case study on vitamin d

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• Published: 10 August 2020

Non-classical presentation of vitamin D deficiency: a case report

• Mohanad Kamaleldin Mahmoud Ibrahim 1 &
• Mustafa Khidir Mustafa Elnimeiri 2  

Journal of Medical Case Reports volume  14 , Article number:  126 ( 2020 ) Cite this article

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Vitamin D is a fat-soluble vitamin; vitamin D is essential to sustain health and it protects against osteoporosis. It is crucial to the human body’s physiology in terms of muscular movement and neurological signal transmission, and to the immune system in defense against invading pathogens.

Case presentation

This was a case of a 26-year-old Sudanese woman who presented with a 2-year history of anosmia, recurrent nasal polyps, back pain, and chronic fatigue. She was diagnosed as having a case of vitamin D deficiency and responded well to treatment.

There is an association between vitamin D deficiency and recurrent allergic nasal conditions.

Peer Review reports

Vitamin D is a fat-soluble vitamin; it is naturally present in some foods and as dietary supplements. It is also produced endogenously through exposure to ultraviolet rays from sunlight. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and produces 25-hydroxyvitamin D (25(OH)D), also known as calcidiol. The second occurs in the kidney and forms the physiologically active 1,25-dihydroxy vitamin D (1,25(OH) 2 D), also known as calcitriol [ 1 ].

Vitamin D is found in cells throughout the body; vitamin D is essential to sustain health and it protects against osteoporosis. It is crucial to the human body’s physiology in terms of muscular movement and neurological signal transmission, and to the immune system in defense against invading pathogens [ 2 ].

Although there are different methods and criteria for defining vitamin D levels, the criteria Holick proposed have been widely accepted. In this proposal, vitamin D deficiency is defined as blood level of less than 20 ng/ml; insufficiency of vitamin D is defined as blood levels ranging between 20 and 29.9 ng/ml and sufficiency if greater than or equal to 30 ng/ml [ 3 ]. About one billion people globally have vitamin D deficiency and 50% of the population has vitamin D insufficiency. The majority of affected people with vitamin D deficiency are the elderly, obese patients, nursing home residents, and hospitalized patients. Vitamin D deficiency arises from multiple causes including inadequate dietary intake and inadequate exposure to sunlight. Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, some medications and cystic fibrosis may also lead to vitamin D deficiency [ 4 ].

Vitamin D deficiency is now more prevalent than ever and should be screened in high-risk populations. Many conflicting studies now show an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and neuropsychiatric disorders [ 5 , 6 ].

This was a case of a 26-year-old Sudanese woman, married, who has a 3-year-old boy. This woman presented to our ear, nose, and throat (ENT) department complaining of anosmia for the past 2 years. She had a history of two functional endoscopic sinus surgeries (FESSs) for nasal polyps: the first one was 6 years ago and the second one was 3 years prior to presentation. She complained of being highly sensitive to different irritants including dust, weather change, perfumes, and pets.She also stated that she attended more than three different physicians due to generalized fatigue and getting tired easily after simple daily activity in addition to sleeping for more than 10 hours a day.She attended an orthopedic clinic for unspecified lower back pain that was not related to any type of trauma or physical activity; a lumbosacral magnetic resonance imaging (MRI) was done and revealed no abnormal findings.She mentioned that she is known to be anxious most of the time and aggressive toward simple reactions from her family members. She had no psychiatric history and was not using any medications.

She was not known to be diabetic or hypertensive or to have any chronic illnesses; she was not on any regular medication. She is a housewife of high socioeconomic status; she is well educated, graduated from dental school with a bachelor’s degree, but currently not employed. She has never consumed tobacco or alcohol; she practiced regular cardio exercises.On examination, she looked healthy, well, not pale or jaundiced. Her pulse rate was 74/minute and her blood pressure was 118/70. Her body mass index (BMI) was 26.8. All systems examinations were normal except for bilateral nasal polyps. Complete blood count (CBC), renal function test (REF), electrolyte, liver function test (LFT), thyroid function test (TFT), urine analysis (general urine test), antinuclear antibody (ANA), and rheumatoid factor (RF) were all normal. An imaging profile included lumbo-sacral MRI, a computed tomography (CT) scan of her sinuses, and electrocardiogram (ECG), which were normal except for bilateral nasal polyps and severe sinusitis that looked allergic to fungi in nature.She underwent FESS surgery to remove the polyps and clean out her sinuses; up to 6 weeks after surgery she used nasal steroids (mometasone furoate 0.005%) two times a day, but her symptoms regarding anosmia were not improved. MRI of her brain and a CT scan of her sinuses were done and both revealed normal features. A vitamin D deficiency was suggested and the laboratory results revealed a low vitamin D level of 7 ng/ml. Treatment with vitamin D supplement was prescribed at 50,000 international units (IU) weekly for 8 weeks and then 1000 IU maintenance dose daily, she was advised to take food rich in vitamin D and get exposed to sunlight for 20 minutes three times a week after the loading dose of supplement. She was at regular follow-up for 6 months; at rates of weekly for the first month, every 2 weeks for the second month, and monthly for the rest of the follow-up period. At each visit, she was assessed with clinical history and examination. It was noticed that the symptoms of tiredness, sleeping, anosmia, and back pain were dramatically improving during that period. At the 6 months follow-up, her blood level of vitamin D was normal, she described her condition as free from all symptoms, and she returned back to normal physical activity.

