D3 5,000 IU + K2 120 mcg by Wonder Laboratories

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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EFFECTIVE

• Familial hypophosphatemia. Oral vitamin D in combination with phosphate is effective for bone disorders in patients with familial hypophosphatemia. Details: Taking calcitriol or dihydrotachysterol orally in combination with phosphate supplements is effective for treating bone disorders in people with familial hypophosphatemia (11818).
• Hypoparathyroidism. Oral vitamin D increases serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism. Details: Vitamin D2 (ergocalciferol) is effective in high doses for increasing serum calcium concentrations in people with hypoparathyroidism or pseudohypoparathyroidism (11820). Also, taking vitamin D (form unspecified) or calcitriol postoperatively is effective for preventing hypocalcemia in people with hypoparathyroidism due to thyroidectomy (39045).
• Osteomalacia. Oral vitamin D is effective for osteomalacia. Details: Oral calcifediol is effective for treating osteomalacia secondary to liver disease (hepatic osteodystrophy) and anticonvulsant-induced osteomalacia. Vitamin D2 (ergocalciferol) is effective for osteomalacia due to malabsorption syndromes, Fanconi syndrome, and corticosteroid-induced osteomalacia (11819,11821).
• Renal osteodystrophy. Oral calcitriol prevents renal osteodystrophy in patients with chronic renal failure. Details: Taking calcitriol orally manages hypocalcemia and prevents renal osteodystrophy in patients with chronic renal failure undergoing dialysis (11823).
• Rickets. Oral vitamin D prevents and treats rickets. Details: Vitamin D is effective for preventing and treating rickets, a consequence of vitamin D deficiency. Calcitriol should be used in patients with renal failure (11824). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to prevent nutritional rickets in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). A large clinical study in pregnant adults shows that taking vitamin D 28,000 IU weekly from the second trimester up to 6 months post-partum decreases the risk of biochemical rickets by about 84% in the offspring at 6-12 months of age when compared with placebo. However, taking vitamin D 4200, 16,800, or 28,000 IU weekly from the second trimester to delivery does not decrease the risk of rickets in the offspring when compared with placebo (114503).
• Vitamin D deficiency. Oral vitamin D prevents and treats vitamin D deficiency. Details: Vitamin D is effective for preventing and treating vitamin D deficiency using a wide range of doses and dosing frequencies (7555,16888,16891,17476,115590). Optimal blood levels of 25-hydroxyvitamin D for maintaining bone density is controversial; however, it is typically estimated that blood levels of 20-100 ng/mL are needed. Toxicity usually does not occur until levels exceed 150 ng/mL (17476,93945). Vitamin D also alleviates symptoms and syndromes associated with vitamin D deficiency. Administering vitamin D2 (ergocalciferol) intramuscularly or orally seems to help treat severe proximal myopathy associated with severe vitamin D deficiency. Several case reports suggest vitamin D therapy can provide prompt relief of muscle weakness and restore mobility (11923,84348,84687).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral vitamin D prevents corticosteroid-induced osteopenia and osteoporosis. Details: Taking calcifediol, cholecalciferol, calcitriol, or alfacalcidol orally prevents corticosteroid-induced osteopenia and osteoporosis (7555,83933). Vitamin D3 metabolites, including calcitriol and alfacalcidol, seem to be more effective at preventing bone loss compared to cholecalciferol in these patients, although the vitamin D3 metabolites seem to be inferior to bisphosphonates (83955). Furthermore, taking activated vitamin D or other forms of vitamin D alone or along with calcium improves bone mineral density in people with corticosteroid-induced osteoporosis (38493,38581).
• Osteoporosis. Adequate intake of vitamin D in conjunction with adequate calcium intake helps to prevent the progression of osteoporosis. It might also reduce the risk of a first fracture in some patients. However, its place in the prevention of secondary fracture is unclear. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate vitamin D intake of 800-1000 IU daily along with adequate calcium intake for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake, with a target serum vitamin D level of 30 ng/mL (109425). In the US, foods that contain at least 120 IU vitamin D can be labelled with a health claim regarding the relationship between adequate vitamin D intake and a reduced risk for osteoporosis (97001). However, vitamin D supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Clinical research shows that vitamin D3 (cholecalciferol) and calcium can decrease postmenopausal bone loss, improve bone density, help prevent osteoporosis, and decrease the risk of fractures (10932,12926,12930,12934,12952) (38973,39015,39026,84003,113584). According to one analysis, taking oral vitamin D3 700-800 IU daily with or without calcium reduces fracture risk in ambulatory and institutionalized elderly people (12933). Other analyses suggest that taking vitamin D as cholecalciferol, ergocalciferol, calcifediol, calcitriol, or alfacalcidol with or without calcium can reduce the risk of all fractures by up to 17%, nonvertebral fractures by up to 49%, and hip fractures by up to 30% in older adults. However, the incidence of vertebral fractures does not appear to be reduced with vitamin D supplementation (38942,38970,38973,39015,39026,84660,109053). Despite the majority of research showing benefit, some studies have not found a positive effect of vitamin D on fracture risk. Some analyses of clinical evidence, including patients with and without osteoporosis, show that taking vitamin D3 or vitamin D2 (ergocalciferol) alone does not reduce fracture risk, suggesting that adequate calcium intake is needed for any benefit to be realized (39015,84471). Also, some evidence suggests that vitamin D3 400 IU daily is not effective for the prevention of osteoporotic fractures in elderly nursing home residents (109053). Another clinical trial found that taking vitamin D3 800 IU daily with calcium 1200-1500 mg daily for 2 years does not increase bone mineral density (BMD) in Black postmenopausal adults. This may be due to the fact that Black females have a lower rate of bone remodeling, an increased calcium absorption efficiency, and reduced calcium excretion when compared with other ethnic groups; therefore, supplementation with vitamin D3 and calcium might not be as beneficial in these patients (16878). There is concern that vitamin D might not be effective for secondary prevention of fractures in elderly patients. A meta-analysis of clinical studies, including many studies cited above, and a large clinical study in elderly adults with a previous osteoporotic fracture show that taking vitamin D3 400-4000 IU daily or as a single dose up to 500,000 IU orally or injected annually with or without calcium 480-1200 mg daily for up to 5 years does not reduce the risk of hip, vertebral, or other fractures when compared with placebo or no treatment (13073,112486). Another study also shows that taking vitamin D3 800 IU and calcium 1000 mg daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (under 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). However, these studies have been criticized for failing to measure vitamin D levels and low adherence to study protocol (12931). Also, one of these studies did not use a placebo control (12929). Taking alfacalcidol orally seems to maintain BMD in prostatic carcinoma patients at risk for osteoporosis when treated with luteinizing hormone-releasing hormone analogue (LHRH-a). Alfacalcidol maintains, but does not increase, BMD in these patients (6360).
• Psoriasis. Topical vitamin D or vitamin D analogues improve symptoms of psoriasis. This benefit is not seen with oral vitamin D. Details: Topical application of vitamin D in the form of calcitriol or other vitamin D analogues, such as calcipotriene, maxacalcitol, and paricalcitol, effectively treats plaque psoriasis in some patients, including those with chronic plaque psoriasis (11822,84325). Applying topical vitamin D or its analogues in combination with topical corticosteroids such as betamethasone seems to be more effective for treating plaque psoriasis than either agent used alone (22283,82572,84325,84536,84647). Despite evidence that patients with psoriasis have low baseline serum levels of vitamin D, taking oral vitamin D does not seem to prevent psoriasis, improve symptoms, or reduce the severity of psoriasis in general (11822,22283,82572,84325,84536,84647,98193,108426,112481,112482). An analysis of a large clinical study in older adults with mild psoriasis shows that taking a vitamin D3 (cholecalciferol) loading dose of 200,000 IU followed by vitamin D3 100,000 IU monthly for 1 year does not affect the severity or spread of psoriasis when compared with placebo (98193).

