality calcium + vitamin D
vitamin D
No dose-response in cohort studies for
calcium and CVD mortality
No consistent dose-response for total,
dietary, or supplemental calcium intake
levels and CVD related mortality
Inconsistent dose-response for calcium
and total stroke or stroke mortality
Unknown safety of doses above 2000 to
2500 mg/d
Malihi, 2016 3 Vitamin D Placebo Hypercalcemia Vitamin D increased the RR of
Hypercalcuria hypercalcemia and hypercalcuria versus
≥24 weeks Kidney stones placebo;
No increased RR of kidney stones;
Relationships were not affected by
baseline 25-hydroxyvitamin D, vitamin D
dose and duration, or calcium co-
supplementation
Note. Withdrawal did not differ between
intervention and control overall, however
intervention group was more likely to
report withdrawals than placebo in
studies where calcium supplementation
occurred in both groups
Boland, 2014 4 Vitamin D + Vitamin D alone Myocardial heart No relationship (i.e., vitamin D
calcium disease supplementation with or without calcium
Ischemic heart did not alter RR of any outcome by ≥15%)
disease
Stroke Unknown if vitamin D with or without
CVD calcium affects RR of death
Mortality
Chowdhury, Single dose Placebo or no Mortality In observational studies, higher risk of
2014 5 vitamin D treatment mortality in studies with lower baseline
use of vitamin D supplements
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 5Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
In RCTs, lower RR for overall mortality
with vitamin D3 supplementation versus
comparator
Increased RR for mortality with lower
intervention doses and shorter
intervention periods
Kearns, 2014 6 Vitamin D as NR AEs Vitamin D doses >500,000 IU should be
single large dose used judiciously in order to minimize AEs
Fortmann, 2013 7 Vitamin D and/or NR CVD No overall effect of vitamin D and/or
calcium Mortality calcium on CVD or mortality
“Harms were infrequently reported and
aside from limited paradoxical effects for
some supplements, were not considered
serious.”7
Pregnant Women
Del-Regil, 2016 8 Vitamin D + No supplement or AEs Data were unavailable regarding
calcium; placebo combined calcium and vitamin D
supplements
Vitamin D
No difference between groups for vitamin
D
Recurrent Colorectal Adenoma Patients
Veettil, 2017 9 Calcium Unspecified AEs No SAEs with calcium
supplementation comparator
Increased incidence of hypercalcemia with
calcium
Adults with Chronic Pain
Straube, 201510 Vitamin D Placebo or active AEs No difference between vitamin D and
supplementation comparators Withdrawals placebo for AEs
Withdrawal findings NR
Cystic Fib rosis
Ferguson, Vitamin D Unspecified control Respiratory No AEs
2014 11 outcomes
Vitamin D toxicity
Adults with Diab etic Nephropathy
Zhao, 2014 12 Vitamin D3 Unspecified control AEs No difference in total AEs, gastrointestinal
adverse effects, or fluctuation of blood
pressure
Adults with HIV Infection
Newberry, Vitamin D Placebo, no Safety One trial was identified in adults on ART.
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 6Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
2014 13 treatment, or other The trial was stopped early due to
supplements increased AEs (elevated alanine
transaminase levels) in the high dose
group but not the low dose group
No other AEs were reported for ART-naive
adults, adults on ART, or ART naive
adults with active tuberculosis
Randomized Controlled Trials
General Population
Alyousif, 2016 14 8-week crossover 2 weeks of split Gut motility No difference between groups for
study dose of 500 mg/d frequency or form of stools
of calcium
2 weeks of split phosphate
dose of 500 mg/d “Although stool frequency was normal, the
of elemental 2 week washout healthy females participating in the study
calcium from experienced stools indicating slow
calcium carbonate 2 weeks of split (constipation) and fast (diarrhea) transit.”14
dose of 500 mg/d
2 week washout of elemental
calcium from
2 weeks of split calcium carbonate
dose of 500 mg/d
of calcium
phosphate
Al-Khalidi, 1 pizza/week x 8 28 000 IU vitamin AEs No AEs in either group
2015 15 weeks D3 fortified
mozzarella cheese
200 IU vitamin D3 with pizza
fortified mozzarella
cheese with pizza
Prietl, 2014 16 12 week x 140,000 Placebo Number and function No difference from placebo in Tregs
IU/month oral of CD4(pos), function, frequency of other immune cells,