Discussion and conclusions

This was a non-classical case of vitamin D deficiency of a 26-year-old woman who presented with chronic anosmia and recurrent nasal polyps. She was diagnosed as having a case of vitamin D deficiency and responded well to vitamin D replacement therapy. This case correlated an association between decreased levels of vitamin D and recurrent nasal polyps that led in time to chronic anosmia as a result of chronic high sensitivity reactions triggered by our patient’s autoimmune system. The literature links chronic rhinosinusitis with nasal polyps (CRSwNP) with asthma and allergic rhinitis, but the cellular and molecular mechanisms that contribute to the clinical symptoms are not fully understood. Sinonasal epithelial cell barrier defects, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis [ 7 ].

Despite all the previous surgical and medical interventions over the past 6 years, our patient’s condition did not improve and she still complained of anosmia. A study revealed that this patient was experiencing excessive allergic reactions that led to recurrent nasal polyps. It is well known that classical clinical effects of vitamin D deficiency are bones and musculoskeletal-related disorders, several lines of evidence demonstrate the effects of vitamin D on pro-inflammatory cytokines, regulatory T cells, and immune responses, with a conflicting interpretation of the effects of vitamin D on allergic diseases [ 8 ].

The working diagnosis was suggested in relation to some musculoskeletal symptoms and chronic fatigue especially when the imaging profile for her lower back and all routine investigations were normal. It has been suggested that clinicians should routinely test for hypovitaminosis D in patients with musculoskeletal symptoms, such as bone pain, myalgias, and generalized weakness which might be misdiagnosed as fibromyalgia and chronic fatigue [ 9 ]. The most common causes of anosmia were assessed as well and they were negative, these included sinonasal diseases, post infectious disorder, and post-traumatic disorder, and congenital defects and disorders caused by neurodegenerative disease [ 10 ].

Thus blood level for vitamin D was requested and the results were of low D level.

In the past history of the previous nasal polyps surgeries, our patient noted that there was no anosmia and her main complaints were classic complaints of sinusitis, including sneezing, nasal blockage and headache. Soon after surgery her symptoms improved except for the allergy-related symptoms, despite usage of inhaled steroids spray. She stated that, at the last time, the presentation was different since it was only anosmia, indicating that there was significant inflammation that affected the smell receptors around the olfactory epithelium. After the last nasal polyps and sinuses drainage surgery, the symptoms related to allergic reactions, including chronic sneezing, did not improve for up to 6 weeks and she was still suffering from hyposmia, although that was a fair postoperative period for recovery.

The symptoms of anosmia and sneezing, and other systematic symptoms, gradually started to improve after vitamin D supplements, indicating that the main reason behind her symptoms was vitamin D deficiency. She was followed up for up to 6 months after establishment of vitamin D supplements and at the last follow-up she had a normal sense of smell, and she was free from back pain, fatigue, and allergy-related symptoms.

This was a non-classical presentation as our patient was young and she did not have alkaline phosphatase, calcium, and phosphorus abnormalities [ 11 ] that are expected in cases of vitamin D deficiency.

This case revealed an association between decreased levels of vitamin D and recurrent nasal polyps that led to anosmia as a result of hypersensitive reactions produced by the body’s systems.

Although vitamin D deficiency is prevalent, measurement of serum 25(OH)D level is expensive, and universal screening is not supported. However, vitamin D testing may benefit those at risk for severe deficiency.

It is highly recommended to consider vitamin D deficiency among all patients with unspecified symptoms or in cases of non-diagnosed disorder regardless of the presenting complaint.