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Some research suggests that oral vitamin D reduces symptoms of allergic rhinitis in children and adults. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention of allergic rhinitis in the child. Details: Preliminary clinical research in adults with allergic rhinitis and vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 8 weeks along with cetirizine improves overall symptom severity when compared with placebo and cetirizine. This improvement was not significant at 4 weeks, suggesting that symptom improvement might not occur until vitamin D has been adequately replenished (102120). Another moderate-sized clinical study conducted in China in adults with moderate to severe allergic rhinitis and vitamin D levels at the low end of the normal range shows that taking vitamin D 800 IU daily for 4 weeks along with mometasone nasal spray improves runny nose, itchy nose, and nasal congestion but does not reduce sneezing when compared with placebo and mometasone (112483). In children aged 5-15 years, 4 small- or moderate-sized clinical trials show that taking vitamin D 800 IU or 1000 IU daily for 1-6 months modestly reduces symptoms such as nasal congestion and rhinorrhea when compared with placebo or no supplementation (109728). It is unclear whether these children had vitamin D deficiency at baseline. Vitamin D supplementation during pregnancy has also been evaluated. A meta-analysis of three large clinical studies shows that prenatal vitamin D supplementation does not reduce the risk of the child developing allergic rhinitis when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Coronavirus disease 2019 (COVID-19). Clinical research suggests that vitamin D deficiency is associated with greater risk for and severity of COVID-19 infection. Research of varying quality has evaluated the use of vitamin D supplementation in adults with COVID-19 infection, suggesting that it does not reduce overall mortality, but may reduce the risk of intubation and admission to the intensive care unit (ICU). It is unclear whether any benefits are correlated to baseline vitamin D status. Details: Clinical and observational research suggests that prophylactic vitamin D supplementation may reduce the risk for and severity of COVID-19 infection in people with vitamin D deficiency or insufficiency at baseline. An umbrella review of meta-analyses summarizing data from 9 observational studies suggests that vitamin D deficiency is associated with an increased risk for COVID-19 infection and a greater severity of illness when compared with control (114583). Additionally, a separate meta-analysis of 12 observational studies conducted early in the COVID-19 pandemic suggests that low baseline vitamin D status (25-hydroxyvitamin D levels below 30 ng/mL) is associated with a greater risk of severe COVID-19 pneumonia and mortality when compared with higher levels. However, patients with lower vitamin D levels were also more likely to have baseline hypertension and cardiovascular disease (107206). While earlier meta-analyses suggested that vitamin D supplementation did not prevent COVID-19 (109040,112488), a larger and more recent meta-analysis of 5 clinical studies conducted in healthcare workers, of whom 85-94% had vitamin D insufficiency or deficiency, shows that taking vitamin D reduces the odds of developing a COVID-19 infection by about 80% when compared with control. A separate meta-analysis of 2 clinical studies in the general population found no correlation between vitamin D supplementation and risk of COVID-19 infection; however, the people in these studies had adequate vitamin D levels at baseline (113590). The benefits of vitamin D prophylaxis in people with sufficient vitamin D levels is unclear. Clinical studies have evaluated the use of vitamin D supplementation in hospitalized adults with COVID-19, assessing hospital length of stay (LOS), the risk of ICU admission, and rate of intubation. Although meta-analyses conducted in the first year of the COVID-19 pandemic did not identify an association between vitamin D supplementation and any of these outcomes (107206,109733,112490), more recent meta-analyses suggest benefit in certain populations. Meta-analyses of clinical studies in adults with COVID-19 show that vitamin D supplementation may be correlated with a modest reduction in hospital LOS in certain patients when compared with placebo or a lower dose of vitamin D. Subgroup analyses suggest that this reduction may be limited to patients with non-severe disease and those aged 60-65 years and older (115575,115578). Additionally, more recent meta-analyses of clinical studies show that vitamin D supplementation reduces the risk of admission to the ICU when compared with control, although the odds ratio varies depending on the analysis conducted (112488,112490,115578). Similarly, meta-analyses of observational studies suggest that vitamin D supplementation is associated with a reduced odds of ICU admission when compared with control (113590,115578). Also, meta-analyses of clinical studies show that vitamin D supplementation modestly reduces the risk of intubation when compared with control (112488,115578). Meta-analyses of observational studies, as well as studies conducted early in the COVID-19 pandemic, originally suggested a potential reduction in mortality with the use of vitamin D supplementation during hospitalization (109040,114583,115578). However, more recent meta-analyses of prospective clinical studies do not support this finding. A meta-analysis of 19 clinical studies in adults with moderate to severe COVID-19 shows that vitamin D supplementation does not reduce mortality when compared with placebo or standard care, when controlling for heterogeneity. Additionally, a subgroup analysis of 13 clinical studies administering high-dose vitamin D does not show a reduction in mortality (115576). Other meta-analyses of clinical studies also show that vitamin D supplementation does not reduce mortality when compared with control, regardless of baseline vitamin D status (114488,115578). In most studies that provided vitamin D to hospitalized patients, oral doses ranged from 1000-25,000 IU daily for 1-3 weeks, 10,000-25,000 weekly for up to 6 weeks or until hospital discharge, or as a single 140,000-600,000 IU dose. In some studies, vitamin D 200,000-500,000 IU was administered intramuscularly as a single dose. Cholecalciferol was the most common form administered. However, some studies used calcitriol or calcifediol (107206,107208,109040,109733,112488,112490,113590,114583,115575,115578). Overall, the validity of the findings from meta-analyses is limited by the significant heterogeneity of the included studies, which enrolled patients of varying age, disease severity, and baseline vitamin D status, and implemented highly variable vitamin D supplementation protocols. The relationship between vitamin D levels and COVID-19 has also been evaluated in pregnant adults. A meta-analysis of observational research suggests that, while lower vitamin D levels are not associated with an increased risk of COVID-19, the presence of severe COVID-19 symptoms during pregnancy may be correlated to lower vitamin D levels when compared with non-severe COVID-19 symptoms (112025). Vitamin D has also been evaluated for post-COVID-19 symptoms. A clinical study in adults with vitamin D deficiency, as well as fatigue and neuropsychiatric symptoms for at least one month post-COVID-19, shows that taking vitamin D 60,000 IU weekly for 8 weeks modestly improves fatigue, anxiety, and some aspects of cognitive function, but not symptoms of depression, when compared with placebo (115580). It is unclear if the improvements in anxiety and cognitive function were clinically significant. Additionally, it is unclear if vitamin D supplementation is beneficial in adults with adequate baseline vitamin D levels.
• Dental caries. Some research suggests that oral vitamin D reduces the risk of dental caries in children. Details: A meta-analysis of clinical research suggests that vitamin D3 (cholecalciferol) reduces the risk of cavities by 49%, and vitamin D2 (ergocalciferol) reduces the risk by 36% when compared with placebo in infants, children, and adolescents (84690). The validity of this finding is limited by the heterogeneity of the included trials. Also, clinical research shows an inverse correlation between cord blood vitamin D status and the number of decayed primary teeth in the infant at 12 months of age (104620). However, this same research shows that taking two oral prenatal doses of vitamin D2 50,000 IU during pregnancy does not prevent dental caries in the infant at 12 months of age or increase vitamin D levels in the cord blood (104620).
• Heart failure. Limited research suggests that oral vitamin D reduces the risk of developing heart failure in some patients. However, vitamin D does not seem to improve outcomes in patients that have already developed heart failure. Details: Population research has found that vitamin D levels below 15 ng/mL are associated with increased risk of developing heart failure (16615). A meta-analysis of 17 trials, including the landmark Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, shows that vitamin D reduces the risk of heart failure by 21% compared to not taking vitamin D in patients 60 years or older (91343). This finding is limited because none of the included trials were designed to determine effects on cardiovascular outcomes. In contrast, a secondary analysis of data from the Women's Health Initiative trial shows that taking vitamin D 400 IU with calcium 1000 mg daily is not associated with a reduced risk of heart failure in postmenopausal adults. However, a subgroup analysis of that trial shows that taking vitamin D plus calcium is associated with a 37% lower risk of developing heart failure in postmenopausal adults classified as low-risk for heart failure at baseline. It is speculated that high-risk patients might not benefit from vitamin D plus calcium due to negative interactions with medications used to manage cardiovascular risk factors in this group (97307). While vitamin D might be associated with a reduced risk of developing heart failure, most evidence suggests that vitamin D is not beneficial in patients already diagnosed with heart failure. In one small clinical trial, taking vitamin D3 50,000 IU weekly along with calcium citrate 800 mg daily for 6 months was not associated with an improvement in 6-minute walk test, timed get up and go test (TGUG), electrocardiographic variables, or health status when compared with placebo in adults with heart failure; mortality was not evaluated (97299,97300). In another clinical trial, taking vitamin D3 2000 IU daily did not decrease the risk of mortality when compared with placebo in New York Heart Association (NYHA) class 2 heart failure patients (16620).
• Hyperparathyroidism-related bone loss. Limited evidence suggests that oral vitamin D is beneficial in patients with this condition. Details: Taking vitamin D3 (cholecalciferol) orally seems to help decrease secondary hyperparathyroidism and bone turnover in females. In one study, supplementation with vitamin D3 increased serum levels of 25-hydroxyvitamin D, reduced levels of parathyroid hormone, and decreased production of markers of bone turnover (3463).
• Respiratory tract infections. Clinical research shows that oral vitamin D supplementation reduces the risk for respiratory tract infections (RTIs) in children but not in adults or older adults. Some clinical practice guidelines recommend vitamin D supplements or fortified foods for children to potentially lower the risk of RTIs. It is unclear if oral vitamin D is beneficial for the treatment of RTIs. Details: Prenatally, increased levels of vitamin D during pregnancy have been associated with a lower incidence of childhood RTIs (98197). However, two meta-analyses of small clinical studies and one meta-analysis of large clinical studies show no effect of prenatal vitamin D supplementation on the incidence of infant or childhood RTIs, including lower RTIs, when compared with control. Results related to risk of wheeze are conflicting (95910,95912,108438). In children, most research shows that vitamin D supplementation reduces the risk of RTIs. A meta-analysis of clinical trials in children aged 1-16 years shows that taking vitamin D decreases the odds of having an RTI by about 29% when compared with control, although this study also identified a high likelihood of publication bias (105721). Daily or weekly vitamin D doses seem to be more beneficial than single bolus doses, although the largest meta-analysis failed to confirm this result (84689,93766,105721). One clinical study in preterm Black infants shows that taking vitamin D3 (cholecalciferol) 200 IU daily and then 400 IU daily until 6 months of age does not affect the rate of RTIs, but does reduce wheeze by 11%, when compared with a normal diet without vitamin D supplementation (98191). This study may not have been powered to detect a difference in RTIs between groups. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from vitamin D fortified foods, vitamin D supplements, or vitamin formulations that contain vitamin D to potentially lower the risk of RTIs in children and adolescents aged 1 to 18 years. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502). In adults, vitamin D supplementation does not seem to reduce the risk of RTIs. Observational research in adults has found that low levels of vitamin D are associated with worsened RTI complications, and even increased mortality in older adults ages 50-75 years (103659). However, meta-analyses of prospective clinical trials in adults show that taking vitamin D supplements 300-4000 IU daily for 7 weeks to 5 years or taking vitamin D 30,000-100,000 IU monthly or 96,000-120,000 IU every 2 months for 1-5 years does not reduce the odds of developing an RTI or severe respiratory complications, such as emergency department utilization, hospitalization, and death, when compared with placebo. These results were similar in subgroup analyses evaluating overall vitamin D dose and baseline vitamin D status (84689,105721,114506). The largest single clinical trial, conducted in adults at least 60 years of age, shows that taking vitamin D3 (cholecalciferol) 60,000 IU once monthly for up to 5 years reduces the duration of total and severe respiratory symptoms by approximately 0.5 days, but does not reduce the incidence of respiratory illness or hospitalization, when compared with placebo (105726,110825). When adults and children are evaluated together, vitamin D supplementation does not seem to reduce the risk of respiratory infections. Two large meta-analyses of 40 clinical studies in both children and adults shows that taking vitamin D does not reduce the risk of acute RTIs. While subgroup analyses suggest a potential modest reduction in risk of acute RTIs in studies not exceeding 4 months' duration and with daily supplementation of 400-1200 IU during winter, spring, and autumn, these findings are limited by the low quality of the evidence and publication bias (108435,115582). Vitamin D has also been evaluated for the treatment of RTIs. A large meta-analysis of clinical studies in both children and adults shows that taking vitamin D improves outcomes (e.g., sputum conversion, survival rate, therapeutic success, need for intensive care admission) by a small, but not clinically relevant, amount. In subgroup analyses, these beneficial effects only persisted in studies considered to be of low quality (108436). The validity of these findings is limited by publication bias.
• Tooth retention. Oral vitamin D with calcium seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking vitamin D3 (cholecalciferol) 700 IU daily along with calcium citrate malate 500 mg daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Most research shows that taking vitamin D with or without calcium does not reduce the risk of CVD or CVD complications. There is some speculation that there might be modest benefit in the elderly, but more research is needed to confirm. Details: Population research has found that low vitamin D levels, especially those below 15 ng/mL, are associated with an increased risk of developing CVD (15630,16618,93944,113588). However, taking vitamin D supplements does not seem to prevent CVD. The majority of evidence from clinical research, population research, and meta-analyses shows that vitamin D supplementation, with or without calcium, does not reduce the risk of mortality, myocardial infarction, cardiac-related hospitalizations, or stroke when compared with placebo in patients with or without CVD risk factors (91343,97296,97305,97308,98902,98916,99762,109729,110811,110827)(112021,112022,113588). The most reliable evidence comes from two meta-analyses of mainly high-quality clinical research investigating the effect of supplementation with vitamin D alone or with calcium for at least 1 year. These analyses show that vitamin D does not reduce major adverse cardiovascular events, stroke, CVD mortality, or all-cause mortality, regardless of baseline vitamin D level, vitamin D dosage, sex, formulation, or concomitant calcium supplementation (99762,109729). One large clinical trial in individuals at increased CVD risk shows that taking vitamin D as cholecalciferol 60,000 IU monthly modestly INCREASES the risk of CVD- and presumed CVD-related mortality (110827). The effect of vitamin D supplementation in elderly adults on CVD outcomes has also been evaluated. In some research, taking vitamin D 700-1000 IU daily shows a trend towards lower CVD events and reduced risk of major adverse cardiovascular events in elderly patients (11931,98916,99762). However, another study in adults aged 70 years or older without a history of cardiovascular events and who are vitamin D replete at baseline shows that taking vitamin D 2000 IU daily for 3 years does not decrease the risk of coronary heart disease, heart failure, stroke, or hypertension when compared with placebo (113581). Larger, high-quality trials with prespecified primary outcomes are needed to determine whether or not vitamin D supplementation reduces CVD risk in elderly populations.
• Critical illness (trauma). Taking vitamin D 540,000 IU as a single oral dose does not reduce death or hospital stay in critically ill patients. However, limited research suggests that taking a smaller dose of vitamin D long-term might have a modest benefit. Details: The most robust evidence to date shows that correcting vitamin D levels in critically ill patients with vitamin D deficiency does not reduce mortality rate or duration of hospital stay. A large, multicenter clinical study in critically ill patients with vitamin D deficiency shows that administering a single, enteral dose of vitamin D 540,000 IU does not reduce 90-day all-cause mortality, duration of hospital stay, ventilator-free days, or other clinical outcomes when compared with placebo (103656). A previous meta-analysis of clinical research showed that vitamin D supplementation administered for a duration of 7 days or up to 6 months reduces the risk of death by 30% in critically ill hospitalized patients (95913). However, included studies were of low methodological quality, had high heterogeneity, assessed patients with and without vitamin D deficiency, and used variable vitamin D dose regimens and administrations methods (95913,95914).
• Fractures. Most evidence shows that oral vitamin D alone does NOT prevent factures in people who do not have osteoporosis. Some research shows that taking vitamin D with calcium prevents fractures; however, more research is needed to determine who is most likely to benefit. Details: Clinical research shows that taking vitamin D alone does not seem to prevent fractures in older adults. Most adults in these studies did not have osteoporosis, although osteoporosis status was unclear in some research (10140,12933,14282,38970,39015,84660,95822,97296,102145,104619)(109059,110827). However, several meta-analyses suggest that taking higher doses of vitamin D (about 800 IU daily) in combination with calcium might reduce overall fracture risk in older patients (38942,38970,39015,84660,102145,110809). One meta-analysis of clinical research in community- or long-term care-living males and females at least 65 years of age shows that taking vitamin D 800 IU daily in combination with calcium reduces the risk of hip and non-vertebral fractures by 25% and 20%, respectively, compared with placebo (110809). However, discrepancies exist which are possibly related to the dose and form of calcium used in combination with vitamin D and/or the patient population. Some research shows that taking vitamin D 800 IU daily in combination with calcium 1200 mg daily as tricalcium phosphate reduces fracture risk by up to 31% while taking vitamin D with calcium carbonate does not reduce fracture risk (12929,14282,16878,110809). Some individual clinical studies in postmenopausal females aged 50-79 years show that taking vitamin D plus calcium daily for 2-7 years does not prevent fractures when compared with placebo (14282,16878). Other confounding variables include the possible additional effects of hormonal therapy when given with calcium to postmenopausal adults and/or the inclusion of institutionalized patients with unclear osteoporotic status (95822,97296). Most research shows that taking vitamin D in combination with omega-3 fatty acids does not prevent fractures. A large clinical study shows that taking vitamin D 2000 IU daily alone or with omega-3 fatty acids 1 gram daily and/or strength training three times weekly does not prevent fractures in adults over 70 years of age when compared with placebo (104619). Another large clinical trial shows that taking vitamin D 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, over approximately 5 years does not prevent overall fractures, nonvertebral fractures, or hip fractures in adults over 50 (males) or 55 (females) years old when compared with placebo. Although the osteoporosis status of the population was unclear, findings were consistent in adults at high fracture risk based on use of osteoporosis medications and/or a history of fragility fractures (109059). As of April 2018, the US Preventative Services Task Force (USPSTF) recommends against supplementing with vitamin D 400 IU daily or less along with calcium 1000 mg daily or less for preventing primary fractures in community-dwelling postmenopausal adults. The USPSTF also concludes that there is insufficient evidence to determine whether supplementing with doses of vitamin D greater than 400 IU daily along with calcium doses greater than 1000 mg daily is safe or effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture (95695). For information on patients WITH osteoporosis, refer to the Osteoporosis discussion. There is limited research available regarding the effects of vitamin D supplementation for fracture prevention in children. Preliminary research in children aged 2 to 17 years with vitamin D insufficiency and one or more previous fractures shows that taking vitamin D 2000 IU daily with calcium 600 mg daily for 6 months modestly reduces the risk of forearm fractures over 12 months compared with children not given vitamin D or calcium (110820).
• Hypertension. Overall, vitamin D does not seem to prevent or lower high blood pressure in most patients; however, it may lower blood pressure in hypertensive patients with vitamin D deficiency. Details: Although population research has found that lower vitamin D levels are associated with a higher risk of developing hypertension, clinical research shows vitamin D supplementation does not prevent hypertension (15630). A large clinical trial in postmenopausal adults shows that taking vitamin D3 400 IU with calcium 1000 mg daily does not reduce the risk of developing hypertension (16714). Most meta-analyses and clinical trials in patients with existing hypertension show that vitamin D supplementation does not lower blood pressure when compared with placebo, regardless of vitamin D formulation, dose, or duration of supplementation (16714,91340,96405,103657,104619,113583,113668). However, a meta-analysis of 5 clinical studies in patients with hypertension and vitamin D deficiency shows that supplementation with vitamin D reduces systolic and diastolic blood pressure by about 7 mmHg and 3 mmHg, respectively, when compared with placebo (100895). Another meta-analysis of 11 clinical trials in patients over 60 years of age with hypertension and vitamin D deficiency shows that taking vitamin D supplements significantly reduces systolic, but not diastolic, blood pressure when compared with placebo, especially in trials lasting more than 8 weeks where the total dose of vitamin D is above 400,000 IU (113592). An individual clinical study in patients with hypertension and vitamin D deficiency or insufficiency shows that taking vitamin D 50,000 IU weekly or 1000 IU daily reduces systolic blood pressure by about 6 mmHg and mean arterial pressure by about 4 mmHg, but does not affect diastolic blood pressure, when compared to baseline (108440).
• Prostate cancer. Oral vitamin D does not appear to affect prostate cancer progression or cancer-related mortality. Details: A meta-analysis of three clinical trials shows that vitamin D supplementation does not affect prostate cancer progression as measured by prostate-specific antigen (PSA), or mortality in patients with prostate cancer (99770).
• Psychosis. Oral vitamin D does not seem to improve symptoms in patients with a functional psychotic disorder. Details: A clinical study in adults with a functional psychotic disorder shows that taking oral vitamin D3 (cholecalciferol) 20,000 IU monthly for 6 months has no effect on total positive and negative syndrome scale score (PANSS) when compared with placebo. The majority of patients included in this study were deficient in vitamin D at baseline (107226).