cholecalciferol CD25(high), and no clinically relevant safety concerns
FoxP3(pos),
CD127(dim),Tregs
Safety
Effect on the
frequency of immune
cells: monocytes,
dendritic cells,
natural killer cells,
natural killer T cells,
B cells and
subgroups of T cells
Yaron, 2014 17 Random order 600 mg of calcium Arterial stiffness No clinically significant changes in the
cross-over trial from dairy (pulse wave velocity) vascular parameters from baseline or
Augmentation index between groups
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 7Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
1 dose 600 mg Followed by Large and small
calcium citrate arterial compliance A decrease in heart rate with no change in
600 mg calcium Endothelial function cardiac output was noticed after the
citrate (flow-mediated supplement
600 mg of calcium dilation)
from dairy
Gallagher, 1200-1400 mg/day Placebo Hypercalcemia “Hypercalcemia occurred in 7% and
2013 18 calcium to Hypercalciuria hypercalciuria in 15%. Events were
maintain total unrelated to vitamin D dose.” 18
calcium intake
plus:
Either 400,
800, 1600, 2400,
3200, 4000, or
4800 IU of vitamin
D3 daily
Zwart, 2013 19 G1: 50 mug/day Placebo x 3 Hypercalcemia Higher RR of hypercalciuria in G3 than in
calcium (2000 months Hypercalciuria the placebo group
IU/d, analysed
dose 70 mug/day), No difference between G1 or G2 versus
placebo
G2: 250 mug/week
(10 000 IU/week,
analysed dose 331
mug/week)
G3:1250
mug/week (50 000
IU/week, analysed
dose 1544
mug/week) for 4
weeks and then
1250 mug/ month
for 2 months
Vitamin D Deficiency
Takacs, 2017 20 Vitamin D3 Unspecified control Safety parameters No difference in safety parameters
3-months
G1: A daily single
dose of 1000 IU
G2: to a once-
weekly 7000 IU
dose
G3: monthly
30,000 IU dose
Schleck, 2015 21 G1: 50,000 IU of No non-active AEs No related AE was recorded
vitamin D3 at week control
0; 25,000 IU at
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 8Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
weeks 4 and 8
G2: 100,000 IU of
vitamin D3 at week
0; 50,000 IU at
weeks 4 and 8
G3: 200,000 IU of
vitamin D3 at week
0; 100,000 IU at
weeks 4 and 8
Zabihiyeganeh, Single 6 oral doses of Safety No difference between groups for safety
2013 22 intramuscular 300,000 IU
injection of cholecalciferol
300,000 IU across 3 months
cholecalciferol
Adults with Allergic Rhinoconjunctivitis or Asthma
Matysiak, 2017 23 Calcium carbonate Placebo 3 Allergic reactions “Calcium preparations were well
(1000 mg) 3 times/day x 3 days tolerated.”24
times/day x 3 days
Pregnant Women
Omatayo, 2017 24 200 IU 200 IU Adherence The low-dose calcium supplementation
cholecalciferol and cholecalciferol and Supplement intake regimen had a lower supplement intake
calcium pill and a calcium pill and a than the standard regimen. The difference
separate IFA pill separate IFA pill in intake was clinically, but not statistically
significant
and and
Adherence did not differ between groups
Low-dose Standard regimen:
regimen: 3 x 500 mg Ca/day
2 x 500 mg Ca/d in 3 pill taking
in 2 pill-taking events
events;
Mir, 2016 25 G1: 1000 IU of G3: 2000 IU of Safety “We concluded that Vitamin D
vitamin D daily; Vitamin D daily supplementation with 2000 IU/day or
60,000 IU/month is very effective and safe
G2: 30,000 IU of G4: 60,000 IU in achieving Vitamin D sufficiency in
vitamin D monthly Vitamin D monthly pregnant women”26
(G1 and G2 (G3 and G4
analyzed together) analyzed together)
Harrington, Oral vitamin D3: Placebo Fetal and neonatal No difference between groups in transient
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 9Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
2014 26 35,000 IU / week calcium hypercalcemia or hypercalcuria; all cases
concentrations were asymptomatic, spontaneously
26 to 29 weeks resolved and not associated with
gestation nephrocalcinosis at age 1 month
Yap, 2014 27 High dose of oral Recommended Glucose metabolism High dose of vitamin D3 was well tolerated
vitamin D3: 5,000 pregnancy dose:
IU / day 400 IU / day
< 20 weeks < 20 weeks
gestation to gestation to
delivery delivery
Dawodu, 2013 28 G1: vitamin D3 Recommended Safety No AEs reported
2000 IU / day pregnancy dose:
vitamin D3 400 IU / Safety measurements were similar across
G2: vitamin D3 day groups
4000 IU / day
12-16 weeks
gestation to
delivery
Pre/Post-Menopausal Women
Li, 2013 29 800 mg calcium / Placebo Serum cholesterol Menopausal status moderated the effect