In conclusion, there is an association between vitamin D deficiency and recurrent allergic nasal conditions.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Chronic rhinosinusitis with nasal polyps

Computed tomography

Electrocardiogram

Ear, nose, and throat

Functional endoscopic sinus surgery

Body mass index

Complete blood count

Renal function test

Liver function test

Thyroid function test

Antinuclear antibody

Rheumatoid factor

International unit

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Community Medicine and Epidemiology, Faculty of Medicine, Ibn Sina University, Khartoum, Sudan

Mohanad Kamaleldin Mahmoud Ibrahim

Preventive Medicine and Epidemiology, Alneelain University, Khartoum, Sudan

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MI analyzed and interpreted the findings of the case report and was the major contributor in writing the manuscript. ME reviewed the report and added valuable comments. All authors read and approved the final manuscript.

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Correspondence to Mohanad Kamaleldin Mahmoud Ibrahim .

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Ibrahim, M.K.M., Elnimeiri, M.K.M. Non-classical presentation of vitamin D deficiency: a case report. J Med Case Reports 14 , 126 (2020). https://doi.org/10.1186/s13256-020-02454-1

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• Review Article
• Published: 23 November 2021

The health effects of vitamin D supplementation: evidence from human studies

• Roger Bouillon   ORCID: orcid.org/0000-0002-6446-3763 1 ,
• Despoina Manousaki 2 ,
• Cliff Rosen   ORCID: orcid.org/0000-0003-3436-8199 3 ,
• Katerina Trajanoska 4 ,
• Fernando Rivadeneira   ORCID: orcid.org/0000-0001-9435-9441 5 &
• J. Brent Richards 6 , 7  

Nature Reviews Endocrinology volume  18 ,  pages 96–110 ( 2022 ) Cite this article

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• Endocrine system
• Endocrine system and metabolic diseases

Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.

Vitamin D and calcium supplementation can cure nutritional rickets and can modestly decrease the risk of major fractures in older adults with poor vitamin D status or calcium intake.

Large supplementation trials recruiting vitamin D-replete adults (serum 25OHD concentration >50 nmol/l) have demonstrated no effects on the incidence of cancer, cardiovascular events or type 2 diabetes mellitus (T2DM) and no benefits in terms of bone density and the risk of falls.

Post-hoc analysis of large supplementation trials has suggested that supplementation of individuals with vitamin D deficiency modestly delays age-related bone loss and progression to T2DM, and improves lung function.

A meta-analysis suggested that vitamin D supplementation results in a modest decrease in cancer mortality.

Over 60 Mendelian randomization studies have examined causal links between genetically lower vitamin D levels and health outcomes; most studies generated null effects except four studies that demonstrated an increased risk of multiple sclerosis.

In conclusion, supplementation of vitamin D-replete individuals does not generate overall health benefits; however, correction of severe vitamin D deficiency remains essential.

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Vitamin D deficiency 2.0: an update on the current status worldwide

Absence of causal association between Vitamin D and bone mineral density across the lifespan: a Mendelian randomization study

Targeted 25-hydroxyvitamin d concentration measurements and vitamin d3 supplementation can have important patient and public health benefits, introduction.

There is consensus that daily intake of 400 IU of vitamin D can prevent nutritional rickets in infants and children 1 . However, the skeletal effects of vitamin D deficiency in adults and older adults (aged >65 years), and the potential extra-skeletal effects of vitamin D are more controversial. Some people consider that vitamin D supplementation is futile 2 . By contrast, others have suggested that the vitamin D intake requirement is much higher than currently achieved by the general population and that people should aim to achieve 25-hydroxyvitamin D (25OHD, the major marker of vitamin D status) concentrations similar to those found in certain tribes in equatorial Africa with a sun exposure lifestyle that might be similar to that of early humans 3 , 4 , 5 , 6 , 7 .

The potential extra-skeletal effects of the vitamin D endocrine system (which refers to vitamin D in its active form, its precursors and metabolites, and vitamin D receptor) are based on several arguments. For example, the vitamin D receptor (VDR) and CYP27B1 (the enzyme primarily responsible for producing the active form of vitamin D, 1,25-dihydroxyvitamin D or 1,25(OH) 2 D 3 ) are widely expressed, including in tissues that are not involved in calcium or phosphate transport (Fig.  1 ). In addition, ~3% of the human and mouse genomes are under the direct or indirect control of 1,25(OH) 2 D 3 (refs 8 , 9 ). Finally, many diseases and illnesses in humans are associated with a poor vitamin D status, as measured by low serum levels of 25OHD. Therefore, one of the major clinical questions in the field is whether poor vitamin D status plays a causal role in the diseases and conditions associated with low 25OHD levels, such as cancer, impaired muscle strength and falls, and immune, metabolic or cardiovascular diseases. Furthermore, if the link is causal, the threshold serum level of 25OHD below which the risk of these diseases is increased must be identified 8 .