• Tuberculosis. Oral vitamin D seems to be ineffective for reducing the severity of tuberculosis or mortality from tuberculosis. Limited research suggests that vitamin D may have small benefits in newly diagnosed patients receiving tuberculosis treatment for the first time. Details: Although population research has found that tuberculosis is associated with vitamin D deficiency, most clinical research shows that taking vitamin D does not improve clinical outcomes in people with tuberculosis infection. Meta-analyses and individual clinical studies show that taking vitamin D as a single 100,000 IU dose, or as 400 IU daily for 2 months, along with standard care does not improve tuberculosis severity or reduce the risk of mortality in children or adults with tuberculosis, regardless of their baseline vitamin D levels (82570,82475,98913,103655,103668,104022). However, some research has identified modest benefits in newly diagnosed patients receiving anti-tuberculosis treatment for the first time. A meta-analysis of clinical research in this population shows that taking vitamin D at a dose of 1000 IU daily or 600,000 IU monthly modestly increases the odds of sputum smear conversions by 1.2-fold, but does not improve the time to sputum smear conversions, when compared with placebo (98235). A small clinical study in treatment-naïve adults with low levels of serum vitamin D shows that taking calcitriol 0.25 mcg twice daily for up to 6 months, starting with anti-tuberculosis treatment initiation, decreases the time to sputum smear conversion and 50% lesion absorption by about 3 days when compared with not taking vitamin D (109045). Additionally, a small clinical study in children aged 6-18 years with vitamin D insufficiency receiving standard treatment for newly diagnosed pulmonary tuberculosis shows that taking vitamin D 1000 IU daily reduces the duration of fever and cough by 1 and 2 weeks, respectively, when compared with placebo (108437).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral vitamin D is beneficial for acne. Details: A small clinical trial in patients with acne and vitamin D deficiency shows that taking cholecalciferol 1,000 IU daily for 2 months reduces the number of inflammatory lesions by about 35%, compared with 6% in those taking placebo. There was no effect on the total or non-inflammatory lesion count (106127). Other preliminary clinical research shows that taking alfacalcidol (One Alpha, LEO Company, Denmark) 0.25 mcg daily for 3 months modestly improves acne severity when compared with taking placebo (106128). In addition, population research has found that individuals with acne have modestly lower vitamin D levels than healthy controls. The odds of vitamin D deficiency were approximately three times higher in patients with acne when compared with healthy controls (106105).
• Age-related cognitive decline. It is unclear if oral cholecalciferol is beneficial for preventing age-related cognitive decline. Details: Pooled results of two large clinical sub-studies in community-dwelling adults aged 60 years or older show that taking cholecalciferol 2000 IU daily for 2-3 years has no effect on cognitive decline when compared with placebo. A subgroup analysis in Black patients suggests a modest effect of vitamin D when compared with placebo (108428).
• Alzheimer disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Some population research has found that lower serum concentrations of vitamin D are associated with higher risk of Alzheimer disease, and also with decreased cognition. People with Alzheimer disease seem to have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without Alzheimer disease (84672,103666). However, other population research has found that vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) is not associated with increased risk of Alzheimer disease (100899).
• Asthma. Oral vitamin D might reduce asthma exacerbations in adults and children with mild, but not severe or persistent, asthma. Vitamin D supplementation during pregnancy or the first 6 months of an infant's life does not seem to prevent the development of asthma later in infancy or childhood. Details: Population research in patients with asthma suggests that low vitamin D levels are associated with an increased risk of exacerbations and increased need for medication therapy (94693). However, findings from clinical research are mixed. Some meta-analyses of clinical trials in adults and children with asthma show that taking vitamin D for 3 months to 1 year reduces the rate of asthma exacerbations by 31% to 38% when compared with control (92690,94686,115584). However, other meta-analyses show that vitamin D supplementation does not reduce the risk of asthma exacerbations when compared with placebo (109728,109732,110833). The reasons for this discrepancy are not clear. However, some clinical research suggests that vitamin D supplements might only prevent asthma in people with non-persistent asthma (92690,94685,94686,94688,104020). Also, many studies are small and do not represent patients with severe asthma exacerbations (92690,94687). Baseline levels of vitamin D may play a role. A clinical study in children aged 6-16 years with persistent asthma and low vitamin D levels shows that taking vitamin D 4000 IU daily for 48 weeks does not reduce severe asthma exacerbations when compared with placebo (104020). However, a meta-analysis including this study shows that taking vitamin D does reduce risk of asthma exacerbations in children with low baseline vitamin D levels (109728). Additionally, two meta-analyses show that taking vitamin D seems to modestly improve pulmonary function when compared with placebo (109732,115584). Vitamin D doses have varied, with oral doses of 200-4000 IU daily, 1000-14,000 IU once weekly, 60,000 IU once monthly, 120,000 IU every 2 months, 100,000 IU 14 days apart, or 100,000 to 600,000 IU as a bolus dose followed by 400-4000 IU daily (92690,94686,104020,109728,110833,115584). Vitamin D supplementation for the prevention of asthma in infants has also been evaluated. A meta-analysis of 4 large clinical studies shows that taking vitamin D 400-1200 IU daily for the first 6 months of life does not reduce the risk of asthma or wheezing at 6-30 months of age when compared with control (112031). Vitamin D supplementation during pregnancy has also been evaluated (97306,99763,102146,112031). A meta-analysis of 3 large clinical studies shows that taking vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy reduces the risk of recurrent wheezing by 23% but does not reduce the risk of asthma diagnosis within the first 3-6 years of life when compared with vitamin D 400 IU daily (112031). Some research suggests that the dose of vitamin D plays a role. A meta-analysis shows that prenatal vitamin D 800 IU daily reduces the odds of wheeze or asthma by 32%, while lower or higher vitamin D doses were not beneficial (103661).
• Athletic performance. It is unclear if oral vitamin D is beneficial for athletic performance. Details: One small clinical trial in athletes shows that taking vitamin D 20,000 or 40,000 IU once weekly for 2 doses does not affect performance on vertical jumps, sprints, or leg and bench presses when compared with placebo (98188). Another small clinical trial in professional rugby players shows that taking vitamin D3 (cholecalciferol) 50,000 IU once every two weeks over 12 weeks does not improve sprinting speed or the ability to perform bench presses, bench pulls, and chin-ups when compared with placebo (98189). Also, most research shows that taking vitamin D does not improve measures of cardiorespiratory fitness. One small study in young males undergoing resistance training shows that taking vitamin D 8000 IU daily for 12 weeks does not improve cardiorespiratory fitness compared with taking placebo (110812).
• Atopic dermatitis (eczema). Most research shows that oral vitamin D reduces eczema severity in children. However, most research shows that oral vitamin D, taken during pregnancy or infancy, does not prevent eczema in the child. Details: A meta-analysis of eight moderate-quality clinical trials in children shows that taking vitamin D, most commonly 1000-2000 IU daily for 4-12 weeks, modestly reduces severity of eczema when compared with placebo (109728). Most of the children in these studies were also given conventional medications. Oral vitamin D has also been evaluated for eczema prevention. A meta-analysis of two clinical studies shows that consuming vitamin D 2800-4400 IU daily during the 2^nd and 3^rd trimesters of pregnancy is not associated with a reduced risk for eczema in children during the first 3 years of life when compared with vitamin D 400 IU daily (97306). Another meta-analysis of five large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing eczema when compared with low-dose vitamin D, placebo, or no intervention (108438).
• Atrial fibrillation. It is unclear if oral vitamin D is beneficial for preventing atrial fibrillation. Details: A large clinical trial in adults without cardiovascular disease shows that taking vitamin D 2000 IU daily for an average of 5 years does not reduce the incidence of atrial fibrillation when compared with placebo or fish oil 840 mg daily (105209). However, observational research in postmenopausal adults with osteoporosis found that vitamin D supplementation is associated with a lower occurrence of atrial fibrillation when compared with not taking vitamin D (98922). Also, one large observational study in vitamin D-deficient patients with no history of atrial fibrillation has found that vitamin D supplementation for at least 6 months is associated with up to a 16% decreased risk of atrial fibrillation when compared with not taking vitamin D. There were also modest improvements in atrial fibrillation-free survival. In males 65 years and older with hypertension or diabetes at baseline, blood levels of at least 30 ng/mL following vitamin D supplementation were associated with decreased risk of atrial fibrillation; a post-supplementation blood level of 21-29 ng/mL was not associated with decreased risk (109043).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin D is beneficial for ADHD. Details: A small clinical trial in children 5-12 years of age with ADHD and vitamin D insufficiency shows that taking vitamin D 2000 IU daily along with methylphenidate for 8 weeks seems to improve parental ratings of evening, but not morning or overall, symptoms of inattentiveness and impulsivity when compared with methylphenidate alone. Vitamin D insufficiency was defined as levels less than 30 ng/mL (98196). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive use in children with ADHD, especially those with insufficient intake or skin exposure to sunlight (110318).
• Autism spectrum disorder. It is unclear if oral vitamin D is beneficial for autism spectrum disorder. Details: A small clinical study in children aged 2.5-8 years with autism spectrum disorder shows that taking vitamin D 2000 IU daily for 12 months modestly reduces irritability and hyperactivity when compared with placebo (99767).
• Autoimmune thyroiditis. It is unclear of oral vitamin D improves outcomes in patients with Hashimoto's thyroiditis. Details: A meta-analysis of 12 clinical trials in patients with Hashimoto's thyroiditis shows that taking vitamin D for at least 12 weeks increases free triiodothyronine (T3) and thyroxine (T4) levels, and reduces levels of thyroid stimulating hormone, thyroglobulin antibody, and anti-thyroid peroxidase antibody, when compared with placebo or no treatment (113593).
• Back pain. It is unclear if oral vitamin D is beneficial for reducing chronic low back pain. Details: A meta-analysis of 10 clinical studies in adults with chronic low back pain shows that taking vitamin D does not reduce pain scores when compared with placebo, regardless of baseline vitamin D status or duration of supplementation. Oral vitamin D dosages used in these studies included 400-4000 IU daily for 1-6 months, 50,000 IU once weekly for 8 weeks, or 150,000-300,000 IU as a single dose. Intramuscular dosages ranged from 150,000-300,00 IU as a single dose (115588).
• Bacterial vaginosis. It is unclear if oral vitamin D is beneficial for bacterial vaginosis. Details: Preliminary clinical research in females at high risk for sexually transmitted disease shows that taking vitamin D along with standard therapy for bacterial vaginosis does not reduce the prevalence of bacterial vaginosis when compared with placebo. Patients in this study had been treated with metronidazole 500 mg orally twice daily for 7 days along with vitamin D3 (cholecalciferol) 50,000 IU each week for 4 weeks and then every 4 weeks for the remaining 20 weeks (91348).
• Bariatric surgery complications. It is unclear if vitamin D supplementation after bariatric surgery attenuates any bone health-related complications. Details: Clinical research in adults who had undergone bariatric surgery shows that vitamin D supplementation in doses of 800-7900 IU daily improves vitamin D status when compared with placebo. It is unclear if vitamin D supplementation in these doses for 1 year improves parathyroid hormone levels or bone mineral density or reduces fracture risk (115589).
• Breast cancer. It is unclear if oral vitamin D is beneficial for the prevention of breast cancer. Details: Some population research evaluating intake of calcium plus vitamin D suggests that higher vitamin D intake is not associated with a reduced risk of breast cancer in premenopausal or postmenopausal adults (15631). Similarly, a large observational study in females with a biological sibling with breast cancer has found that taking vitamin D recently or prior to enrollment is not associated with a reduced risk of breast cancer when compared with nonrecent vitamin D use or never taking vitamin D, respectively (107215). However, other research found that higher vitamin D intake is associated with a 17% reduced risk of breast cancer in premenopausal and perimenopausal, but not postmenopausal, adults (39001). Observational research has also examined the association between blood levels of vitamin D and risk of developing breast cancer. A meta-analysis found that those with serum levels of about 52 ng/mL had a 50% lower risk of developing breast cancer when compared with those with serum levels of less than 13 ng/mL. This high serum level of vitamin D corresponds to a high dose of about 4000 IU daily (16049). Other observational research has found that baseline vitamin D levels of more than 20 ng/mL are associated with a 48% reduced risk of developing breast cancer over approximately 9 years in Latina females in the US when compared with levels below 20 ng/mL; however, this association was not present in Black females (109058). Despite the contradictory findings from observational research, results from clinical research are generally negative. Evidence from one large-scale clinical trial (Women's Health Initiative) shows that postmenopausal adults who take vitamin D3 (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years do not have a significantly reduced risk of developing breast cancer (16715,98895). Also, a meta-analysis of two large-scale clinical trials, which did not include the Women's Health Initiative trial, shows that taking vitamin D 800-1000 IU daily, alone or with calcium, for 3-4 years does not reduce the incidence of breast cancer in postmenopausal adults, although there was a trend towards reduced risk with higher doses of vitamin D supplementation (97301). While vitamin D and calcium supplementation during the intervention period of the Women's Health Initiative trial was not associated with a reduced risk of developing breast cancer or ductal carcinoma in situ (DCIS), a precursor to breast cancer, a secondary post-hoc analysis of the data shows that supplementation reduces the risk of developing DCIS by 18% over a median follow-up of 19 years (107216). Additional research is needed regarding an optimal dose of vitamin D, timing of initiation, and whether any benefit is affected by menopausal status.
• Bronchopulmonary dysplasia. Limited research suggests that vitamin D deficiency is linked with bronchopulmonary dysplasia in the infant. Details: Observational research has found that vitamin D deficiency at birth is associated with about a 2-fold increased odds of developing bronchopulmonary dysplasia (104021). However, it is unclear if vitamin D supplementation is beneficial.
• Cancer. Vitamin D does not seem to reduce overall cancer risk. However, some research shows that vitamin D might slightly reduce the risk of metastatic cancer and cancer-related mortality. Details: There is interest in vitamin D for cancer PREVENTION, as observational research suggests that higher vitamin D intake and higher 25-hydroxyvitamin D levels are associated with a lower risk of cancer (111150). While individual clinical trials evaluating vitamin D for cancer have produced inconsistent findings, most meta-analyses and clinical trials show that taking vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) alone or with calcium does not significantly reduce the risk of developing cancer (15629,91344,93943,97296,98916,104024,104618,110811). However, vitamin D supplementation might reduce the risk of metastatic cancer and cancer-related mortality. A large clinical trial shows that taking vitamin D3 2000 IU daily for a median of 5.3 years slightly reduces the risk of advanced metastatic or fatal cancers when compared with placebo (104618). Additionally, meta-analyses of several large clinical trials show that taking vitamin D 400-4000 IU daily, with or without calcium, for 1-7 years reduces the risk of cancer-related mortality by 12-13% when compared with control, while intermittent bolus dosing of vitamin D at high doses for 1-5 years does not appear to reduce the risk of cancer-related mortality (104024,111149). The role of vitamin D in cancer TREATMENT is unclear. A meta-analysis of clinical and observational research suggests that supplementation of vitamin D after a cancer diagnosis is associated with a modest improvement in overall survival, but not progression-free or cancer-specific survival (109726). Doses used in clinical research ranged between 1200 IU and 8000 IU daily or 100,000 IU every 50 days, after surgery and/or during treatment (99195,99196,109726). Other clinical research in patients with luminal gastrointestinal cancers shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse when compared with placebo (99195). It is unclear which, if any, types or stages of cancer respond best to vitamin D, and what dose of vitamin D is optimal.
• Child growth. It is unclear if oral vitamin D is beneficial for improving infant growth or bone structure. Details: Meta-analyses and individual clinical trials show that vitamin D supplementation during pregnancy modestly increases length at birth and bone mineral density at up to 7 years of age when compared with control, usually placebo or vitamin D 400 IU daily. However, there was no effect on length in the infant up to one year of age, weight at birth or up to one year of age, head circumference at birth or up to 6 years of age, bone mineral content at up to 6 years of age, or neonatal bone mineral density, bone mineral content, bone area, or femur or humoral length (98198,109737,112028,115585). In the available research, vitamin D was taken in doses of 200 IU to 4400 IU daily, 4200 IU to 50,000 IU weekly, 50,000 IU every 2 weeks, or 60,000 IU every 4-8 weeks, starting from the early to late stages of pregnancy and usually continued until birth (98198,109737,115585).
• Chronic kidney disease (CKD). It is unclear if oral vitamin D is beneficial in patients with CKD. Most research suggests that it does not reduce the risk for adverse cardiovascular events. Details: Population research in patients on dialysis has found that vitamin D levels less than 17.8 ng/mL are associated with a higher risk of all-cause mortality compared with higher levels (16619). A meta-analysis and individual clinical studies show that vitamin D and vitamin D analogues decrease parathyroid hormone (PTH) levels and urine protein levels in people with CKD (84376,84377,84628,98233,98236). However, taking vitamin D does not appear to decrease the risk of death or parathyroidectomy in CKD patients (84376,84377). Also, taking vitamin D increases the risk for hypercalcemia and hyperphosphatemia in this patient population (84376,84377,98236). Vitamin D has also been evaluated for the prevention of cardiovascular events in adults with CKD. Observational research has found that vitamin D deficiency in patients with CKD is associated with adverse cardiovascular events. However, vitamin D supplementation does not seem to be beneficial. One clinical study shows that taking paricalcitol, an active form of vitamin D, titrated to maintain adequate serum calcium levels, for 48 weeks does not affect the size of the left ventricle or heart function when compared with placebo (98233). Other clinical research in Japanese patients on hemodialysis for CKD shows that adding alfacalcidol, another active form of vitamin D, 0.5 mcg daily to standard treatment for 4 years does not affect mortality or cardiovascular events such as myocardial infarctions, stroke, aortic dissection, and others compared to standard treatment only (98920). Also, a large clinical trial in patients with CKD shows that taking vitamin D as cholecalciferol 2000 IU daily, alone or with omega-3 fatty acids 1 gram daily, does not affect major cardiovascular events or invasive cancer when compared with placebo (110811). Vitamin D has also been evaluated for musculoskeletal health in adults with CKD. A small clinical study shows that taking cholecalciferol 4000 IU daily, with or without physical activity, for 3 months improves bicep strength, but not back flexibility or aerobic fitness capacity, when compared with baseline. In patients taking cholecalciferol in combination with physical activity, musculoskeletal health was similar when compared with cholecalciferol alone (108431). However, this study was inadequately powered to detect a difference between groups, and it is unclear if the improvement from baseline differed between groups. Vitamin D has also been evaluated for the improvement of iron status in adults with CKD and secondary hyperparathyroidism. Clinical research shows that taking Vitamin D as cholecalciferol (Vitamin D3 Forte Renapharma) 8000 IU daily for 12 weeks does not improve iron status compared with taking placebo. However, a sub-analysis shows that hemoglobin levels are modestly improved in patients with a low Vitamin D status at baseline suggesting that Vitamin D might improve iron availability in these patients (110819).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin D is beneficial for COPD; benefits may be limited to patients with severe vitamin D deficiency. Details: Population research has found an association between low vitamin D levels and reduced lung function, increased risk of developing COPD, and worsening COPD severity (17685,96401). However, 3 meta-analyses of clinical research in adults with COPD show that, overall, oral vitamin D does not have beneficial effects on mortality, rate of COPD exacerbations, pulmonary function, or most measures of symptom severity when compared with placebo (109732,112485,115586). A subgroup analysis suggests that any benefits of vitamin D supplementation may be limited to patients with severe vitamin D deficiency (25-hydroxyvitamin D levels below 25 nmol/L) at baseline (115586).
• Cognitive function. It is unclear if oral vitamin D is beneficial for cognitive function. Details: Population research has found that low vitamin D levels are associated with worse cognitive performance and cognitive decline when compared to high vitamin D levels in healthy adults (84672,95916). However, the effect of vitamin D supplementation on cognitive function is unclear. One small meta-analysis of clinical research shows that vitamin D supplementation does not improve cognitive function (95916). However, the included trials evaluated a widely heterogeneous study population and utilized variable measures of cognitive function.
• Cognitive impairment. It is unclear if oral vitamin D is beneficial for older adults with mild cognitive impairment. Details: A small clinical study in older adults with mild cognitive impairment shows that taking vitamin D3 10,000 IU three times weekly for 20 weeks in addition to exercise and cognitive training does not improve cognitive function when compared with placebo and exercise with or without cognitive training. However, most participants had sufficient serum vitamin D levels at baseline (112489).
• Colorectal cancer. It is unclear if oral vitamin D is beneficial for the treatment or prevention of colorectal cancer. Details: Epidemiological research has found that a higher serum vitamin D level is associated with decreased risk of mortality and increased survival in patients with colorectal cancer (16101,99196). However, it is unclear whether vitamin D supplementation improves survival in patients with colorectal cancer, as research has generally involved small populations and results are somewhat conflicting. A subgroup analysis of one clinical study shows that taking vitamin D 2000 IU daily does not reduce the risk of relapse or death, death due to any cause, or relapse over 5 years when compared with placebo in patients with colorectal cancer (99195). However, this subgroup may have been underpowered to detect between-group differences. Another small clinical trial in patients with advanced or metastatic colorectal cancer shows that taking high-dose vitamin D 8000 IU daily during the first cycle of chemotherapy, and then 4000 IU daily for subsequent cycles, does not increase median progression-free survival when compared with taking vitamin D 400 IU daily. However, patients taking high-dose vitamin D were 36% less likely to experience disease progression or death during follow-up when compared with patients taking the lower dose of vitamin D (99196). This latter result suggests that high-dose vitamin D supplementation might be beneficial for patients with advanced or metastatic colorectal cancer, but larger, multicenter studies are needed to confirm. The role of vitamin D in colorectal cancer prevention has also been investigated. A meta-analysis of epidemiological research has found that a higher serum vitamin D level is associated with a decreased colorectal cancer risk; however, sub-analyses suggest that this association only occurs in females, not males (109740). Most studies have evaluated vitamin D supplements in combination with calcium; the effects of vitamin D supplementation alone are unclear. One meta-analysis of clinical research suggests that taking vitamin D plus calcium is not associated with a decreased incidence of colorectal cancer in people with a low baseline risk of colorectal cancer (39042). Another meta-analysis of clinical research shows that vitamin D supplementation, with or without calcium, does not reduce the incidence of colorectal cancer or colorectal adenomas (109730). Additionally, a large clinical trial suggests that postmenopausal adults who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290,98895). One clinical study shows that taking calcium supplements reduces the risk of colorectal adenomas, but not in people with lower than average vitamin D levels (12118).
• Crohn disease. Limited evidence suggests that vitamin D reduces relapses in patients with Crohn disease. Details: A meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). The validity of these findings is limited by the heterogeneity of the included studies.
• Dementia. It is unclear if oral vitamin D is beneficial for dementia. Details: Population research has found that patients with any type of dementia have serum concentrations of vitamin D that are about 2.5 ng/mL lower than patients without dementia (84672). However, it is unclear if vitamin D supplementation is beneficial.