day concentrations of calcium supplementation on serum
2 years Carotid intima-media cholesterol concentrations and carotid
2 years thickness intima-media thickness
Calcium supplementation increased
serum cholesterol concentrations and
carotid intima-media thickness after 2
years in post-menopausal women
“In postmenopausal women with
dyslipidemia, calcium supplements should
b e prescrib ed with caution.”30
Prentice, 2013 30 1,000 mg Placebo Cardiovascular data Unclear effects of supplementation on the
elemental calcium Total mortality risks of myocardial infarction, coronary
carbonate plus heart disease, total heart disease, stroke,
400 IU of vitamin overall CVD, colorectal cancer, or total
D3 daily or mortality
placebo
Kidney Transplant Recipients
Barros, 2016 31 266 mcg oral 266 mcg oral Safety Vitamin D supplementation with oral
calcifediol calcifediol biweekly calcifediol, in a biweekly or monthly
monthly regimen, is safe in kidney transplant
recipients
Metab olic Syndrome or Type II Diab etes
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 10Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
Forouhi, 2016 32 100,000 IU oral 100,000 IU oral Safety “No important safety issues were
vitamin D2 vitamin D3 identified.”33
(ergocalciferol) (cholecalciferol)
monthly monthly
4 months 4 months
Sansanayudh, G1: ergocalciferol Placebo: 2 Adverse reactions Adverse reactions did not differ between
2014 33 20,000 IU / week capsules / week groups
G2: ergocalciferol
40,000 IU / week
8 weeks
Multiple Sclerosis
Sortirchos, 10,400 IU 800 IU AEs “Adverse events were minor and did not
2016 34 cholecalciferol cholecalciferol differ b etween the 2 groups.”35
daily daily
“This study provides Class I evidence that
6 months 6 months cholecalciferol supplementation with
10,400 IU daily is safe and well-tolerated
in patients with MS.”35
Golan, 2013 35 Low dose vitamin High dose vitamin AEs No hypercalcemia or other potential major
D3: D3: adverse events in either group
800 IU / day 4,370 IU per day
(high dose) for
1 year
1 year
Pre-Menopausal Women with Systemic Lupus Erythematosus
Andreoli, 2015 36 Intensive regimen: Standard regimen: Safety The intensive regimen was safe; safety of
300,000 UI 25,000 UI standard regimen NR
cholecalcipherol cholecalcipherol
(vitamin D3) (vitamin D3)
initial bolus monthly
followed by 50,000
UI monthly 1 year
1 year Crossover to
intensive regimen
Crossover to
standard regimen 1 year
1 year
Hemodialysis Patients
Bhan, 2015 37 G1: oral Placebo Safety Similar all-cause and cause-specific
ergocalciferol, hospitalizations across groups
50,000 IU weekly 12 weeks
No difference between ergocalciferol-
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 11Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
G2: oral treated groups for lower all-cause
ergocalciferol, mortality
50,000 IU
monthly
12 weeks
Li, 2014 38 50,000 IU / week No Safety No effect of supplementation on sustained
cholecalciferol supplementation hypercalcemia
(vitamin D3)
12 months
Delanaye, Cholecalciferol Placebo Safety No hypercalcaemia was reported in either
2013 39 25,000 IU every 2 group
weeks
Authors concluded cholecalciferol is safe
1 year
Seibert, 2013 40 Serum level- Placebo Safety No relevant side effects were reported
adapted de novo
oral cholecalciferol
12 weeks
HIV Patients
Overton, 2015 41 vitamin D3 + Placebo AEs Similar distribution of AEs between
calcium groups; no hypercalcemia cases and 1
case of nephrolithiasis in placebo group
48 weeks
Pulmonary Tub erculosis
Tukvadze, G1: oral vitamin Placebo Safety Similar distribution of AEs between groups
2015 42 D3 50,000 IUs
(1.25 mg) 3 doses
/ week
G2: oral vitamin
D3 50,000 IU
every 2 weeks
8 weeks
Hydrocholorthiazide Users
Chandler, 2014 43 G1: cholecalciferol Placebo Hypercalcemia Low frequency of hypercalcemia with
(vitamin D3) vitamin D3 supplementation up to 4000 IU
G2: cholecalciferol
(vitamin D3) 2000
IU / day
G3; cholecalciferol
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 12Table 2: Calcium and Vitamin D Supplementation for Adults: Safety and Guidelines
First Author, Supplement / Comparators Outcomes Findings
Year Intervention
(vitamin D3)
4000 IU / day
3 months
AE = adv erse ev ents or ef f ects; ART = antiretrov iral therapy ; CVD = cardiov ascular disease; NR = not reported; RCT = randomized controlled trials; RR = relativ e risk;
SAE = serious adv erse ev ent.