The potential skeletal and extra-skeletal target tissues and effects of the vitamin D endocrine system (vitamin D and vitamin D receptor) as based on preclinical and observational studies, Mendelian randomization studies and randomized controlled trials (RCTs). In vitro studies have identified many molecular and genetic targets of vitamin D action. Animal models have confirmed a variety of skeletal and extra-skeletal actions. Human observational data are largely in line with preclinical data. However, Mendelian randomization studies and RCTs have not confirmed such a widespread action profile in vitamin D-replete adults. Therefore, the health consequences of poor vitamin D status remain controversial. The strength of the relationship between the vitamin D endocrine system and health effects are indicated by the arrow thickness. FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.

Up to about a decade ago, there was tremendous uncertainty about vitamin D supplementation for the maintenance of adequate health levels. Large, randomized placebo-controlled trials with clinically important outcomes and/or surrogates had yet to be performed and only a few meta-analyses of randomized controlled trials (RCTs) were available. On the other hand, many observational studies had been conducted that were confounded by multiple variables. The Institute of Medicine (IOM) guidelines were developed to provide an answer based on the best available evidence at that time 10 . The IOM Committee established minimal dosing to maintain adequate serum levels of 25OHD in young and older individuals and established the tolerable upper limits of supplementation. The Committee also examined the totality of evidence relating vitamin D supplementation to numerous outcomes, and concluded that large randomized trials were needed to establish efficacy and safety. Other societies, such as the Endocrine Society 11 , and governmental organizations also generated a variety of guidelines 12 . The minimal serum level of 25OHD that was considered to provide vitamin D sufficiency varied from 30 nmol/l (UK Scientific Advisory Committee on Nutrition 13 ), to 50 nmol/l (IOM and many other governmental guidelines) 12 , 14 , 75 nmol/l (Endocrine Society and some other societies) 11 and even >100 nmol/l (refs 12 , 14 ). Of note, serum levels of >100 nmol/l are found in people living in Africa under conditions of sun exposure supposed to be similar to that of early humans.

In this Review, we summarize the results of recent (2017–2020) RCTs as well as Mendelian randomization studies, while not reviewing observational studies, which have been well-documented previously 9 . We have chosen these two study designs because they are both types of causal inference studies and can help provide insights into the role of vitamin D in the aetiology of common diseases. The reviewed studies do not provide evidence that vitamin D supplementation prevents negative health outcomes in vitamin D-replete adults. However, all these studies reveal new suggestions for potential effects of vitamin D supplementation. Note that throughout the text vitamin D refers to vitamin D 3 unless otherwise specified.

RCTs: 2017–2020

Many small-scale RCTs have been published over the past few years. In addition, several large studies have generated a wealth of new data (Table  1 ; Supplementary Box  1 ). The new major RCTs deal with more than 35,000 study participants who have a generally better health profile than participants in older studies. These studies used higher dosages than previous studies and the volunteers were mostly vitamin D-replete at baseline. These differences might explain why these large RCTs generated mostly null results in the intention-to-treat (ITT) analysis.

The largest trial to date is the VITAL study 15 that recruited more than 25,000 adults from 44 centres in the USA and evaluated daily doses (2,000 IU) of vitamin D for a mean duration of 5.3 years. The Vitamin D Assessment Study (ViDA study) 16 evaluated the effects of monthly high-dose vitamin D supplementation in more than 5,000 adults in New Zealand followed for a mean duration of 3.3 years. The primary aim of the D2d study of 2,423 US participants was to evaluate the effects of a daily dose of vitamin D (4,000 IU per day) for a mean duration of 2.5 years on the conversion of prediabetes to type 2 diabetes mellitus (T2DM) 17 . The DO-HEALTH study evaluated the effects of vitamin D (2,000 IU per day) in 2,157 older adults in Europe for a duration of 3 years 18 . The Calgary study was not really a megatrial, as it included only 311 Canadian adults and explored the effects on bone structure and quality and the safety of daily high-dose vitamin D (4,000 and 10,000 IU versus 400 IU) for 3 years 18 , 19 , 20 .