• Depression. It is unclear if oral vitamin D is beneficial for treating depression. Vitamin D does not seem to prevent the development of depression. Details: The role of vitamin D in the treatment of depression is unclear. Earlier meta-analyses of clinical research show that vitamin D supplementation does not improve overall symptoms of depression. However, some subgroup analyses suggest that vitamin D may be beneficial for improving the symptoms of depression in people with clinically significant symptoms, as well as those with baseline vitamin D deficiency (97295,97298). More recent meta-analyses of several clinical trials, that include some of the same studies, show that vitamin D modestly improves symptoms of depression in adults; however, subgroup analysis suggests that vitamin D does not improve depressive symptoms in older adults (110832,112786). These analyses are mixed over whether baseline vitamin D status affects results (110832,112786) and one of these analyses shows no evidence that the type of depression affects findings (110832). Another meta-analysis of generally small clinical trials in patients with type 2 diabetes and depression shows that taking vitamin D modestly improves depressive symptoms when compared with placebo or no intervention (110814). Although, results of an individual clinical trial in patients with type 2 diabetes are in contrast (108423). The evaluated research implemented one-time doses of 150,000-500,000 IU, as well as daily and weekly doses ranging between 400-5000 IU daily or 5000-100,000 IU weekly for 6 weeks to 2 years, with the most evidence of benefit related to one-time high doses. Cholecalciferol was the most common form of vitamin D used (97295,97298,108423,110814,110832,112786). Significant heterogeneity between studies and the wide variability in dosing strategies limit the validity of these findings, as well as identification of an effective dose or target population. Vitamin D has also been evaluated for the prevention of depression. One large clinical study (VITAL-DEP) in healthy patients 50 years and older shows that taking vitamin D 2000 IU daily for about 5.3 years does not prevent depression or depressive symptoms, or improve mood, when compared with placebo (103670). An analysis of a cohort of patients from the VITAL-DEP trial also shows that taking vitamin D 2000 IU daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores in patients with subthreshold depression or risk factors for late-life depression when compared with placebo (112032). In addition, a meta-analysis of several clinical studies suggests that vitamin D supplementation does not prevent depression based on subgroup analysis of patients without depression at baseline (112786). Based on these and other preliminary findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is weakly recommended for adjunctive or monotherapy use in patients with depression, especially those with insufficient intake or skin exposure to sunlight (110318).
• Diabetes. Oral vitamin D might improve glycemic indices in some patients with type 2 diabetes and gestational diabetes. It is unclear if oral or intramuscular vitamin D is beneficial for the prevention of type 1 or gestational diabetes. Details: Most meta-analyses of mainly small clinical trials show that vitamin D supplementation is beneficial for measures of glycemic control in adults with diabetes. However, the best evidence of benefit is in people with baseline vitamin D deficiency. Five meta-analyses of clinical studies in patients with type 2 diabetes show that vitamin D supplementation reduces glycated hemoglobin (HbA1c) by 0.2% to 0.3%, and improves serum insulin, fasting blood glucose, and measures of insulin resistance when compared with control (96403,110822,112487,115581,115583). Supplemental vitamin D seems to be most beneficial in patients with baseline vitamin D deficiency or insufficiency (96403,107210,110822,112487,115581). Furthermore, correlation analysis suggests an inverse relationship between serum vitamin D levels and serum insulin, fasting blood glucose, and measures of insulin resistance (112487). In most clinical studies vitamin D supplementation ranged from 1000-6000 IU daily, 20,000-60,000 IU weekly, or 100,000-400,000 IU once over 8-48 weeks (96403,107210,110822,115581,115583). Most analyses exhibited significant heterogeneity related to vitamin D dosing regimen, geographic location, and patient population. However, one meta-analysis of clinical research in patients with diabetes shows that vitamin D improves HbA1c, insulin resistance, and insulin measures in studies lasting less than 6 months, but not in studies lasting longer than 6 months (99764). An additional meta-analysis suggests that most evidence of benefit is associated with doses of more than 2000 IU daily for 4-12 weeks (110822). Another meta-analysis suggests that benefits may be greater in adults with less severe obesity and a shorter duration of type 2 diabetes (115583). Vitamin D has been evaluated for the prevention of type 1 diabetes. There is preliminary evidence that daily vitamin D supplementation (form not specified) in infants during the first year of life is associated with a reduced incidence of type 1 diabetes development later in life (10139). Also, a meta-analysis of population studies has found that vitamin D supplementation in early childhood is associated with a 29% reduced risk of developing type 1 diabetes later in life (84225). Vitamin D has been evaluated in adults with gestational diabetes, yielding conflicting findings. One clinical trial shows that oral vitamin D 50,000 IU every 4 weeks modestly reduces levels of insulin, as well as measures of insulin resistance, with no effect on fasting blood glucose (106125), whereas other clinical research shows that this same dosing regimen modestly reduces levels of fasting blood glucose and HbA1c, with no effect on insulin measures (106126). A separate clinical study shows that taking oral vitamin D 500 IU twice daily in yogurt modestly improves all measures of glycemic indices (101775). Additionally, a large clinical trial shows that taking oral vitamin D 1600 IU daily modestly reduces fasting blood glucose when compared with vitamin D 400 IU daily (112020). Some clinical research also shows that oral vitamin D modestly improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared with control (106125,110823), although not all research agrees (106126). Also, a meta-analysis of clinical research shows that taking oral vitamin D reduces the risk of premature birth and neonatal hospitalization by approximately 63% and 62%, respectively (110823). A meta-analysis of 5 small clinical studies shows that taking oral vitamin D 400-1000 IU daily for 6 weeks or 50,000 IU twice over 6 weeks along with calcium decreases fasting plasma glucose and serum insulin when compared with placebo (115579). One small clinical study shows that giving vitamin D 300,000 IU as a single intramuscular injection at 24-28 weeks' gestation does not affect HbA1c (106124). Vitamin D has also been evaluated for the prevention of gestational diabetes. A Cochrane analysis of one large clinical study shows that taking vitamin D during pregnancy does not lower the risk of gestational diabetes when compared with no supplementation (114587). In addition, a meta-analysis of population studies suggests that there is a U-shaped association between serum vitamin D levels and the risk of developing gestational diabetes, with 25-hydroxyvitamin D levels of 40-90 nmol/L associated with the lowest risk (106109). A meta-analysis of clinical research in adults with insulin resistance during pregnancy, but not gestational diabetes, shows that taking vitamin D at varying doses for 6-26 weeks modestly decreases measures of insulin resistance when compared with placebo (110821). However, this study did not evaluate whether vitamin D prevented the development of gestational diabetes in these patients. Vitamin D has also been evaluated in combination with other ingredients. One study evaluated vitamin D in combination with eicosapentaenoic acid (EPA) 360 mg plus docosahexaenoic acid (DHA) 240 mg twice daily, suggesting that this combination improves glycemic markers when compared with taking vitamin D alone (106122). Other clinical research in patients with gestational diabetes shows that taking vitamin D with omega-3 fatty acids 8,000 mg twice daily for 6 weeks modestly improves glycemic indices when compared with placebo (106114). However, it is unclear if these effects are due to vitamin D, other ingredients, or the combination.
• Diabetic foot ulcers. It is unclear if oral vitamin D is beneficial for diabetic foot ulcers. Details: A meta-analysis of clinical research in patients with diabetic foot ulcers shows that taking vitamin D modestly reduces ulcer size and improves glycemic and lipid indices when compared with placebo (110835). This meta-analysis is limited by the availability of three small clinical trials, as well as the heterogeneous doses of vitamin D in the included studies.
• Diabetic nephropathy. Limited evidence suggests that vitamin D improves some markers of kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical studies in patients with diabetic nephropathy shows that taking vitamin D or its analogs reduces inflammatory markers and protein in the urine, but does not affect measures of kidney function such as serum creatinine or glomerular filtration rate, when compared to control (99771).
• Diabetic retinopathy. It is unclear if oral vitamin D is beneficial in diabetic retinopathy. Details: There is weak evidence from observational research suggesting a link between vitamin D deficiency and diabetic retinopathy (112095). However, clinical research addressing the effectiveness of vitamin D supplementation for treatment or prevention of diabetic retinopathy is lacking.
• Dysmenorrhea. Limited evidence suggests that oral vitamin D reduces pain in patients with dysmenorrhea. Details: A meta-analysis of 9 small clinical studies in patients with dysmenorrhea shows that taking vitamin D in doses ranging from 5000 IU daily to 300,000 IU monthly modestly reduces pain when compared with control (112029). However, the validity of these findings is limited by a high degree of heterogeneity across the studies, including differences in blinding and control interventions, vitamin D doses and frequency of supplementation, and baseline vitamin D levels. Another small clinical study in adolescent patients with dysmenorrhea shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces pain when compared to baseline (98912). The validity of this finding is limited by the lack of a control group.
• Erectile dysfunction (ED). It is unclear if oral vitamin D is beneficial for ED. Details: Although some data suggest ED is associated with low serum 25-hydroxy-vitamin D levels, preliminary research in males aged 60-84 years shows that taking vitamin D 60,000 IU once monthly for up to 5 years does not prevent or improve ED when compared with placebo (113580).
• Exercise-induced muscle damage. Small studies suggest that vitamin D does not improve exercise-induced muscle damage. Details: A meta-analysis of 6 small studies shows that taking vitamin D before and/or during exercise does not improve circulating levels of creatine kinase, lactate dehydrogenase, or myoglobin when compared with placebo (107218).
• Fall prevention. The role of vitamin D in fall prevention is confusing and controversial. Most clinical research shows that taking vitamin D 800-1000 IU daily decreases the risk of falls, with effects most apparent with daily over intermittent dosing and in those with vitamin D deficiency or insufficiency. Taking vitamin D at doses higher or lower than this may be associated with increased risk of falls. Details: Higher serum levels of vitamin D have been associated with improved lower-extremity function in elderly adults (15636). Clinical research in older adults shows that taking vitamin D or vitamin D analogues, with or without calcium, reduces the number of people who have a fall by up to 19% (39038,84215,84374,84539,94130,104023,113595,114504). Other research shows that vitamin D, with or without calcium, reduces number of falls by 19% to 50% (11939,16275,84404,93941,109053). The beneficial effect does not appear to depend on the form of vitamin D used (ergocalciferol, cholecalciferol, calcitriol, or alfacalcidol) (39038,84374,113595). Multiple meta-analyses of clinical research show that taking vitamin D leads to a decreased rate of falls in patients with low baseline levels of vitamin D, but not in those with adequate vitamin D levels (84670,84684,109053,114504). One meta-analysis also suggests that taking vitamin D as cholecalciferol up to 1000 IU daily reduces fall risk by up to 19%, whereas higher doses do not reduce fall risk (109053). Also, daily dosing, but not intermittent dosing, seems to be associated with a reduced risk of falling (109053,114504). Similarly, another meta-analysis of clinical research shows that taking vitamin D 800-1000 IU daily, with or without calcium, lowers the risk of falls by about 15-26% when compared with placebo, no treatment, or calcium alone. However, taking vitamin D 500 IU or less daily and vitamin D 1100 IU or more daily, with or without calcium, is not associated with a lower risk of falls and may even increase the risk of falls by 22-44% (114504). Despite the above meta-analyses, other clinical research shows that vitamin D does not reduce the risk of falling (84404,84670), the rate of falls overall (84670,93942), or the rate of injurious falls (93942) in elderly patients (93942). One study in adults over 70 years of age with a history of falling found that taking high-dose vitamin D, either as 60,000 IU monthly or 24,000 IU plus calcifediol 300 mcg monthly, increased both the risk of falling and the mean number of falls compared to a lower dose of 24,000 IU monthly (93940). One meta-analysis of 20 trials including nearly 30,000 patients shows that taking vitamin D, with or without calcium, does not reduce the risk of falling in elderly patients, regardless of baseline 25-hydroxyvitamin D levels, level of 25-hydroxyvitamin D achieved with treatment, duration of treatment, or residential status of the patients (91342). While a meta-analysis of 10 trials in nearly 6,000 patients shows that taking vitamin D 700-1000 IU daily with calcium 1000-2000 mg daily reduces the risk of falling in the elderly by 12% when compared with placebo or no treatment, a meta-analysis of 21 trials in nearly 52,000 patients shows that vitamin D alone is only associated with a reduced risk of falls in patients with baseline vitamin D levels of less than 50 nmol/L when compared with placebo or no treatment (107224). The 2018 US Preventative Services Task Force (USPSTF) guidelines for fall prevention acknowledges this research by recommending AGAINST vitamin D supplementation for fall prevention in community dwelling adults 65 years of age and older who do not have osteoporosis or vitamin D deficiency (95703). The reasons for the disparate study results may have to do with the way in which clinical trials have reported outcomes. Clinical trials assessing the effect of vitamin D on fall risk may report results as the number of patients who experience one or more falls, the total number of falls, or the rate of falls per individual. This can affect ultimate conclusions and, in some cases, can be misleading. For example, when studies report on only the total number of falls, it is unclear if vitamin D reduces the rate of falls across the study population, or if it only reduces falls in a small subset of patients. Also, analyses of research suggest that the size of the clinical study appears to affect the trial results. Most trials showing significant reductions in fall risk have been small and of short duration (91342,94132); whereas larger and longer-term studies tend to show no benefit (13073,84399).
• Fetal and premature infant mortality. Taking vitamin D during pregnancy might reduce the risk of fetal or early infant death. Details: A meta-analysis of clinical research shows that vitamin D supplementation during pregnancy reduces the risk of intrauterine or neonatal death by 31% when compared with not supplementing with vitamin D. A sub-analysis shows that this benefit was limited to doses of up to 4000 IU daily (109055). However, a Cochrane review suggests that the evidence linking vitamin D supplementation to a lower risk of fetal or neonatal death is very uncertain (114587). Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of intra-uterine and neonatal mortality, preeclampsia, preterm birth, and small for gestational age (SGA) birth. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Fibromyalgia. A small clinical study suggests that vitamin D might improve pain in patients with fibromyalgia. Details: A small clinical study in fibromyalgia patients with low vitamin D levels shows that taking vitamin D3 (cholecalciferol) 1200-2400 IU daily seems to reduce pain, but not mood or quality of life, when compared with placebo (91349).
• Food allergies. It is unclear if prenatal or infant oral vitamin D supplementation reduces the risk of developing food allergies. Details: A meta-analysis of two large clinical studies shows that prenatal or infant vitamin D supplementation does not reduce the risk of developing food allergies when compared with low-dose vitamin D or no intervention (108438).
• Frailty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of frailty in older adults. Details: Frailty involves a combination of muscle loss and weakness, with exhaustion and reduced ability for physical activity. Some observational research has found that low vitamin D status is associated with frailty occurrence. However, clinical research in community dwelling older adults shows that taking vitamin D as 1000 IU, 2000 IU, or 4000 IU daily for 24 months does not prevent frailty or attenuate the worsening of frailty when compared with low-dose vitamin D 200 IU daily. Baseline vitamin D status did not affect these findings. Also, a sub-analysis suggests that vitamin D 2000 IU might increase frailty; however, only a small number of participants were randomized to this dose (109046). Other clinical research in community dwelling adults at least 70 years of age shows that taking cholecalciferol 2000 IU daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo. However, when taken in combination with omega-3 fatty acids 1 gram daily and a home exercise program, the odds of becoming pre-frail is reduced by 39% (110829).
• Generalized anxiety disorder (GAD). A small clinical study suggests that vitamin D may modestly improve anxiety in patients with GAD. Details: A small clinical study in patients with GAD shows that taking vitamin D 50,000 IU once weekly for 3 months, in addition to taking an antidepressant and an anxiolytic, moderately reduces anxiety scores when compared with taking these medications alone (103654).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral vitamin D is beneficial for improving outcomes in patients receiving HSCT. Details: A small clinical study in patients who have undergone an autologous HSCT shows that taking calcitriol 0.25 mcg three times daily for 30 days can reduce the time to absolute lymphocyte count recovery, but does not affect time to recovery of absolute neutrophil and platelet counts, when compared with placebo (103665).
• Hepatitis C. Low levels of vitamin D have been associated with an inadequate response to hepatitis C therapy. Adding vitamin D to standard therapy for hepatitis C may improve viral response, especially in specific genotypes. Details: A small clinical trial in patients with hepatitis C genotypes 2-3 receiving standard therapy with PEG-interferon and ribavirin shows that adding vitamin D 2000 IU daily for 24 weeks results in 95% of patients achieving undetectable levels of hepatitis C RNA, compared to only 77% of patients treated with standard therapy alone (98917). Another small clinical study in patients with hepatitis C genotype 1b receiving the same standard therapy shows that adding vitamin D 1000 IU daily for 16 weeks results in about 79% of patients achieving undetectable levels of hepatitis C RNA, compared to about 55% of patients treated with standard therapy alone. The TT genotype seems to be especially susceptible to vitamin D supplementation, while TG/GG genotype does not seem to be susceptible (98923).
• HIV/AIDS. It is unclear if oral vitamin D is beneficial for improving bone mineral density (BMD) in children and young adults with HIV. Details: Vitamin D deficiency and hyperparathyroidism are common in children and young adults with HIV. A meta-analysis of two clinical trials in this population shows that taking cholecalciferol for 12 months does not improve spine BMD when compared with placebo. Also, an analysis of two clinical trials shows that taking doses of 1600 IU to 4000 IU daily does not improve spine BMD when compared with taking doses of 400-800 IU daily. However, taking higher dose vitamin D has a small beneficial effect on total BMD when compared with taking lower doses. There was no improvement on parathyroid hormone levels (110824). This meta-analysis is limited by the availability of small clinical trials, as well as the heterogeneous doses of vitamin D used in the included studies.
• Hyperlipidemia. Although population research has found that higher vitamin D levels are associated with improved lipid levels, it is unclear if vitamin D supplementation is beneficial. Clinical research results are conflicting. Details: Population research has found that higher vitamin D levels are associated with lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels when compared with lower vitamin D levels (15630,98919). However, supplementation might not be beneficial. A meta-analysis of small clinical studies suggests that taking vitamin D as cholecalciferol, ergocalciferol, alfacalcidol, or calcitriol slightly increases LDL cholesterol, but does not affect total cholesterol, triglycerides, or HDL cholesterol, when compared with placebo (84642). The validity of these findings is limited by the variability in patient populations, vitamin D dose and formulation, and study duration. Also, none of the included studies were prospectively designed to test the effect of vitamin D on lipid levels. Another meta-analysis of clinical studies in a mixed population of healthy adults and adults with metabolic disease shows that taking vitamin D 1400-50,000 IU weekly with calcium 500-2000 mg daily results in very modest improvements in total cholesterol, triglyceride, and HDL cholesterol levels, but not LDL or very low-density lipoprotein (VLDL) cholesterol levels, when compared with placebo. Subgroup analyses suggest that effects are more pronounced in people with metabolic disease (107227). The validity of these findings is limited by the heterogeneity of the included studies, which persisted throughout subgroup analyses.
• Hyperthyroidism. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research suggests that serum vitamin D levels are decreased in patients with newly diagnosed Graves' disease. A small preliminary clinical trial in patients with newly diagnosed Graves' disease taking methimazole and low levels of selenium and vitamin D shows that taking vitamin D as cholecalciferol for 270 days, in combination with selenium for the first 180 days, modestly reduces levels of serum free thyroxine and improves quality of life when compared with no vitamin D or selenium. However, taking vitamin D and selenium did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral vitamin D is beneficial in the treatment of subclinical hypothyroidism. Details: Preliminary clinical research in patients with vitamin D deficiency and subclinical hypothyroidism shows that taking vitamin D 50,000 IU weekly for 2-12 weeks decreases mean thyroid stimulating hormone levels by about 20% when compared with placebo, or by 3.55 mIU/L when compared to baseline (107213,113589).
• Ichthyosis. It is unclear if oral vitamin D is beneficial in patients with inherited ichthyosis. Details: A small clinical study in patients with congenital non-syndromic ichthyosis shows that taking vitamin D 2000 IU daily for 24 weeks reduces the clinical severity of disease at 12 weeks, but not 24 weeks, when compared with baseline. When compared with patients taking acitretin 0.5 mg/kg daily, results were similar at both 12 and 24 weeks, but it is unclear if the improvement from baseline differed between groups (108441).
• IgA vasculitis. It is unclear if oral alfacalcidol is beneficial in children with IgA vasculitis. Details: A clinical study in children with IgA vasculitis shows that taking alfacalcidol 0.25 mcg daily along with vitamin C, rutin, dipyridamole, cimetidine, calcium, and glucocorticoids for 4 weeks improves rates of recurrence and incidence of kidney damage when compared with those receiving the same regimen without alfacalcidol. Alfacalcidol also improves cellular immune function and reduces levels of inflammatory biomarkers (107212).
• Irritable bowel syndrome (IBS). It is unclear if oral vitamin D is beneficial for IBS; the available research is conflicting. Details: Although some meta-analyses show that taking vitamin D is moderately more effective than placebo for improving IBS symptom severity and quality of life, other analyses disagree. Doses of vitamin D have included 50,000 IU weekly or every 2 weeks or 2000-4000 IU daily for up to 6 months (109041,109054,109057). The reasons for these discrepancies might be attributed to the inclusion criteria related to the individual trials, the small sample sizes, and varied dosing strategies used in the available research.
• Kidney transplant. It is unclear if oral cholecalciferol is beneficial for improving allograft function or preventing non-skeletal complications in kidney transplant recipients. Details: Following a kidney transplant, patients are at increased risk of vitamin D insufficiency and related outcomes. A large clinical trial shows that taking a high dose of cholecalciferol for 2 years does not reduce the composite risk of developing type 2 diabetes, major cardiovascular events, or cancer, or death when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). The effect of a high dose of vitamin D on these outcomes individually is not clear. However, taking vitamin D does not seem to improve allograft function. A clinical study in kidney transplant recipients shows that taking cholecalciferol 4000 IU daily, beginning 1-month posttransplant and continuing for 11 months, has no effect on allograft function when compared with placebo (108425).