Table 3: Guidelines and Recommendations
First Author, year Association Recommendations
Cesareo, 2018 44 IACE; IAAC “Even though 20 ng/mL (50 nmol/L) can b e considered appropriate in the general
population, we recommend to maintain levels ab ove 30 ng/mL (75 nmol/L) in
categories at risk .”44
Grossman, 2018 45 USPSTF “The USPSTF concludes that the current evidence is insufficient to assess the
b alance of the b enefits and harms of vitamin D and calcium supplementation,
alone or comb ined, for the primary prevention of fractures in community-dwelling,
asymptomatic men and premenopausal women. (I statement) The USPSTF
concludes that the current evidence is insufficient to assess the b alance of the
b enefits and harms of daily supplem entation with doses greater than 400 IU of
vitamin D and greater than 1000 mg of calcium for the primary prevention of
fractures in community-dwelling, postmenopausal women. (I statement) The
USPSTF recommends against daily supplementation with 400 IU or l ess of vitamin
D and 1000 mg or less of calcium for the primary prevention of fractures in
community-dwelling, postmenopausal women. (D recommendation) These
recommendations do not apply to persons with a history of osteoporotic fractures,
increased risk for falls, or a diagnosis of osteoporosis or vitamin D deficiency.”45
The National Institute NICE “This guideline covers vitamin D supplement use. It aims to prevent vitamin D
for Health and Care deficiency among specific population groups including infants and children aged
Excellence (NICE), under 4, pregnant and b reastfeeding women, particularly teenagers and young
2017 46 women, people over 65, people who have low or no exposure to the sun and
people with darker skin.”46
Kopecky, 2016 47 National “The National Osteoporosis Foundation and American Society for Preventive
Osteoporosis Cardiology adopt the position that there is moderate-quality evidence (B level) that
Foundation and the calcium with or without vitamin D intake from food or supplements has no
American Society for relationship (b eneficial or harmful) to the risk for cardiovascular and
Preventive Cardiology cereb rovascular disease, mortality, or all-cause mortality in generally healthy
adults at this time. In light of the evidence availab le to date, calcium intake from
food and supplements that does not exceed the tolerab le upper level of intake
(defined b y the National Academy of Medicine as 2000 to 2500 mg/d) should b e
considered safe from a cardiovascular standpoint.” 47
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 13Table 3: Guidelines and Recommendations
First Author, year Association Recommendations
UK Government SACN “A reference nutrient intake (RNI) of 10 micrograms of vitamin D per day,
Scientific Advisory throughout the year, for everyone in the general population aged 4 years and
Committee on older; an RNI of 10 micrograms of vitamin D per day for pregnant and lactating
Nutrition (SACN), women and population groups at increased risk of vitamin D deficiency; a ‘safe
2016 48 intake’ of 8.5 to 10 micrograms per day for all infants from b irth to 1 year of age; a
‘safe intake’ of 10 micrograms per day for children aged 1 to 4 years.”48
World Health WHO “In populations where calcium intake is low, calcium supplementation as
Organization (WHO), part of the antenatal care is recommended for the prevention of preeclampsia
2013 49 in pregnant women, particularly among those at higher risk of
developing hypertension (strong recommendation).”49
National National “Oral vitamin D3 is the treatment of choice in vitamin D deficiency… Where
Osteoporosis Osteoporosis Society correction of vitamin D deficiency is less urgent and when co-prescrib ing vitamin D
Society, 2013 a 50 supplements with an oral antiresorptive agent, maintenance therapy may b e
started without the use of loading doses.
• Adjusted serum calcium should b e checked 1 month after completing the loading
regimen or after starting vitamin D supplementation in case primary
hyperparathyroidism has b een unmasked.
