Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function
Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.2
The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.
Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.57
The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.55
Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.41,58-62
Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer41,63-66,121 or cardiovascular disease risk.41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.43,72-75,85-90,122
The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.123 RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.124 The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.123 Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.52,53
Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).125,126
Vitamin K
Vitamers: Phylloquinone (K1); menaquinones (K2)
Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism
Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods
Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.2
Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.
Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)91 and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.127 Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.128,129
Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.2 The FDA considers the evidence insufficient at this time to support such a claim.2 Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies94 and supplementation was associated with improved disease measures,130 but no patient-oriented outcomes have been demonstrated.131
The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.
Multivitamins
Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.132 Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.133
Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.
A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.41 Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.134,135 This benefit appears to disappear at 5 years of follow-up.136 RCT data have shown no benefit of multivitamin use on cognitive function,95 and high-quality data suggest there is no effect on all-cause mortality.137 Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.41
The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.138-140 AAP does not recommend multivitamins for children with a well-balanced diet.141 Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.142
The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.143 Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.144 Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.2
Summary
Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.