Mendelian randomization studies

Mendelian randomization is an established genetic epidemiological method, which can be used to test whether genetically decreased 25OHD levels are associated with increased risk of disease. To do this, Mendelian randomization uses single nucleotide polymorphisms (SNPs) that are associated with 25OHD levels in genome-wide association studies (GWAS) as instruments to infer 25OHD levels. Depending on their number, these SNPs can explain from 2% to 10% of the variance in 25OHD levels. This approach offers an alternative analytical technique able to reduce bias from confounding and reverse causation present in observational studies and re-estimates observations in a framework enabling causal inference (Supplementary Box  2 ). The very large number of Mendelian randomization studies of vitamin D have also generated mostly null results; however, they have been handicapped by the low power to predict decreased serum 25OHD concentrations.

Effects of vitamin D on health outcomes

Many observational studies suggest a link between low vitamin D status and T2DM 9 .

Evidence from RCTs

In the large D2d RCT of patients with prediabetes (Table  1 ), vitamin D supplementation only showed a non-significant trend to slow down the progression of prediabetes into T2DM. The study design intentionally included people with a high risk of progression to T2DM, who received vitamin D (4,000 IU per day). In the ITT analysis, the hazard ratio for the development of T2DM in the group receiving vitamin D was 0.88 (95% CI 0.75–1.04; P  = 0.12) compared with the placebo group. In a post hoc analysis, however, a significant effect was observed in individuals with a baseline BMI below 30 mg/m 2 , severe vitamin D deficiency at baseline, perfect adherence to treatment during the study or serum 25OHD above 100 nmol/l throughout the study 21 (Tables  2 , 3 ). Analysis of the combined data from the D2d trial and two other trials specifically designed and conducted to investigate the effectiveness of vitamin D supplementation in preventing T2DM showed that vitamin D supplementation (when compared with placebo) reduced the risk of developing T2DM from 23% to 13% (a 10% reduction) in persons with prediabetes not selected for vitamin D deficiency 22 . This finding is in line with two meta analyses published in 2020 dealing with eight 23 and seven 24 RCTs in people with prediabetes. These meta-analyses concluded that vitamin D supplementation decreased the risk to progress to T2DM by about 10%, especially when using doses above 1,000 IU per day and in participants without obesity. Participant-level meta-analysis of these trials might provide a better estimate of risk reduction and identify populations of patients with prediabetes who are likely to benefit the most from vitamin D supplementation.

Evidence from Mendelian randomization

Since 2015, seven large Mendelian randomization studies have investigated the causal effect of genetically altered 25OHD levels on risk of T2DM and related traits (Supplementary Box  3 ). These Mendelian randomization studies included very large numbers of participants and mostly recruited white individuals and Chinese individuals. One study 25 generated conflicting results, as part of the study using only two SNPs concluded that high predicted serum levels of 25OHD protected against T2DM (OR 0.86 of T2DM for a 25 nmol/l higher 25OHD concentration than that seen in the general population). However, in a slightly larger group of the same study that included two additional SNPs, the odds ratio became insignificant (Supplementary Box  3 ). All the other Mendelian randomization studies, including more than 500,000 volunteers, did not find a significant odds ratio for the relationship between predicted 25OHD and risk of T2DM.

Vitamin D and T2DM — summary

Although observational data have consistently confirmed lower serum 25OHD concentrations in patients with T2DM or the metabolic syndrome 9 , most Mendelian randomization studies have not supported these conclusions. Importantly, the large D2d RCT only showed a non-significant trend to slow down the progression of prediabetes into T2DM. In a small subgroup of individuals with overweight (rather than obesity) and prediabetes, supplementation provided some modest benefit, albeit lower than lifestyle modifications or metformin 26 . Furthermore, analysis of the combined results of the D2d trial and two other trials showed that vitamin D supplementation reduced the risk of developing T2DM in people with prediabetes not selected for vitamin D deficiency 22 . Additional studies or more in-depth analysis of the existing studies are needed to validate these findings. In summary, the evidence from large-scale Mendelian randomization studies and RCTs are convergent and do not support the use of vitamin D supplementation for the prevention of T2DM.

Strong preclinical data exist that link vitamin D with cell cycle control and cancer. Furthermore, many observational studies have associated poor vitamin D status with increased risk of cancer or poor prognosis 27 .