• Routine monitoring of serum 25OHD is generally unnecessary b ut may b e
appropriate in patients with symptomatic vitamin D deficiency or malabsorption
and where poor compliance with medication is suspected.”50
USPSTF = US Prev entiv e Serv ices Task Force; IACE = Italian association of clinical endocrinologists; IAAC = Italian chapter o f the American Association of Clinical;
Endocrinologists; NICE = The National Institute f or Health and Care Excellence; SACN = UK Gov ernment Scientif ic Adv isory Committee on Nutrition; WHO = World
Health Organization.
a
The f ull set of recommendations can be obtained in the f ollowing link : https://nos.org.uk/media/2073/vitamin-d-and-bone-health-adults.pdf .
References Summarized
Health Technology Assessments
No literature was identified.
Systematic Reviews and Meta-analyses
General Population
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supplementation in adult populations: a systematic review. Endocr Pract. 2014
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7. Fortmann SP, Burda BU, Senger CA, Lin JS, Beil TL, O’Connor E, et al. Vitamin,
mineral, and multivitamin supplements for the primary prevention of cardiovascular
disease and cancer. a systematic evidence review for the U.S. Preventive Services
Task Force. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013
Nov.https://www.ncbi.nlm.nih.gov/books/NBK173987/ Accessed 2018 Jun 6.
Pregnant Women
8. De-Regil LM, Palacios C, Lombardo LK, Peña-Rosas JP. Vitamin D supplementation for
women during pregnancy. Cochrane Database Syst Rev. 2016 Jan.
PubMed: PM26765344
Recurrent Colorectal Adenoma Patients
9. Veettil SK, Ching SM, Lim KG, Saokaew S, Phisalprapa P, Chaiyakunapruk N. Effects
of calcium on the incidence of recurrent colorectal adenomas: a systematic review with
meta-analysis and trial sequential analysis of randomized controlled trials. Medicine
(Baltimore). 2017 Aug;96(32):e7661.
PubMed: PM28796047
Adults with Chronic Pain
10. Straube S, Derry S, Straube C, Moore RA. Vitamin D for the treatment of chronic painful
conditions in adults. Cochrane Database Syst Rev. 2015 May;6(5).
PubMed: PM25946084
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 15Cystic Fibrosis
11. Ferguson JH, Chang AB. Vitamin D supplementation for cystic fibrosis. Cochrane
Database Syst Rev. 2014 May;14(5).
PubMed: PM24823922
Adults with Diabetic Nephropathy
12. Zhao J, Dong J, Wang H, Shang H, Zhang D, Liao L. Efficacy and safety of vitamin D3
in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.
Chin Med J. 2014;127(15):2837-43.
PubMed: PM25146624
Adults with HIV Infection
13. Newberry SJ, Chung M, Shekelle PG, Booth MS, Liu JL, Maher AR, et al. Vitamin D and
calcium: a systematic review of health outcomes (update). Evid Rep Technol Assess
(Full Rep). Rockville (MD): Agency for Healthcare Research and Quality (AHRQ). 2014
Sep.
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calcium_research.pdf
Accessed 2018 Jun 6.
Randomized Controlled Trials
General Population
14. Alyousif Z, Ford AL, Dahl WJ. Calcium supplementation does not contribute to
constipation in healthy women. Can J Diet Pract Res. 2016 Jun;77(2):103-5.
PubMed: PM26771423
15. Al-Khalidi B, Chiu W, Rousseau D, Vieth R. Bioavailability and safety of vitamin D3 from
pizza baked with fortified mozzarella cheese: a randomized controlled trial. Can J Diet
Pract Res. 2015 Sep;76(3):109-16.
PubMed: PM26280790
16. Prietl B, Treiber G, Mader JK, Hoeller E, Wolf M, Pilz S, et al. High-dose cholecalciferol
supplementation significantly increases peripheral cd4(+) tregs in healthy adults witho ut
negatively affecting the frequency of other immune cells. Eur J Nutr. 2014
Apr;53(3):751-9.
PubMed: PM23999998
17. Yaron M, Roach V, Izkhakov E, Ish-Shalom M, Sack J, Sofer Y, et al. Effects of a typical
acute oral calcium load on arterial properties and endothelial function in healthy
subjects. Eur J Clin Nutr. 2014 May;68(5):608-12.
PubMed: PM24619106
18. Gallagher JC, Peacock M, Yalamanchili V, Smith LM. Effects of vitamin D
supplementation in older African American women. J Clin Endocrinol Metab. 2013
Mar;98(3):1137-46.