• Kidney transplant-related bone loss. Oral vitamin D might be beneficial for preventing bone loss associated with kidney transplantation. Details: A large clinical trial shows that taking a high dose of cholecalciferol for 2 years modestly reduces the odds of a fracture by 76% when compared to taking a lower dose. The high and low doses of vitamin D were 100,000 IU or 12,000 IU, respectively, every 2 weeks for 2 months, followed by monthly doses for the next 22 months (110830). A prespecified secondary analysis of a clinical study in patients at 1-month post-kidney transplant from a living donor in Japan shows that taking vitamin D (cholecalciferol) 4000 IU daily for months 1-12 posttransplant reduces whole blood parathyroid hormone levels by 15%, but does not alter levels of tartrate-resistant acid phosphatase 5-b or bone-specific alkaline phosphatase, when compared with placebo. The greatest effects on parathyroid hormone levels are observed in those with more severe vitamin D deficiency, hypocalcemia, and more preserved kidney function. Vitamin D supplementation also attenuates changes in bone mineral density (BMD) at the lumbar spine, but not the distal radius, from prior to transplant. Patients taking vitamin D had a loss of only 0.2%, compared with a loss of 2% in those receiving placebo. The greatest effects are observed in those with osteoporosis or osteopenia (107220). Conversely, a small clinical trial shows that taking calcitriol (1,25-dihydroxyvitamin D3) 0.25 mcg daily in combination with calcium carbonate 500 mg daily does not decrease bone loss associated with kidney transplantation. However, calcitriol might reduce osteoclast suppression, help maintain trabecular bone volume and wall thickness, and improve axial BMD (4823).
• Impaired glucose tolerance (prediabetes). Taking vitamin D might slow prediabetes progression to diabetes in people with low baseline levels of vitamin D or in people achieving high levels of vitamin D following supplementation. It is unclear if vitamin D supplementation is beneficial in people with prediabetes and sufficient vitamin D levels. Details: Observational research has found that low vitamin D levels are linked with a higher risk of prediabetes and higher dietary vitamin D is linked with a lower chance of developing diabetes (84594,103669). Meta-analyses and individual clinical studies in patients with prediabetes and unclear or sufficient vitamin D levels show that vitamin D supplementation might improve some glycemic indices, but does not seem to prevent progression of prediabetes to diabetes (84594,91347,99769,108421). However, a more recent meta-analysis of 3 clinical studies designed to evaluate the preventative effects of oral vitamin D shows that taking it in the form of cholecalciferol 4000 IU daily or 20,000 IU weekly or eldecalcitol 0.75 mcg daily reduces the risk of developing diabetes with an absolute risk reduction of 3.3% over 3 years when compared with placebo. However, the actual risk reduction is highly dependent on vitamin D status. Patients achieving the highest serum vitamin D levels have absolute 3-year risk reductions of 11.4% to 18.1% (110810). In patients with vitamin D deficiency and prediabetes, vitamin D might improve beta-cell function, suggesting reduced disease progression (99768,107210). One clinical study in adults with vitamin D deficiency shows that taking vitamin D 50,000 IU weekly for 3 months, and then monthly for 3 months, modestly improves insulin resistance and beta-cell function as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but does not affect fasting or postprandial glucose levels when compared with placebo (99768). Further, a meta-analysis of randomized controlled trials in patients with vitamin D deficiency and prediabetes shows that oral vitamin D at a median dose of 50,000 IU weekly for 26 weeks modestly improves fasting blood glucose and some markers of islet function, but not postprandial blood glucose or glycated hemoglobin (HbA1c) levels, when compared with control. Additionally, a significantly greater proportion of patients receiving vitamin D supplementation regressed from prediabetes to normal glucose status (107210). A meta-analysis of clinical studies in overweight or obese children and adolescents shows that high doses of vitamin D, 4000 IU daily or higher for 12-52 weeks, reduce HOMA-IR and C-reactive protein levels, but do not affect body weight, cholesterol, or parathyroid hormone (113596). A study in females with vitamin D deficiency and prediabetes shows that taking vitamin D 60,000 IU weekly for 8 weeks, followed by a maintenance dose of 200 IU daily, has no effect on the incidence of type 2 diabetes at 2 years (107211). Clinical practice guidelines from the Endocrine Society conditionally recommend, with moderate certainty of evidence, empiric vitamin D supplementation in addition to lifestyle modification for adults with high-risk prediabetes to reduce the risk of progression to diabetes. Empiric vitamin D supplementation is defined as vitamin D from supplements or fortified food above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Infant development. It is unclear if giving oral vitamin D in doses above the recommended dietary allowance during infancy is beneficial for improving neurodevelopment. It is also unclear if oral vitamin D during pregnancy is beneficial for improving cognitive development in the offspring. Details: Clinical research shows that giving vitamin D 1200 IU daily to healthy term infants of Northern European ethnicity starting at 2 weeks of age does not improve measures of neurodevelopment at 2 years of age when compared with giving the standard dose of vitamin D 400 IU (106121). Overall, the evidence from population research is mixed as to whether vitamin D status during gestation is associated with infant developmental outcomes. However, some population research has found that increased vitamin D status during pregnancy is associated with improved anthropomorphic and neurodevelopmental outcomes (104621,105724). Two meta-analyses of observational research show that low vitamin D status during pregnancy is associated with reduced head circumference and cognitive development scores, and higher odds of the offspring developing autism and attention deficit hyperactivity disorder (105724,105725). However, one meta-analysis suggests these risks may be limited to those with very low vitamin D status (serum level < 12 ng/mL) (105724). Multiple meta-analyses show that vitamin D status during pregnancy does not appear to affect motor development (105724,105725). In one observational study, plasma vitamin D concentrations in the second trimester of pregnancy was associated with increased IQ scores in the offspring at age 4-6 years. Each 10 ng/mL increase in vitamin D levels was associated with a 1.17-point increase in IQ (104621). In contrast, clinical research shows that taking vitamin D3 2800 IU daily during the third trimester does not improve neurodevelopmental outcomes in the first 6 years of life when compared to taking lower doses of 400 IU daily (104623).
• Infertility. It is unclear if oral or intramuscular vitamin D is beneficial in females with infertility. Details: Observational research in females undergoing in vitro fertilization suggests no association between dietary vitamin D intake and oocyte quality, successful embryo transfer, clinical pregnancy rate, or term pregnancy rate (112097). Additionally, a meta-analysis of clinical research in females with infertility shows that, although there was no effect of taking vitamin D on implantation rate or miscarriage, taking vitamin D increases the odds of clinical pregnancy by 49% when compared with placebo. However, sub-analyses of clinical and observational research found that benefits on clinical pregnancy rates were limited to populations with vitamin D insufficiency, but not vitamin D deficiency, and for doses between 1000 to 10,000 IU daily for 30-90 days (110818). Most studies included in the analysis used oral vitamin D; however, intramuscular vitamin D was used in one cohort study. A smaller meta-analysis of clinical studies in females with infertility and vitamin D insufficiency undergoing IVF shows that taking vitamin D increases the rate of chemical pregnancy by 50%, but has no effect on the clinical pregnancy rate (108432).
• Lichen planus. It is unclear if oral vitamin D is beneficial for lichen planus. Details: A small clinical study in patients with oral lichen planus and vitamin D deficiency or insufficiency shows that taking vitamin D 60,000 IU weekly in combination with systemic steroids for 1 month reduces pain severity and improves healing of lesions when compared with systemic steroids alone (114586). The validity of the study is limited by the lack of a placebo.
• Low birth weight. It is unclear if oral vitamin D can reduce the risk for low birth weight; the available evidence is conflicting. Details: A meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with lower birth weight and increased odds of SGA births. However, these risks have not been demonstrated in those with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Most research also shows that vitamin D supplementation during pregnancy reduces the risk of low birth weight. A meta-analysis of three clinical trials shows that supplementation with vitamin D 800-1000 IU daily starting between 27 and 32 weeks' gestation, or 200,000 IU administered as a single dose or in two divided doses during the seventh and eighth month of pregnancy, reduces the risk of delivering a low birth weight infant by 60% (84659). Other meta-analyses of clinical research show that supplementation with vitamin D during pregnancy results in a 31% to 60% reduced risk of low birth weight and a 103 gram greater average birth weight when compared with placebo or no intervention (99766,114587). However, some meta-analyses show that vitamin D supplementation during pregnancy does not reduce the risk of low birth weight when compared with no supplementation (95910,109055). One meta-analysis that included studies that did not directly measure birth weight shows no effect of vitamin D supplementation during pregnancy on the rate of low birth weight, despite showing an increase in overall birth weight of about 58 grams (95910).
• Lung cancer. It is unclear if oral vitamin D prevents lung cancer or improves lung cancer prognosis. Details: A small meta-analysis of randomized controlled trials and observational research has found that high intake of vitamin D is associated with a 10% reduction in the risk of developing lung cancer when compared with low vitamin D intake. In terms of prognosis, high vitamin D intake is associated with improvements in both overall survival and relapse-free survival (107217).
• Male infertility. It is unclear if oral cholecalciferol is beneficial in males with infertility. Details: A small clinical study in males with infertility shows that taking cholecalciferol 2500 IU daily for 6 months modestly improves progressive sperm motility, sperm concentration, and sperm morphology when compared with baseline (108427). The validity of these findings is limited by the lack of a comparator group.
• Melanoma. It is unclear if oral vitamin D is beneficial in patients with melanoma. Details: A meta-analysis of 14 observational studies suggests that vitamin D deficiency is associated with a 45% greater risk of melanoma when compared with normal vitamin D levels (112027). However, a small clinical study in patients with newly resected stage II melanoma shows that taking vitamin D3 100,000 IU every 50 days for 3 years does not improve disease-free survival when compared with placebo. Most patients in this study had vitamin D deficiency or insufficiency at baseline (106113).
• Metabolic syndrome. It is unclear if oral vitamin D is beneficial for preventing or treating metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking vitamin D 50,000 IU weekly for 16 weeks does not affect most metabolic or anthropometric factors when compared with placebo, although there was a modest decrease in triglyceride levels (106123). However, almost all of the individuals in this study were vitamin D deficient or insufficient, and many remained in that category even after supplementation. It is unclear if vitamin D supplementation is beneficial in vitamin D sufficient patients with metabolic syndrome. There is conflicting evidence about the association between vitamin D and metabolic syndrome (14265,16713,98234). Some population research has found that higher vitamin D levels are associated with a lower risk of metabolic syndrome, while other research found no association (14265,16713). Furthermore, a small clinical trial in patients with metabolic syndrome shows that taking vitamin D 20,000 IU or 40,000 IU weekly for 8 weeks does not affect metabolic risk factors when compared with placebo (98234).
• Migraine headache. It is unclear if oral vitamin D reduces the frequency of migraine. Details: A meta-analysis of three small high-quality clinical studies in patients with migraine shows that taking vitamin D 2000 or 4000 IU daily for 12-24 weeks or 500,000 IU weekly for 2 months reduces the frequency of migraines by 2-3 attacks monthly when compared with usual care or placebo (108439).
• Miscarriage. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing vitamin D 50 mcg, alpha-lipoic acid, hyaluronic acid, magnesium, and vitamin B6 daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to vitamin D, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo for the control group.
• Multiple sclerosis (MS). Although vitamin D supplementation has been linked with a lower risk of developing MS, taking oral vitamin D supplements does not seem to reduce MS relapses. Details: Vitamin D deficiency appears to be linked to the risk of MS development and progression. Population research suggests that long-term supplementation with vitamin D 400 IU is associated with a 40% lower risk of MS in females. The effect seems to be dose-dependent. Consumption of at least 400 IU daily, mainly in the form of a multivitamin supplement, appears to have the greatest protective effect (11356). Additional population research in over 7 million people suggests that higher levels of calcifediol are associated with a lower risk of developing MS. In white adults, for every 20 ng/mL increase in vitamin D levels, there appears to be a 41% decrease in MS risk. However, this was not found in black and Hispanic adults (15159). Vitamin D supplementation has also been examined in patients with MS. Population research suggests that taking vitamin D supplements and the maintenance of optimal blood levels of vitamin D are associated with a reduction in the development of new areas of demyelination detected by magnetic resonance imaging (MRI) over 24 months. However, there are no correlations between vitamin D consumption or vitamin D blood levels and clinical outcomes (110816). Also, vitamin D supplementation does not seem to impact MS relapses or most symptoms in patients with MS. Meta-analyses of preliminary clinical research show that vitamin D supplementation does not affect the rate of MS relapses, overall symptoms, disability scores, or the number of MS nerve lesions detected by MRI, regardless whether the vitamin D was low-dose or high-dose (98192,98914,106119,113586). However, one meta-analysis of 6 small clinical studies shows that taking vitamin D for 8-96 weeks slightly improves fatigue scores when compared with placebo (112024). These analyses are limited by the small size and heterogeneity of most of the included studies and variability in dosing and duration of vitamin D regimens.
• Muscle strength. It is unclear if oral vitamin D improves muscle strength in middle aged or older adults with low or sufficient levels of vitamin D. The available research is conflicting. Details: Clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not increase muscle strength when compared with placebo (11814,104619,108429). In patients 40-80 years of age with low vitamin D levels, taking vitamin D3 100,000 IU (2500 mcg) once, followed by 20,000 IU (500 mcg) weekly for 4 months, does not improve muscle strength when compared with placebo (103658). Similarly, meta-analyses of clinical research show that vitamin D does not increase grip strength, muscle mass, global muscle strength, or back extensor strength when compared with control (91341,113595). However, some research has found some benefit with the use of vitamin D supplements. One meta-analysis shows that taking vitamin D increases grip strength after menopause when compared with placebo or low-dose vitamin D, although a sub-analysis shows that beneficial effects are limited to individuals aged 60-69 years, when vitamin D is taken without calcium, when baseline vitamin D levels are at least 30 ng/mL, or when the treatment consists of the vitamin D analog alfacalcidol. This suggests heterogeneity between studies (109048). Another meta-analysis in elderly adults shows that taking vitamin D as calcifediol 10-30 mcg daily for a median of 24 weeks modestly improves hand grip strength and leg extension, but not leg flexion, when compared with baseline (109042). Also, some individual clinical research in older adults with low levels of vitamin D at baseline shows that taking vitamin D3 800 IU daily or vitamin D2 (ergocalciferol) 1000 IU daily for 12 months in combination with calcium 1000 mg daily modestly improves lower extremity or hip strength by 8% to 23% when compared with calcium alone (38915,84530).
• Myalgia. It is unclear if oral vitamin D is beneficial for reducing myalgia associated with obesity. Details: Preliminary clinical research in obese individuals with vitamin D deficiency who are on a low-calorie diet shows that taking vitamin D 50,000 IU weekly, alone or in combination with an aerobic exercise program three times weekly for 12 weeks, modestly reduces muscle pain when compared with only aerobic exercise three times weekly (106118).
• Myelodysplastic syndromes. It is unclear if oral vitamin D is beneficial for patients with myelodysplastic syndromes. Details: A small observational study in patients with myelodysplastic syndromes has found that taking calcitriol or calcifediol orally is associated with slowed disease progression (11825).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral or intramuscular vitamin D is beneficial in children or adults with NAFLD. Details: Although findings from individual research are mixed, one meta-analysis of mainly small clinical trials in patients with NAFLD shows that vitamin D modestly improves insulin resistance and serum alanine aminotransferase (ALT) levels, with no effect on serum aspartate aminotransferase (AST) levels. Most studies included in the analysis used oral vitamin D 1000 IU daily or 50,000 IU weekly or biweekly for 3-6 months and compared with placebo; however, one study used a single intramuscular injection of vitamin D 600,000 IU compared with lifestyle modifications (109056). Vitamin D has also been evaluated in combination with fish oil. A clinical study in adults with NAFLD shows that taking oral vitamin D3 1680 IU daily in combination with fish oil or fish oil alone for 3 months improves serum ALT levels similarly to a control group (107186). Vitamin D has also been evaluated for use in children with NAFLD. One clinical study in children with obesity and biopsy-proven NAFLD shows that taking oral vitamin D3 2000 IU daily for 6 months with a hypocaloric diet improves liver histopathology in terms of steatosis, lobular inflammation, and NAFLD activity score at 6 months, but not hepatocyte ballooning or fibrosis, when compared with baseline. These improvements were not seen in the group receiving placebo with a hypocaloric diet, but it is unclear if the improvement from baseline differed between groups (107222).
• Nonmelanoma skin cancer. It is unclear if oral vitamin D is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking vitamin D3 1000 IU daily for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking vitamin D3 with calcium 1200 mg daily as calcium carbonate reduces the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but has no effect on the risk of basal cell carcinoma. Vitamin D taken alone has no effect on the risk for either type of cancer (104622).
• Obesity. The evidence for the use of oral vitamin D in obesity is conflicting and unclear. Details: Population research has found that people with lower vitamin D levels are significantly more likely to be obese when compared to people with higher vitamin D levels (15630). Also, a large-scale, high-quality clinical trial in postmenopausal adults taking calcium 1000 mg plus vitamin D3 (cholecalciferol) 400 IU daily for 3 years shows that these patients are more likely to lose weight and maintain their weight when compared with those taking placebo. This beneficial effect is mainly seen in females who have inadequate intake of calcium, less than 1200 mg/day, before starting a calcium supplement (15604). However, other evidence suggests that vitamin D alone does not improve weight loss. One clinical trial shows that taking vitamin D3 2000 IU/day without calcium for 12 months does not increase weight loss when compared with placebo in overweight and obese postmenopausal adults who are deficient in vitamin D at baseline (91345).
• Orthostatic hypotension. It is unclear if oral vitamin D is beneficial for prevention of orthostatic hypotension. Details: A secondary analysis of a clinical study in older patients with vitamin D insufficiency who are at an increased risk for falls shows that taking vitamin D 1000-4000 IU daily for up to 2 years has no effect on the risk of orthostatic hypotension or orthostatic symptoms when compared with those receiving vitamin D 200 IU daily (107223).
• Osteoarthritis. It is unclear if oral vitamin D is beneficial for osteoarthritis. Details: The evidence for the use of vitamin D in osteoarthritis is conflicting. Some clinical research shows that taking vitamin D3 (cholecalciferol) 2000 IU daily, or at a higher dose to reach serum vitamin D levels over 36 ng/mL, for 2 years does not reduce knee pain or loss of cartilage when compared with placebo in patients with symptomatic osteoarthritis (84688). However, another clinical study shows that taking vitamin D3 daily for 10 days and then vitamin D3 60,000 IU monthly for 12 months modestly reduces pain and improves function when compared with placebo in patients with osteoarthritis and vitamin D insufficiency (98199). It is possible that higher doses of vitamin D have an effect on osteoarthritis, while lower doses do not. Due to this conflicting and low-quality evidence, the American College of Rheumatology (ACR) recommends against the use of vitamin D for any form of osteoarthritis (102114).
• Otitis media. It is unclear if oral vitamin D is beneficial in patients with otitis media. Details: The relationship between vitamin D status and otitis media is unclear. Population research has found that having otitis media is associated with lower blood levels of vitamin D; however, lower vitamin D levels were not associated with greater risk of otitis media (98194).
• Overactive bladder. It is unclear if oral vitamin D is beneficial for overactive bladder in children or adults. Details: A large clinical trial in older males shows that taking vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the odds of weekly overactive bladder when compared with placebo. In males with low baseline serum vitamin D, taking vitamin D reduces the odds of overactive bladder at 5 years by 49%, including 34% reduced odds of overactive bladder with urinary incontinence and 81% reduced odds of overactive bladder without incontinence. However, urinary incontinence while sleeping or napping was increased (109738). Vitamin D has also been evaluated for overactive bladder in children with low vitamin D levels. A large, single-blind clinical study in children with overactive bladder without urinary incontinence, and with vitamin D insufficiency or deficiency, shows that taking vitamin D 2400 IU daily for 8 weeks with standard urotherapy reduces voiding frequency by about 3 or 4 voids daily when compared with standard urotherapy, with or without solifenacin 5 mg daily (115574,115591). Standard urotherapy was defined in this study as medical education, timed voiding, and pelvic floor muscle training.
• Overall mortality. Taking oral vitamin D alone does not seem to reduce mortality; however, there is some evidence that taking certain forms of vitamin D with calcium might have a modest benefit. Details: While higher vitamin D levels have been associated with a small reduction in mortality when compared with lower vitamin D levels (98187), clinical research shows that taking vitamin D does not reduce the risk of mortality. A comprehensive meta-analysis shows that vitamin D supplementation alone does not reduce all-cause mortality when compared to control (100900). However, giving vitamin D with calcium may modestly reduce the risk of mortality. Meta-analyses show a 4% to 9% reduced risk of mortality when trials of vitamin D alone and vitamin D with calcium are pooled together (16102,97296,98186,112022). Finally, some research suggests that the type of vitamin D supplementation might influence the results. A meta-analysis of clinical research found that vitamin D3 (cholecalciferol) with or without calcium reduces mortality risk by 6%, while alfacalcidol, calcitriol, and vitamin D2 (ergocalciferol) do not have benefit (84595,98186). Other clinical research suggests that vitamin D supplementation in older adults may reduce the risk of all-cause mortality by about 4%, with an estimated effect size of 6 fewer deaths per 1000 individuals. This finding informed the 2024 Endocrine Society Clinical Practice Guidelines on vitamin D for the prevention of disease in the general population. The Endocrine Society conditionally recommends, with moderate certainty of evidence, empiric vitamin D supplementation from fortified foods or vitamin D-containing supplements in the general population aged 75 years and older to potentially lower the risk of mortality. Empiric vitamin D is defined as vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status. For empiric supplementation and for those who have indications for vitamin D treatment or supplementation, daily lower-dose versus intermittent higher doses was suggested (114502).
• Pain (chronic). It is unclear if oral vitamin D is beneficial for chronic pain. Details: A meta-analysis of clinical research in patients with chronic pain shows that taking vitamin D for 1-24 months produces a 43% greater decrease in pain score when compared with placebo. However, the final follow-up pain score is similar for both groups (96402). The effect of vitamin D on pain based on pain-related diagnosis, vitamin D status, or dose is unknown.
• Parkinson disease. It is unclear if oral vitamin D is beneficial for this condition. Details: Population research found that higher levels of vitamin D are associated with milder Parkinson disease symptoms, while deficiency is associated with increased risk of Parkinson disease (97000,99772). One small study shows that taking vitamin D3 (cholecalciferol) 1200 IU daily for one year might modestly slow the progression of Parkinson disease based on the Hoehn and Yars staging criteria. However, there was no improvement in disease severity according to the more widely used Unified Parkinson Disease Rating Stage (UPDRS). The UPDRS includes measures of activities of daily living and non-motor symptoms. Vitamin D had no effect on most quality of life measures (95915).