The largest RCT (VITAL) did not find an effect of daily vitamin D supplementation on invasive cancer incidence (HR 0.96, 95% CI 0.88–1.06) in US adults during a 5.3-year follow-up 15 . Further subanalysis (not statistically corrected for multiple comparisons) revealed a significant reduction in cancer risk in individuals with a normal BMI (<25 kg/m 2 ) and a trend for decreased cancer risk in African Americans. Baseline serum 25OHD concentrations did not influence cancer incidence or mortality but the number of participants with vitamin D deficiency at baseline (<50 nmol/l) was low (~10% of the total cohort) 28 . In the ViDA trial in New Zealand adults, monthly vitamin D supplementation did not modify cancer incidence (overall or specific types of cancer, excluding non-melanoma skin cancers) with an overall hazard ratio of 1.01 (95% CI 0.81–1.25) 16 .

Cancer mortality, as evaluated in a Cochrane systematic review 29 , was modestly decreased by vitamin D supplementation in four RCTs (44,492 participants), with a relative risk (RR) for cancer mortality of 0.88 (95% CI 0.78–0.98) in individuals receiving a mean daily dose of 1,146 IU (compared with no supplementation) during a mean follow-up of 6.3 years. Cancer mortality was also evaluated in several large RCTs (Supplementary Box  4 ). In the ITT analysis of the VITAL trial, a non-significant trend of reduction in total cancer mortality (HR 0.83, 95% CI 0.67–1.02) was observed in the vitamin D supplementation group. When excluding cancer deaths during the first year, or the first and second year after randomization, a significant reduction in cancer mortality was observed in the vitamin D supplementation group compared with no supplementation (HR 0.75, 95% CI 0.59–0.96). In a Kaplan–Meier plot, the cumulative increased risk of cancer mortality was visible from year 4 of follow-up onwards 28 . In the ViDA trial, however, the number of cancer deaths was not influenced by vitamin D supplementation (HR 0.97), even after exclusion of cancer deaths registered in the first year after randomization (HR 0.95) 16 . This discrepancy might be related to the short duration of follow-up. The ViDA trial lasted <4 years, whereas the effect of vitamin D supplementation in the VITAL study was only significant 4 years after randomization. An updated summary from the VITAL study 28 confirmed a small but significant effect on cancer death in vitamin D-supplemented individuals (HR 0.87, 95% CI 0.79–0.96; P  = 0.005). As the final serum concentration of 25OHD in the VITAL trial (~110 nmol/l) and the ViDA trial (~125 nmol/l or 50 ng/ml) were in the high normal range it is unlikely that higher doses would be more effective.

The Ovarian Cancer Association Consortium (10,065 patients with ovarian cancer, 21,654 control individuals) 30 found a 27% increase in the risk of epithelial ovarian cancer per 20 nmol/l decrease in genetically determined 25OHD serum concentration (OR 1.27, 95% CI 1.06–1.51). However, the results were not corroborated by another Mendelian randomization study 31 which also showed no evidence of an association between 25OHD and risk of colorectal, breast, prostate, lung and pancreatic cancer or neuroblastoma. Similar findings were reported in a separate study 32 in relation to total incident cancer and cancer subtypes such as breast, colorectal and lung cancer in 23,294 women. A null effect of genetically determined 25OHD on colorectal carcinoma was confirmed in men and women after including two additional SNPs 33 . Similarly, a large-scale two-sample Mendelian randomization study (122,977 patients with breast cancer and 79,148 patients with prostate cancer) did not show any effects of genetically predicted 25OHD concentrations on these cancers (Supplementary Box  5 ). Evidence from Mendelian randomization also refutes a link between 25OHD concentrations with risk of oesophageal adenocarcinoma 34 , melanoma and non-melanoma skin cancer 35 (Supplementary Box  5 ).

Vitamin D and cancer — summary

No effects of vitamin D supplementation on cancer risk were observed in the large VITAL and ViDA trials. In line with prior studies and Mendelian randomization results, it thus seems clear that vitamin D supplementation in vitamin D-replete adults does not change cancer risk. However, a subanalysis of the VITAL trial showed that vitamin D supplementation might have some minor benefits in individuals with a normal BMI, but this finding was not corrected for multiple end point analysis 15 . In addition, several independent trials have suggested, in post hoc analysis, potential benefits of vitamin D supplementation on cancer mortality, especially when the follow-up is longer than 4 years 28 (Supplementary Box  4 ). Therefore, a link between vitamin D status and cancer incidence or mortality cannot be excluded, but will be very difficult to verify. Small changes in vitamin D status are unlikely to affect cancer incidence based on several Mendelian randomization studies.