PubMed: PM23386641
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 1619. Zwart SR, Parsons H, Kimlin M, Innis SM, Locke JP, Smith SM. A 250 mug/week dose
of vitamin D was as effective as a 50 mug/d dose in healthy adults, but a regimen of
four weekly followed by monthly doses of 1250 mug raised the risk of hypercalciuria. Br
J Nutr. 2013 Nov;110(10):1866-72.
PubMed: PM23595003
Vitamin D Deficiency
20. Takacs I, Toth BE, Szekeres L, Szabo B, Bakos B, Lakatos P. Randomized clinical trial
to comparing efficacy of daily, weekly and monthly administration of vitamin D3.
Endocrine. 2017 Jan;55(1):60-65.
PubMed: PM27718150
21. Schleck ML, Souberbielle JC, Jandrain B, Da Silva S, De Niet S, Vanderbist F, et al. A
randomized, double-blind, parallel study to evaluate the dose-response of three different
vitamin D treatment schemes on the 25-hydroxyvitamin D serum concentration in
patients with vitamin D deficiency. Nutrients. 2015 Jul 3;7(7):5413 -22.
PubMed: PM26151178
22. Zabihiyeganeh M, Jahed A, Nojomi M. Treatment of hypovitaminosis D with
pharmacologic doses of cholecalciferol, oral vs intramuscular; an open labeled RCT.
Clin Endocrinol. 2013 Feb;78(2):210-6.
PubMed: PM22882353
Adults with Allergic Rhinoconjunctivitis or Asthma
23. Matysiak K, Matuszewski M, Feleszko W. Calcium preparations do not inhibit allergic
reactions: a randomized controlled trial. Pol Arch Intern Med. 2017 Sep 29;127(9):582 -
588.
PubMed: PM28724883
Pregnant Women
24. Omotayo MO, Dickin KL, Pelletier DL, Mwanga EO, Kung'u JK, Stoltzfus RJ. A
simplified regimen compared with who guidelines decreases antenatal calcium
supplement intake for prevention of preeclampsia in a cluster-randomized noninferiority
trial in rural Kenya. J Nutr. 2017 Oct;147(10):1986-1991.
PubMed: PM28878035
25. Mir SA, Masoodi SR, Shafi S, Hameed I, Dar MA, Bashir MI, et al. Efficacy and safety of
vitamin D supplementation during pregnancy: a randomized trial of two different levels
of dosing on maternal and neonatal vitamin D outcome. Indian J Endocrinol Metab.
2016 May-Jun;20(3):337-42.
PubMed: PM27186550
26. Harrington J, Perumal N, Al Mahmud A, Baqui A, Roth DE. Vitamin D and fetal-neonatal
calcium homeostasis: findings from a randomized controlled trial of high-dose antenatal
vitamin D supplementation. Pediatr Res. 2014 Sep;76(3):302-9.
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SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 1727. Yap C, Cheung NW, Gunton JE, Athayde N, Munns CF, Duke A, et al. Vitamin D
supplementation and the effects on glucose metabolism during pregnancy: a
randomized controlled trial. Diabetes Care. 2014 Jul;37(7):1837 -44
PubMed: PM24760259
28. Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW. Randomized
controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with
endemic vitamin D deficiency. J Clin Endocrinol Metabol. 2013 Jun;98(6):2337-46.
PubMed: PM23559082
Post-Menopausal Women
29. Li S, Na L, Li Y, Gong L, Yuan F, Niu Y, et al. Long-term calcium supplementation may
have adverse effects on serum cholesterol and carotid intima-media thickness in
postmenopausal women: a double-blind, randomized, placebo-controlled trial. Am J Clin
Nutr. 2013 Nov;98(5):1353-9.
PubMed: PM24047919
30. Prentice RL, Pettinger MB, Jackson RD, Wactawski-Wende J, Lacroix AZ, Anderson
GL, et al. Health risks and benefits from calcium and vitamin D supplementation:
women's health initiative clinical trial and cohort study. Osteoporos Int. 2013
Feb;24(2):567-80.
PubMed: PM23208074
Kidney Transplant Recipients
31. Barros X, Rodriguez NY, Fuster D, Rodas L, Esforzado N, Mazza A, et al. Comparison
of two different vitamin D supplementation regimens with oral calcifediol in kidney
transplant patients. J Nephrol. 2016 Oct;29(5):703-9.
PubMed: PM26454858
Metabolic Syndrome or Type II Diabetes
32. Forouhi NG, Menon RK, Sharp SJ, Mannan N, Timms PM, Martineau AR, et al. Effects
of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk
among people at risk of type 2 diabetes: results of a randomized double-blind placebo-
controlled trial. Diabetes Obes Metab. 2016 Apr;18(4):392-400.