• Periodontitis. It is unclear if oral vitamin D is beneficial for periodontal disease. Details: A meta-analysis of mostly observational research suggests that vitamin D levels are not associated with an increased or decreased risk of periodontitis (112026). Other population research suggests that higher blood levels of vitamin D may be associated with a reduced risk of periodontal disease in adults 50 years of age or older. However, this association was not found for adults younger than 50 years (15634).
• Physical performance. It is unclear if oral vitamin D improves muscle strength in elderly adults. Details: Some clinical research in healthy older adults who are not deficient in vitamin D shows that oral vitamin D3 (cholecalciferol) supplementation, with 800 IU, 1000 IU, or 2000 IU daily or 50,000 IU monthly, alone or in combination with a resistance training program, does not improve physical performance when compared with placebo (11814,104619,108429). Also, results from one meta-analysis of clinical research in postmenopausal females with low levels of vitamin D shows that taking vitamin D does not improve the timed up and go test when compared with placebo or low-dose vitamin D (109048). One meta-analysis that included studies specifically evaluating the use of calcifediol in older adults shows a large benefit on gait speed; however, only one study included in the analysis used this endpoint and other measures of physical performance were not affected (109042).
• Pneumonia. High-dose oral vitamin D does not reduce pneumonia severity in children. Details: Although vitamin D supplementation might prevent respiratory tract infections in children, it might not prevent recurrent pneumonia. A small clinical study in children under 5 years of age with recurrent pneumonia and variable vitamin D blood levels shows that taking vitamin D 300,000 IU quarterly for 1 year does not reduce respiratory infections, severity of pneumonia, hospital admissions, or disease complications when compared with placebo (103667). However, it's unknown if vitamin D supplementation using lower and more frequent doses, or supplementation in patients with vitamin D deficiency, might be beneficial. Some observational research has found that having vitamin D deficiency is linked to a higher risk for developing community-acquired pneumonia (CAP) (102118). For information on other respiratory infections, refer to the Respiratory Tract Infection discussion.
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin D improves pregnancy rates and outcomes, clinical symptoms, metabolic parameters, or hormone levels in patients with PCOS. Details: Observational research in adults with infertility, PCOS, and insulin resistance suggests that normal vitamin D levels are associated with better embryo quality and increased pregnancy rate when compared with vitamin D deficiency or insufficiency (100834). It is unclear if supplementation with vitamin D improves pregnancy rates in patients with PCOS. A meta-analysis of several mostly low-quality clinical studies in patients with PCOS and vitamin D deficiency at baseline shows that intramuscular or oral vitamin D 200-10,000 IU daily for up to 24 weeks in addition to fertility treatment improves pregnancy rates and reduces premature miscarriage and premature delivery, but does not impact the incidence of pregnancy complications including gestational hypertension or gestational diabetes, when compared with control. This analysis also suggests vitamin D supplementation improves certain IVF-related outcomes including ovulation rate, fertilization rate, and number of mature oocytes (112787). An earlier meta-analysis of clinical research shows that taking vitamin D 400-12,000 IU daily for 2-6 months improves follicular development when compared with placebo. Taking vitamin D in combination with metformin 1500 mg daily also appears to increase the number of regular menstrual cycles by 85% when compared with metformin alone, but without an effect on follicular development (96404). However, a meta-analysis of 3 clinical studies shows that combining vitamin D with metformin probably does not improve menstrual cycle regulation when compared with metformin alone (113594). The effect of vitamin D on the hormonal and metabolic profiles of patients with PCOS has also been evaluated. An umbrella review of up to 15 meta-analyses of clinical studies in patients with PCOS shows that taking vitamin D 2000-8500 IU daily for 6.5-13.5 weeks reduces levels of serum triglycerides, total and low-density lipoprotein (LDL) cholesterol, and total testosterone, but not body mass index (BMI) or insulin levels, when compared with placebo (115577). A separate meta-analysis of 9 clinical studies, not included in the umbrella review, shows that combining vitamin D with metformin reduces insulin resistance, BMI, and testosterone levels when compared with metformin alone (113594). Additionally, a small clinical study in adults with PCOS and vitamin D deficiency or insufficiency shows that taking vitamin D 2000 IU daily in combination with diet and exercise for 12 weeks reduces insulin resistance, BMI, waist to hip ratio, serum triglyceride levels, and total and LDL cholesterol levels when compared with diet and exercise alone (114580). The interpretation of the results in this clinical study is limited by the lack of a placebo control.
• Post-stroke fatigue. It is unclear if oral vitamin D is beneficial for post-stroke fatigue. Details: A retrospective study in patients with post-stroke fatigue and vitamin D deficiency suggests that vitamin D (cholecalciferol) 600 IU daily is associated with improvements in fatigue severity at months 1 and 3 when compared with control. Neurologic disability also showed improvement at 3 months, but not at 1 month, when compared with control. It is unclear if improvements from baseline differed between groups (107225).
• Pre-eclampsia. It is unclear if oral vitamin D during pregnancy is beneficial for the prevention or treatment of pre-eclampsia. Details: While some clinical research suggests that taking vitamin D during pregnancy does not reduce the risk of pre-eclampsia (113585,114587), clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small for gestational age (SGA) birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Precocious puberty. It is unclear if oral vitamin D is beneficial for the prevention or treatment of precocious puberty. Details: A meta-analysis of 43 mostly observational studies from China suggests that vitamin D deficiency or insufficiency is associated with 2.25-fold greater odds of precocious puberty when compared with normal vitamin D levels. Taking vitamin D 200-1000 IU daily for 3-12 months along with a gonadotropic-releasing hormone analog (GnRHa) is associated with lower luteinizing hormone, follicle-stimulating hormone, and estradiol levels and reduced bone age when compared with GnRHa therapy alone (112019). Another meta-analysis of 15 studies, mainly from China and with high heterogeneity and publication bias, suggests that there is a negative correlation between serum 25-hydroxy-vitamin D concentrations and precocious puberty, and that vitamin D deficiency increases the risk of precocious puberty by about 53% (113578).
• Pregnancy-induced hypertension. It is unclear if oral vitamin D is beneficial for patients with gestational hypertension. Details: Meta-analyses of two low-quality clinical trials show that vitamin D supplementation during pregnancy does not reduce the risk for gestational hypertension when compared with control (95910,114587).
• Prematurity. It is unclear if taking vitamin D during pregnancy prevents respiratory complications in preterm neonates. Details: A large clinical study in pregnant patients with gestational age less than 34 weeks and at risk of preterm delivery shows that a single intramuscular injection of vitamin D 50,000 IU within 72 hours before delivery decreases the risk of respiratory distress syndrome treated by surfactant in the neonate by about 2.25-fold and increases the 5th minute APGAR scores, but not 1st minute APGAR scores, gestational age, neonatal intensive care unit admission, length of hospital stay, or delivery method, when compared with no treatment (114581).
• Premenstrual syndrome (PMS). It is unclear if oral vitamin D is beneficial in patients with PMS. Details: Observational research has found that increasing dietary intake of vitamin D above 706 IU daily is linked to a reduced risk of developing PMS when compared with consuming 112 IU daily (13094). Furthermore, a clinical study shows that taking vitamin D 400 IU daily in combination with calcium 1000 mg daily can decrease the severity of PMS symptoms (16869). Another clinical study in adolescent females with PMS shows that taking vitamin D3 50,000 IU weekly for 9 weeks modestly reduces PMS symptoms when compared to baseline (98912). A small clinical study in young adults with PMS and vitamin D deficiency shows that taking vitamin D 50,000 IU every 2 weeks for 16 weeks reduces psychological symptom scores by 54% and physical symptom scores by 39% when compared with placebo (113582).
• Preterm labor. It is unclear if oral vitamin D is beneficial for preterm labor. Details: Vitamin D deficiency, defined as serum levels less than 20 ng/mL, during pregnancy has been associated with a 25% greater risk of preterm birth (95911). The risk seems to be especially prominent in those with darker colored skin (103662). However, meta-analyses of clinical research show that vitamin D supplementation during pregnancy does not reduce the risk of a preterm birth when compared with no supplementation with vitamin D (84659,95910,109055,114587). The effect vitamin D specifically in vitamin D-deficient patients is still unclear. Some small, heterogeneous, and low-quality studies show that vitamin D supplementation might reduce the rate of preterm birth in vitamin D-deficient patients (84659,95910). Additional studies are needed to determine the effect of vitamin D supplementation on the risk of preterm birth. Clinical practice guidelines from the Endocrine Society conditionally recommend, based on low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of preterm birth, small for gestational age (SGA) birth, preeclampsia, intra-uterine mortality, and neonatal mortality. Empiric vitamin D supplementation iss defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral vitamin D may not improve symptoms in patients with RA. Details: Population research has found that higher intake of vitamin D from foods or supplements is associated with a lower risk of developing RA (12206,98200). However, a meta-analysis of two small clinical trials shows that vitamin D supplementation does not reduce pain or recurrence of RA when compared with placebo (98190).
• Rhinosinusitis. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking 1 or 2 sachets of a specific combination product (Flogostop Forte, Humana Italia) containing vitamin D 600 IU, black currant, Boswellia serrata, and bromelain along with a nasal corticosteroid daily for 15-30 days reduces symptoms of nasal hyperemia and rhinorrhea when compared with corticosteroid nasal spray alone (111501). It is unclear if these findings are due to vitamin D, other ingredients, or the combination.
• Sarcopenia. It is unclear if oral vitamin D is beneficial in older adults with sarcopenia. Details: A meta-analysis of randomized trials in older adults with sarcopenia shows that taking vitamin D3 (cholecalciferol) 100-800 IU daily, with protein 10-44 grams daily or amino acids 2.5-6 grams daily, for 2-6 months moderately improves muscle strength, but not muscle mass or walking speed, when compared with placebo (105727). The validity of this study is limited by high heterogeneity and an unreported baseline vitamin D status. Similarly, a small network meta-analysis of randomized trials shows that taking vitamin D 500-1600 IU daily or 2500-5000 IU weekly with protein 20-80 grams daily or amino acids 3-32 grams daily with and without exercise for 3-18 months increases hand grip strength and shortens time to chair-stand, respectively, but not gait speed or lower-limb mass when compared with usual care (107221). It is unclear if these effects are due to vitamin D, protein/amino acid supplementation, exercise, or the combinations.
• Schizophrenia. It is unclear if oral vitamin D is beneficial for schizophrenia. Details: Based on preliminary clinical evidence, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that vitamin D in doses of 1500 to 4000 IU daily is not recommended for adjunctive use in patients with schizophrenia (110318). A moderate-sized clinical study in patients with schizophrenia shows that taking a specific combination product (BioZenD, Tak Gen Zist Pharmaceutical Company) containing vitamin D 400 IU in combination with a blend of probiotics (Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, Limosilactobacillus reuteri, Lacticaseibacillus paracasei, Bifidobacterium longum, Bacillus coagulans) 2 x 10⁹ CFU daily for 12 weeks improves cognitive function scores but does not improve the severity of positive and negative schizophrenia symptoms when compared with placebo (114582). It is unclear if this effect is due to vitamin D, the probiotics, or the combination.
• Sciatica. Oral vitamin D has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary research in adults up to 45 years of age with discogenic sciatica shows that taking cholecalciferol 800 IU with alpha-lipoic acid, acetyl-L-carnitine, and resveratrol daily for 30 days, in combination with a 20-session rehabilitation protocol, improves pain, disability, and quality of life when compared with the supplements alone or the rehabilitation protocol alone (112933).
• Seasonal affective disorder (SAD). One small study suggests that a large dose of oral vitamin D can improve symptoms of SAD. Details: A small clinical study in patients with SAD suggests that a single dose of vitamin D2 (ergocalciferol) 100,000 IU improves symptoms after one month when compared to baseline (83791). The validity of this finding is limited by the lack of a control group.
• Seborrheic keratosis. It is unclear if topical vitamin D analogues improve symptoms of seborrheic keratosis. Details: Preliminary clinical research suggests that topical ointments containing activated vitamin D in the form of tacalcitol, calcipotriol or maxacalcitol, applied for 3-12 months, can reduce tumor volume by at least 40% in 75% of patients with seborrheic keratosis. Additionally, over 30% of patients seem to experience complete tumor resolution or a reduction in tumor volume of at least 80% (84033). The validity of this finding is limited by the lack of a control group.
• Sexual dysfunction. One small study suggests that injecting a large dose of vitamin D might improve sexual function. Details: A small clinical study in females with vitamin D deficiency and sexual dysfunction shows that receiving an intramuscular injection of vitamin D as cholecalciferol 300,000 IU once at baseline and a second time 4 weeks later improves sexual function at 4 and 8 weeks when compared with placebo (100896).
• Sickle cell disease. One small study suggests that oral vitamin D reduces pain and improves quality of life in children with sickle cell disease with vitamin D insufficiency or deficiency. Details: A small clinical study in children with sickle cell disease shows that taking vitamin D3 (cholecalciferol) 40,000-100,000 IU weekly for 6 weeks reduces days with pain and improves physical activity and quality of life for up to 6 months when compared with placebo. Of the children included in the study, 82.5% had vitamin D insufficiency, while 52.5% were deficient in vitamin D (98918). It is unclear if vitamin D is effective for patients with sickle cell disease who have adequate levels of vitamin D.
• Small for gestational age (SGA). It is unclear if oral vitamin D can reduce the risk for SGA births; the available evidence is conflicting. Details: Two meta-analyses of clinical research show no effect of vitamin D on the risk of SGA birth (84659,109055). However, one meta-analysis shows a 40% reduction in the risk of SGA births with vitamin D supplementation (95910). Also, one meta-analysis shows that when vitamin D supplementation is initiated before the 20^th week of gestation, the risk of SGA is reduced by 54% (109055). Most individual clinical trials are small and heterogeneous. Also, the formulation of vitamin D and/or vitamin D status at baseline may explain part of the discrepant findings. For example, a meta-analysis of observational research has found that a very low vitamin D status (serum level <12 ng/mL) during pregnancy is associated with increased odds of SGA births. This association does not seem to be present with less severe vitamin D deficiency (serum level <20 ng/mL) (105724). Clinical practice guidelines from the Endocrine Society conditionally recommend, with low certainty of evidence, empiric vitamin D supplementation from daily intake of fortified foods, vitamin D supplements, or prenatal vitamin formulations that contain vitamin D during pregnancy to potentially lower the risk of SGA births, as well as preeclampsia, intra-uterine mortality, preterm birth, and neonatal mortality. Empiric vitamin D supplementation is defined as supplementing with vitamin D above the Recommended Dietary Allowance without having tested serum vitamin D status (114502).
• Statin-induced myalgia. It is unclear if oral vitamin D is beneficial for patients with statin-induced myalgia. Details: Observational research has found that taking oral vitamin D supplements is associated with decreased symptoms of myalgia in patients taking statin drugs. In a small case series, patients who discontinued statins due to myalgia were able to resume statin therapy after starting vitamin D supplements. The majority of patients with myalgia were found to be vitamin D deficient, with vitamin D levels less than 12 ng/mL at baseline (16829). An observational study has also found that administering 50,000 units of vitamin D2 (ergocalciferol) once a week for 12 weeks reversed symptoms of myalgia in 92% of statin treated patients with low serum vitamin D levels of less than 32 ng/mL (16831).
• Stroke. Although low vitamin D levels are associated with higher risk of stroke, taking vitamin D supplements does not seem to reduce stroke risk. Details: Population research has found that low vitamin D levels are associated with an increased risk of stroke. Furthermore, increased dietary intake of vitamin D is associated with a reduced risk of stroke (15630,16618,93944,97303,106106). However, clinical research shows that vitamin D supplementation does not reduce stroke risk. Several meta-analyses and randomized controlled trials show that taking vitamin D alone or with calcium does not reduce the risk of stroke in patients with or without cardiovascular disease risk factors (16616,91343,97296,97308,106106,112022). It is difficult to draw firm conclusions from these studies, as they did not assess whether patients had adequate vitamin D levels at baseline. It is unclear if vitamin D supplementation might prevent strokes in patients with vitamin D deficiency.
• Sunburn. Although there is interest in using oral vitamin D for the treatment of sunburns, there is insufficient reliable information about the clinical effects of vitamin D for this purpose.
• Systemic lupus erythematosus (SLE). It is unclear if oral vitamin D is beneficial in patients with SLE. Details: While some observational research has found that adults with SLE are more likely to have vitamin D deficiency than healthy controls (102119), a small cross-sectional study in females has found no association between serum levels of 25-hydroxyvitamin D, SLE disease activity, and the presence or absence of lupus nephritis (107214). A meta-analysis of three small clinical studies shows that taking vitamin D3 (cholecalciferol) 2000 IU daily or 50,000 IU weekly seems to reduce anti-dsDNA positive, a marker of disease activity, when compared with placebo in patients with SLE (98190). However, the clinical significance of this finding is unclear. A small clinical trial in females with SLE shows that taking vitamin D3 5000 IU daily for 12 weeks modestly improves overall disease activity, but not quality of life, when compared with placebo (109735).
• Thyroid cancer. It is unclear if oral vitamin D is beneficial in patients with thyroid cancer. Details: Observational research in patients undergoing thyroidectomy for differentiated thyroid cancer suggests that taking vitamin D daily for at least 6 months after surgery is associated with a 38% lower risk of all-cause mortality and a 33% lower risk of total cancer-related mortality when compared with no vitamin D supplementation at around 10 years' follow-up. However, vitamin D does not appear to be linked to a lower risk of thyroid cancer-related mortality in these patients (112018).
• Ulcerative colitis. Limited evidence suggests that vitamin D may be beneficial in patients with ulcerative colitis. Details: A meta-analysis of mainly small clinical trials in patients treated with mesalazine shows that taking vitamin D for up to 24 weeks modestly increases clinical efficacy and reduces disease score when compared with mesalazine alone (109044). Also, a meta-analysis of small, low-quality clinical studies in patients with IBD, including Crohn disease and ulcerative colitis, shows that taking high- or low-dose vitamin D for up to 1 year reduces the rate of relapse when compared with control (98915). These findings are limited because of the heterogeneity of the included studies.
• Upper respiratory tract infection (URTI). It is unclear if oral vitamin D is beneficial for dementia. Details: A large clinical trial shows that taking vitamin D 2800 IU daily, starting at gestational week 24 and continuing until one week after birth, reduces the risk of the child developing croup by 3 years of age by 40% when compared with olive oil as placebo. This risk reduction did not change after adjusting for the use of omega-3 fatty acids 2.4 grams daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Urinary incontinence. Limited evidence suggests that vitamin D may be beneficial in middle-aged, but not older, adults with urinary incontinence. Details: Clinical research in middle-aged premenopausal females with stress urinary incontinence and low vitamin D status shows that taking vitamin D 5000 IU once weekly for 12 weeks has a moderate to large beneficial effect on the severity of incontinence and quality of life when compared with placebo. Kegel exercises were performed by all participants (109736). However, vitamin D supplementation does not seem to be beneficial for reducing urinary incontinence in older adults. In older females and males, a large clinical trial shows that vitamin D3 (cholecalciferol) 2000 IU daily for 5 years does not reduce the incidence or progression of urinary incontinence when compared with placebo (109738,109741). In older males with low vitamin D status, vitamin D supplementation may actually increase some types of incontinence (109738).
• Urinary tract infections (UTIs). It is unclear if oral vitamin D is beneficial for the prevention of UTIs in children. Details: A meta-analysis of 13 small observational studies in children suggests that lower levels of vitamin D are associated with 2.8-fold greater odds of UTI when compared with higher vitamin D levels. Further, this analysis shows that vitamin D deficiency in children is linked to 5.5-fold greater odds of UTI when compared with normal vitamin D levels (112030).
• Urticaria. It is unclear if oral vitamin D is beneficial for the prevention or treatment of urticaria. Details: A meta-analysis of population research has found that having urticaria is associated with a slightly lower vitamin D blood level and a greater likelihood of vitamin D deficiency when compared with individuals without urticaria. In addition, a meta-analysis of 6 clinical trials shows that taking vitamin D at an average daily dose of at least 4100 IU has a modest effect on the severity of urticaria symptoms (106115). Pooled data from 2 clinical studies in adults with chronic urticaria shows that taking vitamin D for 12 weeks, either as cholecalciferol 60,000 IU every 2 weeks or as alfacalcidol, 0.25 mcg once daily, reduces pruritus severity when compared with placebo (115587).
• Uterine fibroids. Low vitamin D status is associated with uterine fibroids and some clinical research suggests that taking vitamin D may modestly decrease the size of uterine fibroids. Details: Two meta-analyses of 5 clinical studies in premenopausal adults with uterine fibroids shows that taking vitamin D, either 50,000 IU weekly or biweekly for 8-12 weeks or 1000 IU daily for 1 year, decreases fibroid size when compared with placebo or no treatment (113577,115573). One of the meta-analyses found a 5.7% difference in fibroid size between vitamin D and control (115573). Observational research also suggests that vitamin D status is associated with uterine fibroids. Specifically, meta-analyses of a total 23 observational studies suggest that individuals with uterine fibroids have lower serum vitamin D levels and a 3.7-times higher odds of vitamin D deficiency (115573).
• Vaginal atrophy. It is unclear if oral vitamin D is beneficial for vaginal atrophy. There is limited evidence on the topical use of vitamin D in vaginal atrophy in postmenopausal adults or patients taking tamoxifen. Details: A small cross-sectional study in postmenopausal adults has found that taking a vitamin D supplement for at least one year improves the maturation index of superficial vaginal wall cells when compared with those who do not take vitamin D. However, symptoms of vaginal atrophy were not different between groups (16879). Vitamin D has also been evaluated for vaginal atrophy due to tamoxifen. A small clinical trial in females with breast cancer using tamoxifen shows that receiving vitamin D 1000 IU vaginal suppositories daily for 8 weeks improves maturation index of vaginal walls and self-reported symptoms when compared with placebo (99773).
• Vertigo. It is unclear if oral vitamin D is beneficial in patients with vertigo. Details: An analysis of observational research suggests that lower serum levels of vitamin D are associated with a higher risk of benign paroxysmal positional vertigo (BPPV) when compared with higher vitamin D levels (114579). However, it is unclear if vitamin D supplementation can reduce the risk of BPPV in individuals with low vitamin D levels. Vitamin D has been evaluated in combination with other ingredients for the treatment of BPPV. A large clinical study in adults with recurrent BPPV shows that taking vitamin D 400 IU and calcium 500 mg twice daily for one year reduces the risk of recurrence by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 4 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination.
• Vitiligo. Although there is interest in using oral vitamin D for vitiligo, there is insufficient reliable information about the clinical effects of vitamin D for this condition.
• Warts. Although there is interest in using topical vitamin D derivatives for warts, there is insufficient reliable information about the clinical effects of vitamin D for this condition. More evidence is needed to rate vitamin D for these uses.