Cardiovascular events

Major cardiovascular events.

The results of any observational studies in humans are in line with preclinical data and have demonstrated a consistent association between low vitamin D status and increased risk of cardiovascular diseases, hypertension and cardiovascular events, including ischaemic cardiac events, cardiomyopathy, congestive heart failure, stroke and even cardiovascular mortality. In a meta-analysis of nearly 850,000 individuals, low serum 25OHD concentrations were associated with an increased risk of cardiovascular events (RR 1.43, comparing individuals with the lowest vitamin D status with individuals with a better vitamin D status) 36 .

Two large RCTs (VITAL and ViDA) were designed to include cardiovascular events as one of their primary end points 15 , 37 . During the 5.3 years of follow-up in the VITAL trial, the hazard ratio for the expanded composite end point of major cardiovascular events including coronary revascularization was 0.97 (95% CI 0.85–1.12) in the vitamin D supplementation group, compared with placebo. A similar hazard ratio was found for cardiovascular death (HR 1.11, 95% CI 0.88–1.40), or death from any cause. Exclusion of cardiovascular events or deaths during the first 2 years of follow-up did not change the overall results. Similarly, in the ViDA study, the primary outcome of major cardiovascular events was not influenced by monthly vitamin D supplementation over 3.3 years 37 . The adjusted hazard ratio for a combination of major cardiovascular events in the vitamin D supplementation group was 1.02 (95% CI 0.87–1.20) compared with placebo, and such null findings also applied for a large list of secondary end points (myocardial infarction, heart failure, stroke and hypertension, among others), or cardiovascular deaths. Findings were not dependent on the baseline serum 25OHD concentration or previous cardiovascular status. When the results of these two major trials (including together more than 30,000 participants) were combined with those of previous studies evaluating the potential effects of vitamin D supplementation, a similar general conclusion of no effect of vitamin D supplementation was reached. An analysis of 21 RCTs including more than 80,000 participants showed that major cardiovascular events were not influenced by vitamin D supplementation 38 . The hazard ratios for myocardial infarction, stroke or cardiovascular death were all close to 1 and the 95% confidence intervals included the null. The results are uniformly concordant despite variation in target groups, baseline vitamin D status and vitamin dosage or regimens. Furthermore, vitamin D supplementation of largely vitamin D-replete participants did not significantly reduce first or recurrent hospitalization rates for heart failure compared with no supplementation in the VITAL Heart Failure study (HR 0.93, 95% CI 0.78–1.11; non-significant).

To date, six Mendelian randomization studies have investigated the effect of genetically altered 25OHD levels on cardiovascular events and related outcomes (Supplementary Box  6 ). These studies evaluated the effects of genetically altered 25OHD concentrations (based on two to six SNPs) in more than a million European and Chinese adults and found no significant effects on any cardiovascular event or mortality 39 , 40 , 41 , 42 . A 2020 study 43 , using a substantially larger number of SNPs (242 SNPs associated with 25OHD levels adjusted for BMI, and 232 SNPs associated to 25OHD levels without adjustment for BMI), showed a non-significant odds ratio for coronary artery disease in people with genetically lowered 25OHD levels of 0.98 (95% CI −0.06–0.02) compared with those with normal or high 25OHD level in a sample of 417,580 white British individuals from the UK Biobank.

Hypertension

Observational data also link hypertension with low vitamin D status but this apparent association could have been due to many other confounding factors (for example, related to lifestyle). Causal inference studies, such as RCTs and Mendelian randomization studies, should provide insights that reduce the risk of confounding. The data on blood pressure effects of vitamin D supplementation in the VITAL trial (VITAL Hypertension) are not yet available (NCT01653678; as of October 2021). The ViDA trial, however, studied extensively the effects of vitamin D supplementation in a subgroup of participants using a state of the art invasive technology (suprasystolic oscillometry) 44 . After a mean follow-up of 1.1 years, vitamin D supplementation generated null effects. In participants with vitamin D deficiency at baseline (<50 nmol/l), brachial systolic and diastolic blood pressure decreased by 3 mmHg to 5 mmHg (not statistically significant); however, aortic systolic blood pressure (−7.5 mmHg, P  = 0.03) and other parameters (augmentation index, pulse wave velocity, peak reservoir pressure and backward pressure amplitude) improved on correction of baseline vitamin D deficiency 44 . The DO-HEALTH trial in European older adults did not find any effect of vitamin D supplementation on systolic or diastolic blood pressure 18 .