PubMed: PM26700109
33. Sansanayudh N, Wongwiwatthananukit S, Phetkrajaysang N, Krittiyanunt S.
Comparative efficacy and safety of different doses of ergocalciferol supplementation in
patients with metabolic syndrome. Int J Clin Pharm. 2014 Aug;36(4):771-8.
PubMed: PM24853094
Multiple Sclerosis
34. Sotirchos ES, Bhargava P, Eckstein C, Van Haren K, Baynes M, Ntranos A, et al.
Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis.
Neurology. 2016 Jan 26;86(4):382-90.
PubMed: PM26718578
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 1835. Golan D, Halhal B, Glass -Marmor L, Staun-Ram E, Rozenberg O, Lavi I, et al. Vitamin
D supplementation for patients with multiple sclerosis treated with interferon -beta: a
randomized controlled trial assessing the effect on flu-like symptoms and
immunomodulatory properties. BMC Neurol. 2013 Jun 14;13:60.
PubMed: PM23767916
Pre-Menopausal Women with Lupus
36. Andreoli L, Dall'Ara F, Piantoni S, Zanola A, Piva N, Cutolo M, et al. A 24 -month
prospective study on the efficacy and safety of two different monthly regimens of vitamin
D supplementation in pre-menopausal women with systemic lupus erythematosus.
Lupus. 2015 Apr;24(4-5):499-506.
PubMed: PM25801893
Hemodialysis Patients
37. Bhan I, Dobens D, Tamez H, Deferio JJ, Li YC, Warren HS, et al. Nutritional vitamin D
supplementation in dialysis: a randomized trial. Clin J Am Soc Nephrol. 2015 Apr
7;10(4):611-9.
PubMed: PM25770176
38. Li L, Lin M, Krassilnikova M, Ostrow K, Bader A, Radbill B, et al. Effect of cholecalciferol
supplementation on inflammation and cellular alloimmunity in hemodialysis patients:
data from a randomized controlled pilot trial. PloS One. 2014;9(10).
PubMed: PM25296334
39. Delanaye P, Weekers L, Warling X, Moonen M, Smelten N, Medart L, et al.
Cholecalciferol in haemodialysis patients: a randomized, double-blind, proof-of-concept
and safety study. Nephrol Dial Transplant. 2013 Jul;28(7):1779-86.
PubMed: PM23378417
40. Seibert E, Heine GH, Ulrich C, Seiler S, Kohler H, Girndt M. Influence of cholecalciferol
supplementation in hemodialysis patients on monocyte subsets: a randomized, double-
blind, placebo-controlled clinical trial. Nephron Clin Pract. 2013;123(3-4):209-19.
PubMed: PM23988791
HIV Patients
41. Overton ET, Chan ES, Brown TT, Tebas P, McComsey GA, Melbourne KM, et al.
Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a
randomized trial. Ann Intern Med. 2015 Jun 16;162(12):815-24.
PubMed: PM26075752
Pulmonary Tuberculosis
42. Tukvadze N, Sanikidze E, Kipiani M, Hebbar G, Easley KA, Shenvi N, et al. High -dose
vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled
trial. Am J Clin Nutr. 2015 Nov;102(5):1059-69.
PubMed: PM26399865
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 19Hydrochlorothiazide
43. Chandler PD, Scott JB, Drake BF, Ng K, Forman JP, Chan AT, et al. Risk of
hypercalcemia in blacks taking hydrochlorothiazide and vitamin D. Am J Med. 2014
Aug;127(8):772-8.
PubMed: PM24657333
Guidelines and Recommendations
44. Cesareo R, Attanasio R, Caputo M, Castello R, Chiodini I, Falchetti A, et al. Italian
Association of Clinical Endocrinologists (AME) and Italian chapter of The American
Association of Clinical Endocrinologists (AACE) position statement: clinical
management of vitamin D deficiency in adults. Nutrients. 2018 Apr 27;10(5).
PubMed: PM29702603
45. Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, Davidson KW, 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 Apr 17;319(15):1592-1599.
PubMed: PM29677309
46. NICE. Vitamin D: supplement use in specific population groups.
London, England: National Institute for Health and Care Excellence (NICE); 2014 Nov.
https://www.nice.org.uk/guidance/ph56/evidence Accessed 2018 Jun 6.