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EFFECTIVE

• Hemorrhagic disease. Oral or intramuscular vitamin K1 is effective for preventing hemorrhagic disease in newborns. Details: Vitamin K1 (phytonadione) administered orally or intramuscularly can prevent classic hemorrhagic disease of newborns (15,85367,85484). A single intramuscular administration of vitamin K1 1 mg is considered to be the most effective method, while oral administration of three doses of vitamin K1 1-2 mg over 8 weeks is considered to be an acceptable alternative (85506). The effects of vitamin K on late hemorrhagic disease of newborns is less clear (85367,85484). In the Netherlands, an oral dose of 25 mcg daily for 3 months was used until 2011, when it was increased to 150 mcg daily. A reduction of late intracranial vitamin K deficiency bleeding in the general pediatric population, from 1.6 per 100,000 to 1.3 per 100,000, was associated with this dose increase (102351). The effect of various doses of intramuscular birth vitamin K prophylaxis has also been investigated in premature infants. A small clinical study in premature infants born at or before 32 weeks gestation or who weigh 1500 grams or less shows that administering intramuscular vitamin K1 at doses of 0.3, 0.5, or 1.0 mg (Kenadione, Samarth Life Sciences PVT Ltd) within 1 hour of admission to the neonatal intensive care unit improves subclinical vitamin K deficiency. While infants in all 3 dosing groups had sufficient vitamin K levels at 5 days old, by day 28 those who were initially administered vitamin K 0.3 mg had higher rates of subclinical vitamin K deficiency and lower rates of vitamin K sufficiency. Rates of intraventricular or periventricular hemorrhage, pulmonary hemorrhage, necrotizing enterocolitis, and mortality did not differ across dosing groups (112100).
• Hypoprothrombinemia. Oral or parenteral vitamin K1 is effective for treating and preventing hypoprothrombinemia. Details: Vitamin K1 (phytonadione) 2.5-25 mg, used orally or parenterally, can prevent and treat hypoprothrombinemia caused by vitamin K deficiency or induced by salicylates, sulfonamides, quinine, quinidine, or broad-spectrum antibiotic therapy (15).
• Vitamin K-dependent clotting factors deficiency (VKCFD). Oral and intravenous vitamin K1 is the primary treatment for VKCFD. Details: Oral supplementation with vitamin K 10 mg two to three times weekly seems to prevent major hemorrhages and reduce mucocutaneous bleeding in individuals with VKCFD. Also, intravenous vitamin K may improve the prothrombin time-international normalized ratio (PT-INR) values in these patients. While vitamin K supplementation is the primary treatment method for VKCFD, the response to treatment varies significantly (85481).
• Warfarin anticoagulation. Oral and intravenous vitamin K1 reverse warfarin-related excessive anticoagulation. Evidence for the use of oral vitamin K1 in patients with an unstable INR is conflicting. Details: Taking vitamin K1 (phytonadione) orally or parenterally, but not subcutaneously, can counteract excessive warfarin anticoagulation and restore therapeutic international normalized ratio (INR) levels. Usually a single dose of 1-5 mg is used (85406,85425,85429). Vitamin K might also be effective for stabilizing warfarin anticoagulation in patients with low intake of vitamin K. Patients with a low dietary vitamin K intake are significantly more likely to have an unstable INR than those who ingest higher amounts of vitamin K (16803). It is thought that vitamin K-depleted patients become more sensitive when vitamin K is ingested, even in small quantities, resulting in erratic or unstable INR (16804). One small clinical study and one small retrospective chart review show that taking oral vitamin K1 (phytonadione) 100-150 mcg daily improves INR stability in patients taking warfarin who previously had an unstable INR (16805,16806). However, a larger clinical study found no significant differences in INR stability in patients taking vitamin K 100 mcg daily when compared with placebo (16807). Also, some research suggests that, although taking vitamin K 1250 mcg daily may reduce INR in patients with excessive warfarin anticoagulation more significantly than placebo, there may not be a significant difference in the risk of bleeding complications (23380). It is important to keep in mind that, if a patient is stabilized on warfarin therapy plus vitamin K supplementation, discontinuing vitamin K can significantly increase the INR within 2-3 weeks after discontinuation (17714). The most recent guidelines by the American College of Chest Physicians do not recommend routine use of vitamin K supplementation for patients on warfarin therapy with unstable INR (94926). However, the previous guidelines recommended vitamin K 100-200 mcg daily for these patients. Therefore, some providers still use vitamin K for this purpose (16808).

POSSIBLY EFFECTIVE

• Osteoporosis. Oral vitamin K might reduce the risk of fractures and bone loss in patients with osteoporosis. However, it may not be beneficial in patients at risk for developing osteoporosis. Details: Although observational and clinical research on dietary and supplemental vitamin K for osteoporosis has been conflicting (14364,85392,85445,102354,112106), overall, vitamin K supplementation seems to slightly reduce fracture risk (102354). A meta-analysis combining data from 36 heterogeneous studies in osteoporotic or postmenopausal patients shows that taking different regimens of either vitamin K1 or vitamin K2 is associated with a small reduction in clinical fractures (from 3.1% to 2.2%), but not with changes in vertebral fractures or BMD when compared with control (102354). This analysis is limited by the high variability in study designs and a lack of subgroup analyses stratifying different patient populations and forms of vitamin K. In contrast, a meta-analysis of 16 studies in postmenopausal adults shows that taking various forms of vitamin K2 improves lumbar spine BMD based on 10 studies, especially when combined with other therapies such as vitamin D, calcium, or alendronate. However, vitamin K2 does not improve hip, femoral neck, or forearm BMD when compared with placebo. Furthermore, meta-analyses of 25 studies show that vitamin K2 does not reduce the incidence of fractures when compared with control (91451,112106). However, a sensitivity analysis that excluded the largest negative study of over 4000 postmenopausal Japanese females with mild osteoporosis (85456), shows that vitamin K2 45 mg daily reduces the risk of fractures by 53% and improves lumbar and vertebral BMD in patients with osteoporosis when compared with control (91451). This effect was not seen in patients without osteoporosis (91451). Vitamin K2 also does not seem to benefit patients with osteopenia. A recent clinical trial in postmenopausal patients with osteopenia shows that taking a larger dose of vitamin K2 (375 mcg, MK-7) with calcium 800 mg and vitamin D 1500 IU daily for 3 years does not seem to affect BMD, bone turnover, or bone microarchitecture when compared with placebo (105035). Vitamin K1 (phytonadione) has also been evaluated, with mixed findings. One clinical study in postmenopausal patients with osteopenia shows that taking vitamin K1 5 mg daily with calcium 1500 and vitamin D 800 IU for up to 4 years reduces clinical fractures, but does not reduce clinical fragility fractures or improve BMD, when compared with placebo and vitamin D with calcium (85453). In healthy, non-osteoporotic patients ages 60-80 years, one clinical study shows that taking vitamin K1 500 mcg daily with calcium 600 mg and vitamin D 400 IU for 3 years does not affect BMD, despite increased plasma vitamin K levels and reduced undercarboxylated osteocalcin concentrations, when compared with taking calcium and vitamin D alone (16404). The same null effect on BMD and a reduced undercarboxylated osteocalcin was shown in a small clinical study in patients with Crohn disease without osteoporosis, taking vitamin K1 1-2 mg in combination with vitamin D3 400 IU and calcium 500 mg daily for 12 months (91454). One small clinical trial compared vitamin K1 with vitamin K2 in postmenopausal adults with osteoporosis. This research shows that taking either vitamin K1 1 mg or vitamin K2 45 mg orally daily for 18 months in conjunction with a bisphosphonate does not improve femoral, spine, or hip BMD when compared with taking placebo and a bisphosphonate. All participants also took vitamin D supplements throughout the study (114778).

POSSIBLY INEFFECTIVE

• Intraventricular hemorrhage. Oral vitamin K does not reduce the risk of periventricular hemorrhage in preterm infants. Details: A meta-analysis of results from clinical research shows that administering vitamin K to pregnant patients at risk for very preterm birth does not reduce the overall risk of periventricular hemorrhage in preterm infants, perinatal mortality, or the associated neurological injury by the age of 7 years when compared to control. A subgroup analysis shows that vitamin K might reduce the risk of severe periventricular hemorrhage by 42% in preterm infants. However, when trials with inadequate blinding were excluded, this result was not statistically significant (85469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral vitamin K2 improves athletic performance. Details: A small clinical study shows that taking vitamin K2 (menaquinone) 320 mcg orally daily for 4 weeks followed by 160 mg daily for 4 weeks, increases maximal cardiac output by 12% when compared with placebo in trained athletes performing standardized cycle ergometer exercise tests (95937).
• Beta-thalassemia. Oral vitamin K2 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking the menaquinone-7 (MK-7) form of vitamin K2 50 mcg daily plus vitamin D3 (calcitriol) 5 mcg daily for 12 months modestly improves bone mineral density (BMD) at the lumbar spine when compared to baseline in children with beta-thalassemia aged 3-18 years (91456). It is not clear if this improvement can be attributed to vitamin K, vitamin D3, or the combination.
• Breast cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of breast cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of premenopausal or postmenopausal breast cancer (85474).
• Cancer. It is unclear if dietary intake of vitamin K reduces the risk of cancer or cancer-related mortality. Details: One large population study involving healthy German patients has found that consuming more than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 27% reduced risk of cancer mortality, but not cancer incidence, when compared with consuming less than 23-26 mcg daily. Dietary intake of vitamin K1 (phytonadione) was not associated with the risk of cancer or cancer mortality (85474). Another population study involving Mediterranean patients at high risk for cardiovascular disease has found that consuming about 630 mcg of vitamin K1 daily is associated with a 46% lower risk of cancer mortality when compared with consuming about 171 mcg of vitamin K1 daily. However, higher dietary intake of vitamin K2, 87 mcg daily, was not associated with a lower risk of cancer mortality when compared to those with lower dietary intake (79 mcg daily) (91452). Reasons for these discrepancies may relate to the definitions for high and low intake, the use of different databases to calculate vitamin K intake, and the different populations studied.
• Cardiovascular disease (CVD). It is unclear if dietary or supplemental vitamin K reduces the risk of CVD events; the available research is conflicting. Details: Most population research, including a meta-analysis of 21 observational cohort studies, has found that dietary intake of vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is not associated with reduced risk for most cardiovascular events, such as CVD mortality, nonfatal MI, or stroke, although there might be a slightly reduced risk for CHD (85414,85482,91452,102353,103922). However, some population studies have found benefit. Observational research in a Danish cohort aged 50-65 years with no history of atherosclerotic cardiovascular disease at baseline shows that those in the highest quintile of dietary vitamin K1 intake have a 21% lower risk of CVD-related hospitalization and complications, such as ischemic heart disease, ischemic stroke, or peripheral artery disease, over 17-22 years when compared with the lowest quintile of intake. This inverse association tapers off at intakes above 100 mcg daily. For vitamin K2 intake, the highest quintile has a 14% lower risk of hospitalization when compared with the lowest quintile, although the association is U-shaped, indicating an increased risk at high doses. The researchers theorize that this may be due to the fact that vitamin K2-rich foods include cheese, eggs, and butter (109910,109920). There is also interest in using vitamin K to slow aortic valve calcification (AVC) and coronary artery calcification (CAC), which are CVD risk factors. In healthy patients ages 60-80 years with pre-existing CAC, taking a multivitamin with vitamin K1 (phytonadione) 500 mcg orally daily for 3 years reduces CAC progression by 6% when compared with the multivitamin alone (85461). However, research in patients with AVC has found no benefit. One small clinical study in patients on hemodialysis shows that taking the menaquinone-7 form of vitamin K2, 200 mcg orally daily for 1 year, does not affect the rate of AVC progression when compared with placebo (102352). Also, clinical research in males with significant AVC shows that taking the menaquinone-7 form of vitamin K2 720 mcg and vitamin D 25 mcg orally daily for 2 years does not reduce the rate of AVC progression or the rate of cardiovascular events, heart valve surgery, or all-cause mortality when compared with placebo (109916).
• Cataracts. It is unclear if dietary vitamin K reduces the risk of cataracts in older adults. Details: A secondary analysis of results from clinical research has found that higher dietary vitamin K1 (phytonadione) intake over a mean 5.6 years' follow-up is associated with a lower risk of cataracts and a lower incidence of cataract surgery in older adults at high risk for cardiovascular disease. The hazard ratio for developing cataracts was 0.71 and the hazard ratio for cataract surgery was 0.75 for people in the highest tertile of dietary vitamin K1 intake when compared with the lowest tertile (95936).
• Cognitive impairment. It is unclear if dietary vitamin K alters the rate of decline in adults with cognitive impairment. Details: Clinical research in adults aged 55-75 years with overweight or obesity, metabolic syndrome, and cognitive impairment shows that the largest increases in dietary vitamin K intake over a 2-year period are linked to a slower rate of cognitive decline when compared with the lowest increases in intake. This is demonstrated by higher scores on the mini-mental state examination (MMSE) and verbal fluency tests, and a greater number of patients maintaining an MMSE score of at least 24 (109919).
• Colorectal cancer. It is unclear if dietary intake of vitamin K2 reduces the risk of colorectal cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone) or vitamin K1 (phytonadione) is not associated with a reduced risk of colorectal cancer (85474).
• Cystic fibrosis. It is unclear if oral vitamin K improves coagulopathy in patients with cystic fibrosis. Details: Suboptimal vitamin K status is common in patients with cystic fibrosis, especially those with pancreatic insufficiency, due to problems with fat digestion (85359,85479). Preliminary clinical research in patients with cystic fibrosis shows that taking vitamin K 1-5 mg orally for one month might decrease osteocalcin levels when compared with baseline, which suggests a lower risk of bone fractures (103920). Also, a small clinical trial in adults and children with cystic fibrosis and pancreatic insufficiency shows that taking a supplement containing fat-soluble vitamins A, D, E, and K for an average of 8.6 months reduces the number of patients with abnormal levels of protein induced by vitamin K absence (PIVKA-II), a defective form of prothrombin (85374).
• Depression. It is unclear if dietary intake of vitamin K reduces depression. Details: Population research has found that a dietary intake of vitamin K greater than 232 mcg daily is associated with reduced odds of depressive symptoms when compared with intakes of less than 83 mcg daily in older adults who are not taking vitamin D supplements. For every 100 mcg increase in vitamin K intake per day, the study found an 18% reduction in odds of depressive symptoms. However, there was no association identified in individuals taking vitamin D (100181). The effect of vitamin K for the prevention or treatment of clinical depression has not been investigated.
• Diabetes. It is unclear if oral vitamin K improves glycemic control in adults with diabetes. Details: A small clinical study in patients with diabetes on oral antidiabetes medications shows that taking vitamin K2 (MK-7) 180 mcg twice daily for 12 weeks seems to reduce glycated hemoglobin (HbA1c) by 1.6%, compared with a slight increase in the placebo group (105034). This study is limited by the high dropout rate in the placebo group. A meta-analysis of clinical studies in patients with type 2 diabetes shows that taking vitamin K1 or K2 for 1 to 36 months modestly improves fasting blood glucose levels and markers of insulin resistance when compared with placebo (11475). The validity of this analysis is limited by high heterogeneity, including different forms and dosing regimens of vitamin K. One small clinical study in adults with type 2 diabetes shows that taking vitamin K4 1 mg orally daily for 6 months does not improve HbA1c or fasting blood glucose levels when compared with placebo. However, subjects taking vitamin K4 had a greater improvement in certain markers of insulin resistance and were more likely to be able to reduce the dose of their antidiabetes medications (114776). There is also interest in vitamin K for the prevention of diabetes. A meta-analysis of population research suggests that low dietary vitamin K intake is associated with an increased risk of developing type 2 diabetes when compared with higher intake (114775). The validity of this study is limited by the identification of publication bias.
• EGFR inhibitor-induced acneiform rash. It is unclear if topical vitamin K is beneficial for the treatment or prevention of acneiform rash caused by EGFR inhibitors. Details: Preliminary clinical research in adults receiving treatment with cetuximab, an EGFR inhibitor, shows that applying vitamin K1 (phytonadione) 0.1% cream (Vigorskin, Merck Serono SpA) twice daily to the face and trunk for 12 weeks may modestly reduce the percentage of patients who develop a moderate to severe acneiform rash (91455). The validity of this finding is limited by the lack of a control group. In patients with an existing rash after receiving the EGFR inhibitors cetuximab and panitumumab, a small clinical study shows that applying vitamin K1 (phytonadione) 1% ointment twice daily for 8 weeks to half of the affected area does not reduce the number of acneiform eruptions when compared with using placebo ointment on the other half of the affected area (103919). Patients in this study were allowed to use concomitant antibiotics and moisturizing agents, which may have confounded the results.
• Kidney failure. It is unclear if oral vitamin K2 reduces the incidence or severity of muscle cramps in adults with kidney failure. Details: Preliminary clinical research in patients on maintenance hemodialysis for at least 3 months with treatment-resistant muscle cramps shows that taking the menaquinone form of vitamin K2 360 mcg orally daily for 8 weeks reduces the frequency, severity, and duration of muscle cramps when compared with placebo (109917).
• Kidney transplant. It is unclear if vitamin K is beneficial for reducing cardiovascular risk in kidney transplant recipients. Details: Preliminary clinical research in adults with a stable kidney transplant for at least 1 year shows that taking vitamin K (menadiol diphosphate) 5 mg three times weekly for 1 year does not reduce aortic stiffness or coronary artery calcification, which are markers of cardiovascular disease, when compared with placebo (109913). The effects of long-term supplementation are unclear. Additionally, another very small study in adult kidney transplant recipients with vitamin K deficiency shows that taking supplemental vitamin K2 360 mcg daily for 12 weeks improves vitamin K status and prevents the progression of arterial stiffness but does not reduce serum calcification propensity when compared with placebo (112132).
• Liver cancer. Small clinical studies suggests that vitamin K2 reduces mortality and the risk for hepatocellular carcinoma recurrence. Details: Meta-analyses of 9-11 small clinical trials in patients with resectable hepatocellular carcinoma show that adding vitamin K2 45 mg daily for up to 3 years seems to reduce cancer recurrence by 9.5% and reduce the risk of mortality by 7% when compared with control. Meta-analyses of 3-4 small clinical trials in patients with non-resectable carcinoma show that taking vitamin K2 45 mg for up to 2 years seems to reduce cancer recurrence by 3% and reduce mortality by 16% when compared with control (105032). Most of the included studies were conducted in Japan, so it is unclear if these results are generalizable to other geographic locations.
• Liver disease. It is unclear if dietary intake of vitamin K reduces the risk of liver disease. Details: A small observational study in patients with chronic liver failure due to cholestatic liver disease has found that receiving intramuscular vitamin K1 10 mg daily for an average of 16 days is associated with a lower risk of death when compared with control (103926).
• Lung cancer. It is unclear if dietary intake of vitamin K reduces the risk of lung cancer. Details: Population research has found that consuming greater than 42-46 mcg of vitamin K2 (menaquinone) daily is associated with a 62% lower risk of lung cancer occurrence and a 59% lower risk of lung cancer mortality when compared to those who consume less than 23-26 mcg of vitamin K2 daily. Dietary intake of vitamin K1 (phytonadione) is not associated with a reduced risk of lung cancer or lung cancer mortality (85474).
• Multiple sclerosis (MS). It is unclear if topical vitamin K reduces cutaneous adverse effects of MS treatment. Details: In patients with relapsing-remitting MS, burning and pain can accompany subcutaneous interferon treatment. Preliminary clinical research shows that topical application of vitamin K cream (dose not specified) for 8 weeks reduces burning by approximately 8% and pain by 9% when compared with no prophylactic treatment. Redness of the skin is also reduced with vitamin K (91453).
• Overall mortality. It is unclear if dietary intake of vitamin K reduces overall mortality. Details: Observational research in healthy older adults has found that serum vitamin K levels 0.5 nmol/L or less, which corresponds to consuming about 50% of the recommended vitamin K adequate intake, is associated with a 19% higher risk of overall mortality when compared with higher serum levels of vitamin K (103922). In a Danish cohort of adults with a median age of 56 years at baseline, the comparative risk for all-cause mortality between the highest and lowest quintiles of K1 intake over a period of 17-23 years was 0.76. The risk for cardiovascular mortality was 0.72, and the risk of cancer-related mortality in smokers or former smokers, specifically, was 0.8. However, the correlation tapered off above a daily intake of 100 mcg (109911).
• Pancreatic cancer. It is unclear if dietary intake of vitamin K reduces the risk of pancreatic cancer. Details: Observational research in over 100,000 Americans aged 55-74 years at baseline has found no association between dietary vitamin K2 intake and pancreatic cancer incidence over an average follow-up of 9 years. However, the hazard ratio for development of pancreatic cancer was 0.57 for the highest quintile of dietary vitamin K1 intake when compared with the lowest quintile (109912).
• Polycystic ovary syndrome (PCOS). It is unclear if vitamin K improves PCOS symptoms. Details: Small clinical study in patients with PCOS show that taking vitamin K2 (menaquinone-7) 90 mcg daily for 8 weeks does not reduce fasting blood glucose, acne, hirsutism, or weight, although it improves depression and seems to reduce fasting insulin, when compared with placebo (105036,109918).
• Prostate cancer. It is unclear if dietary intake of vitamin K reduces the risk of prostate cancer. Details: Population research has found that higher dietary intake of vitamin K2 (menaquinone), but not vitamin K1 (phytonadione), is associated with a reduced risk of prostate cancer, particularly advanced prostate cancer (85443,85474).
• Rheumatoid arthritis (RA). It is unclear if oral vitamin K improves RA symptoms. Details: One small clinical study in patients with RA shows that adding the MK-7 form of vitamin K2 (menaquinone) 100 mcg daily to treatment with conventional antirheumatic agents for 3 months improves disease activity and inflammatory markers when compared with antirheumatic agents alone. When compared to the control group, vitamin K2 reduced disease activity scores by 41% (91449). However, another small clinical study in patients with mild to moderate RA shows that taking vitamin K1 (phytonadione) 10 mg daily for 8 weeks with conventional antirheumatic agents does not improve disease activity or inflammatory markers when compared with placebo (100182). These contrasting outcomes may be related to the type of vitamin K used, the duration of treatment, and the severity of the illness.
• Rosacea. Although there is interest in using topical vitamin K1 for rosacea, there is insufficient reliable information about the clinical effects of vitamin K for this condition.
• Stroke. It is unclear if dietary intake of vitamin K1 reduces the risk of stroke. Details: Population research has found that higher dietary intake of vitamin K1 is not associated with a reduced risk of stroke (85482).
• Wound healing. Although there is interest in using topical vitamin K1 for wound healing, there is insufficient reliable information about the clinical effects of vitamin K for this condition. More evidence is needed to rate vitamin K for these uses.

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LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

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LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses (7555,16888,16891,17476,95913,98186,104619,105209,109040,109059)(115580,115590). When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults (17506,99773); however, much higher doses such as 50,000 IU (1250 mcg) weekly orally for 6-12 weeks are often needed for the short-term treatment of vitamin D deficiency (16891,17476,115590). Monthly oral doses of up to 60,000 IU (1500 mcg) have also been safely used for up to 5 years (105726). Toxicity usually does not occur until plasma levels exceed 150 ng/mL (17476).

POSSIBLY UNSAFE ...when used orally in excessive doses, long-term. Taking doses greater than the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily for adults for long periods can increase the risk of hypercalcemia (17506); however, much higher doses are often needed for short-term treatment of vitamin D deficiency. Toxicity typically occurs when levels exceed 150 ng/mL (17476).

CHILDREN: LIKELY SAFE
when used orally and appropriately. When used long-term, doses should not exceed the tolerable upper intake level (UL) of 1000 IU (25 mcg) daily for those 0-6 months of age, 1500 IU (37.5 mcg) daily for those 6-12 months of age, 2500 IU (62.5 mcg) daily for those 1-3 years of age, 3000 IU (75 mcg) daily for those 4-8 years of age, and 4000 IU (100 mcg) daily for those 9 years and older (17506); however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU (350 mcg) weekly for a year in children aged 10-17 years is safe (16875). A meta-analysis of clinical studies shows that 1000 IU (25 mcg) daily in those up to a year of age and greater than 2000 IU (50 mcg) daily in those aged 1-6 years does not increase the risk of serious adverse events (108424).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses for longer than one year. Taking doses greater than the tolerable upper intake level (UL) long-term can increase the risk of hypercalcemia (17506).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506,95910).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily. Hypercalcemia during pregnancy due to excessive vitamin D intake can lead to several fetal adverse effects, including suppression of parathyroid hormone, hypocalcemia, tetany, seizures, aortic valve stenosis, retinopathy, and mental and/or physical developmental delay (17506).

LACTATION: LIKELY SAFE
when used orally and appropriately. Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

LACTATION: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 4000 IU (100 mcg) daily (17506).

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LIKELY SAFE ...when vitamin K1 (phytonadione) or vitamin K2 (menaquinone) is used orally and appropriately. A tolerable upper intake level for vitamin K in adults has not been set, because no adverse effects have been noted at a wide range of studied doses. For example, Vitamin K1 up to 10 mg daily and vitamin K2 up to 45 mg daily have been safely used in clinical trials lasting up to 2 years. (54,55,58,6799,7135,14364). Notably, some of these studied doses are exponentially higher than various recommendations for daily adequate intake. See Dosing & Administration and Effectiveness sections for additional information...when vitamin K1 (phytonadione) is used parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is an FDA-approved drug (7135).

POSSIBLY SAFE ...when vitamin K1 (phytonadione) 0. 1% is used topically in a cream or ointment for up to 12 weeks (91455,103919).

CHILDREN: LIKELY SAFE
when vitamin K1 (phytonadione) is used orally or parenterally and appropriately. Vitamin K1 (phytonadione) in oral and injectable form is FDA approved for use in children. A tolerable upper intake level for vitamin K in children has not been set (7135).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the daily adequate intake level (AI). A tolerable upper intake level for vitamin K in pregnancy and lactation has not been set (7135).

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might increase aluminum absorption and toxicity, but this has only been reported in people with renal failure.  Details The protein that transports calcium across the intestinal wall can also bind and transport aluminum. This protein is stimulated by vitamin D, which may therefore increase aluminum absorption (11595,11597,22916). This mechanism may contribute to increased aluminum levels and toxicity in people with renal failure, when they take vitamin D and aluminum-containing phosphate binders chronically (11529,11596,11597).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin D might reduce absorption of atorvastatin.  Details A small, low-quality clinical study shows that taking vitamin D reduces levels of atorvastatin and its active metabolites by up to 55%. However, while atorvastatin levels decreased, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels did not substantially change (16828). Atorvastatin is metabolized in the gut by CYP3A4 enzymes, and researchers theorized that vitamin D might induce CYP3A4, causing reduced levels of atorvastatin. However, this proposed mechanism was not specifically studied.

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Taking calcipotriene with vitamin D increases the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (15). Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Vitamin D might induce CYP3A4 enzymes and reduce the bioavailability of CYP3A4 substrates.  Details There is some concern that vitamin D might induce CYP3A4. In vitro research suggests that vitamin D induces CYP3A4 transcription. Additionally, observational research has found that increased UV light exposure and serum vitamin D levels are associated with decreased serum levels of CYP3A4 substrates such as tacrolimus and sirolimus, while no association between UV light exposure or vitamin D levels and levels of mycophenolic acid, a non-CYP3A4 substrate, was found (110539). A small, low-quality clinical study shows that taking vitamin D reduces levels of the CYP3A4 substrate atorvastatin and its active metabolites by up to 55%; however, the clinical effects of atorvastatin were not reduced (16828). While researchers theorized that vitamin D might induce CYP3A4, this proposed mechanism was not specifically studied.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hypercalcemia induced by high-dose vitamin D can increase the risk of arrhythmia from digoxin.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (15). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and digoxin concurrently.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of diltiazem for arrhythmia.  Details High doses of vitamin D can cause hypercalcemia. Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically this could also occur with diltiazem. Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and diltiazem concurrently.

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking thiazide diuretics and high-dose vitamin D can increase the risk of hypercalcemia.  Details Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently (3072,11541,69580). This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily (11539,11540).

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Hypercalcemia induced by high-dose vitamin D can reduce the therapeutic effects of verapamil for arrhythmia.  Details Hypercalcemia due to high doses of vitamin D can reduce the effectiveness of verapamil in atrial fibrillation (10574). Avoid vitamin D doses above the tolerable upper intake level (4000 IU daily for adults) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.

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WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = C Vitamin K can antagonize and reverse the therapeutic effects of warfarin.  Details Vitamin K antagonizes the effects of warfarin (15,23380,25507,25508,85425,85429). Excessive vitamin K intake, either from supplements or from changes in the diet, can reduce the anticoagulant effect of warfarin (15).

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

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General ...Orally or intramuscularly, vitamin D is well tolerated.
Serious Adverse Effects (Rare):
Orally or intramuscularly: Excessive doses can lead to vitamin D toxicity with symptoms of hypercalcemia, and also sometimes azotemia and anemia.

Cardiovascular ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Rarely, people develop hypertension (10142). An analysis of clinical research suggests that, when taken orally, vitamin D might modestly increase levels of low-density lipoprotein (LDL)-cholesterol. However, it is not clear if this increase is clinically significant (84642).

Gastrointestinal ...Orally, vitamin D may cause dry mouth. In clinical research, intake of vitamin D 50,000 IU weekly for 4 weeks followed by 50,000 IU monthly for 5 months thereafter was associated with a 3.7-fold increase in reports of dry mouth compared with placebo (91348).Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include pancreatitis (10142,84433). Vomiting occurred in one patient given a single dose of 200,000 IU (104624).

Genitourinary ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms may include decreased libido (10142). Vaginal discharge and itching have been reported in a clinical trial following oral use (91348).

Hematologic ...Lab values of urinary and blood calcium, phosphate, albumin, blood urea nitrogen, serum cholesterol, aspartate aminotransferase, and alanine aminotransferase concentrations might increase with vitamin D use, especially with high doses (10142,91349,93943).
A case of elevated international normalized ration (INR) has been reported for an 84 year-old patient who took vitamin D 50,000 IU daily for 2 months. The patient's serum levels of vitamin D increased from <7 ng/mL to 100 ng/mL over 6 months. To resolve symptoms, vitamin D supplementation was discontinued (84433).

Musculoskeletal ...Vitamin D intoxication can occur when vitamin D supplements are taken in excessive doses (10142,17506). Symptoms of vitamin D toxicity include osteoporosis in adults and decreased growth in children (10142).

Ocular/Otic ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). Symptoms of vitamin D toxicity include calcific conjunctivitis and photophobia (10142).

Psychiatric ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses (10142,17506). In rare cases, symptoms of vitamin D toxicity include psychosis (10142,93002).

Pulmonary/Respiratory ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Advanced symptoms of vitamin D toxicity may include runny nose (10142,17506,93002).

Renal ...Vitamin D intoxication can occur when vitamin D supplements are taken orally in excessive doses. Symptoms of vitamin D toxicity include azotemia. Vitamin D may also cause hypercalcemia, with advanced symptoms including kidney stones or kidney insufficiency due to precipitation of calcium phosphate in the tubules. Symptoms of renal impairment include frequency, nighttime awakening to urinate, thirst, inability to concentrate urine, and proteinuria. Renal impairment is usually reversible with discontinuation of vitamin D supplements (10142,93002,93943,110831,110833).

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General ...Orally, vitamin K is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, nausea, and stomach upset.
Serious Adverse Effects (Rare):
Intravenously: There have been rare cases of anaphylaxis and hyperbilirubinemia (in infants).

Dermatologic ...Orally, intake of vitamin K2 (menaquinone) along with calcium and vitamin D3 can cause an increased incidence of skin and skin appendage lesions compared to taking calcium and vitamin D3 alone. However, the risk of this adverse event is low, with 0.5 incidences per 100 patient-years occurring for patients treated with vitamin K, calcium, and vitamin D3 and 0.1 incidences per 100 patient-years occurring for patients treated with calcium and vitamin D3 alone (85467).

Gastrointestinal ...Orally, vitamin K can cause mild to moderate gastrointestinal side effects (91450,91451). The most common effects include nausea, abdominal pain, and diarrhea (91450,91451).

Hepatic ...Orally, vitamin K3 (menadione) has been linked to hepatotoxicity. Vitamin K3 is no longer used therapeutically in North America because it has been linked to hepatic toxicity and jaundice in animal research (7135).

Other ...Intravenously, vitamin K can cause reactions that resemble hypersensitivity or anaphylaxis (85389). These reactions are rare. It is unclear whether the adverse effect is caused by the drug or a component of the solution. There have been very rare cases of hyperbilirubinemia, particularly in premature neonates, following large doses of vitamin K (15). One clinical study in premature infants shows that intramuscular administration of vitamin K 1.0 mg increases bilirubin levels and the duration of phototherapy when compared with vitamin K 0.3 mg and 0.5 mg. However, the clinical relevance of these findings is unclear, as no differences in bilirubin-induced neurologic dysfunction were reported (112100).

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