47. Kopecky SL, Bauer DC, Gulati M, Nieves JW, Singer AJ, Toth PP, et al. Lack of
evidence linking calcium with or without vitamin D supplementation to cardiovascular
disease in generally healthy adults: a clinical guideline from The National Osteoporosis
Foundation and The American Society for Preventive Cardiology. Ann Int Med. 2016
Dec 20;165(12):867-868.
PubMed: PM27776362
48. UK Government Scientific Advisory Committee on Nutrition (SACN). Vitamin D and
health report. London, England: SACN, UK Government; 2016 Jul.
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachmen
t_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf Accessed 2018 Jun 6.
49. WHO Guidelines Approved by the Guidelines Review Committee. Guideline: Calcium
supplementation in pregnant women. Geneva, Switzerland: World Health Organization
(WHO); 2013.
PubMed: PM24006556
50. Francis R, Aspray T, Fraser W, Gittoes N, Javaid K, Macdonald H, et al. Vitamin D and
bone health: a practical clinical guideline for patient management. Camerton, Bath,
England: National Osteoporosis Society; 2013 Apr.
https://nos.org.uk/media/2073/vitamin-d-and-bone-health-adults.pdf Accessed 2018
Jun 6.
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 20Appendix — Further Information
Previous CADTH Reports
51. Vitamin D supplementation for the prevention of falls and fractures in residents in long -
term care facilities: a review of the clinical effectiveness, cost-effectiveness, or
guidelines. Ottawa (ON): CADTH. 2016 Apr.
https://www.cadth.ca/sites/default/files/pdf/htis/apr-
2016/RC0770%20Vit%20D%20in%20long-term%20care%20Final.pdf Accessed 2018
Jun 6.
52. Vitamin D toxicity associated with different vitamin D dosing regimens: safety. Ottawa
(ON): CADTH; 2014 Dec. https://www.cadth.ca/sites/default/files/pdf/htis/dec-
2014/RB0777%20Vitamin%20D%20Toxicity%20Final.pdf Accessed 2018 Jun 6.
53. Drug‐vitamin D interactions: a systematic review of the literature. 2013. URL:
https://doi.org/10.1177/0884533612467824
https://doi.org/10.3310/hta18450
Systematic Reviews and Meta-Analyses - No Comparator
54. Aune D, Navarro Rosenblatt DA, Chan DS, Vieira AR, Vieira R, Greenwood DC, et al.
Dairy products, calcium, and prostate cancer risk: a systematic review and meta-
analysis of cohort studies. Am J Clinl Nutr. 2015 Jan;101(1):87 -117.
PubMed: PM25527754
55. Robien K, Oppeneer SJ, Kelly JA, Hamilton-Reeves JM. Drug‐vitamin D interactions: a
systematic review of the literature. Nutr Clin Pract. 2013 Apr;28(2):194-208.
PubMed: PM23307906
Randomized Controlled Trials
Age Range Not Specified or Mixture of Ages
56. Cronin BE, Allsopp PJ, Slevin MM, Magee PJ, Livingstone MB, Strain JJ, et al. Effects
of supplementation with a calcium -rich marine-derived multi-mineral supplement and
short-chain fructo-oligosaccharides on serum lipids in postmenopausal women. Br J
Nutr. 2016 Feb 28;115(4):658-65.
PubMed: PM26669430
57. Harris SS, Dawson-Hughes B. Effects of hydration and calcium supplementation on
urine calcium concentration in healthy postmenopausal women. J Am Coll Nutr.
2015;34(4):340-6.
PubMed: PM25856469
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 21Clinical Practice Guidelines – Methodology Not Reported
58. Godel JC. Vitamin D supplementation: Recommendations for Canadian mothers and
infants. Ottawa (ON): Canadian Paediatric Society; 2007 Oct (reaffirmed 2017 Jan).
https://www.cps.ca/en/documents/position/vitamin-d Accessed 2018 Jun 6.
59. Harvey NC, Biver E, Kaufman JM, Bauer J, Branco J, Brandi ML, et al. The role of
calcium supplementation in healthy musculoskeletal ageing : an expert consensus
meeting of The European Society for Clinical and Economic Aspects of Osteoporosis,
Osteoarthritis and Musculoskeletal Diseases (ESCEO) and The International
Foundation for Osteoporosis (IOF). Osteoporos Int. 2017 Feb;28(2):447-462.
PubMed: PM27761590
SUMMARY OF ABSTRACTS Calcium and Vitamin D Supplementation f or Adults 22You can also read