The evidence from Mendelian randomization studies on the effects of predicted serum 25OHD levels on hypertension, systolic and diastolic blood pressure is consistent across five large studies, and overall does not support any of these outcomes (Supplementary Box  6 ). Specifically, a study in 146,581 European individuals 45 , using two SNPs in the two vitamin D synthesis genes showed a marginal decrease in diastolic blood pressure of 0.29 mmHg per 10% increase in 25OHD level. There was no significant effect on systolic blood pressure, and the Mendelian randomization odds ratio for hypertension was 0.92 per 10% increase in 25OHD level (95% CI 0.87–0.97). A 2019 study, using six 25OHD-related SNPs 46 , failed to show any evidence of a causal association between 25OHD levels and systolic blood pressure, diastolic blood pressure or hypertension. Finally, using up to 252 SNPs as instruments for estimating levels of 25OHD, the most recent Mendelian randomization study in this field published in 2020 (ref. 43 ) showed a marginal effect of 25OHD levels on risk of hypertension (Mendelian randomization OR 0.97 per unit increase in rank-based inverse normal-transformed 25OHD level, 95% CI 0.94–1.0) in 417,580 White British individuals from UK Biobank. After adjusting for BMI, this association became non-significant. In non-European populations, Mendelian randomization results thus far are consistent with those in Europeans. Specifically, a Mendelian randomization study 47 on 2,591 Korean adults failed to show any causal effect of 25OHD levels on systolic blood pressure, diastolic blood pressure or risk of hypertension. A Mendelian randomization study 48 in 10,655 Chinese individuals showed equally a null effect of 25OHD on systolic and diastolic blood pressure.

Vitamin D and cardiovascular disease — summary

In summary, convergent evidence from Mendelian randomization studies and RCTs demonstrates that vitamin D supplementation does not decrease the risk of cardiovascular disease. The link between vitamin D status and a variety of cardiovascular events or risk factors was tested previously in mostly small-scale studies. The 2017–2020 megatrials (Table  1 ) and Mendelian randomization studies clearly confirm the lack of benefit of vitamin D supplementation in vitamin D-replete adults. This conclusion most likely also applies to people with vitamin D deficiency as based on subgroup analyses of the VITAL and ViDA trials. Unfortunately, both studies recruited very few participants with severe vitamin D deficiency. A dedicated detailed analysis of the ViDA trial suggested some modest benefits on central (but not peripheral) blood pressure, but the implications of this observations are limited in view of the small scale of this ViDA substudy 44 .

Musculoskeletal effects and falls

Vitamin d and bone health.

Severe vitamin D deficiency is the leading cause of nutritional rickets 1 . The importance of more modest vitamin D deficiency than seen in nutritional rickets for the skeleton of adults and older adults is disputed. Supplementation with vitamin D only is unlikely to be able to reduce fracture risk in older adults; 2 , 49 however, a combination of calcium and vitamin D supplementation can modestly reduce hip and non-vertebral fracture incidence in this population 2 , 50 , 51 . This conclusion is in line with a 2019 overview and meta-analysis on vitamin D and calcium supplementation and fractures 52 , which concluded from observational data (39,0141 participants) that a 25 nmol/l increase in the serum 25OHD concentration reduces the risk of any fracture or hip fracture by 7% and 20%, respectively (both statistically significant). A similar conclusion was reached in another meta-analysis 53 .

Several large RCTs have generated new results regarding the effects of vitamin D supplementation on the adult skeleton. The VITAL Bone Health study is an ancillary study of the VITAL trial, including a subcohort of 771 participants (men aged ≥50 years and women aged ≥55 years; not taking bone active medications) evaluated at baseline and after 2 years (89% retention), and aims to evaluate the effects of vitamin D on bone structure and architecture. Supplemental vitamin D (compared with placebo) had no effect on 2-year changes in areal bone mineral density (BMD) at the spine, femoral neck, total hip or whole body, or on measures of bone structure. This conclusion remained valid in a subgroup analysis, including individuals with the lowest vitamin D status (as measured by total 25OHD) at baseline. New technology allows the direct measurement of free (non-protein-bound) 25OHD as an alternative strategy to define vitamin D status 54 . In participants of the VITAL trial with the lowest directly measured free 25OHD concentrations, vitamin D supplementation generated a slight increase in spine areal BMD (0.75% in the vitamin D group versus 0% in the placebo group; P  = 0.043) and attenuation in loss of total hip areal BMD (−0.42% in the vitamin D group versus −0.98% in the placebo group; P  = 0.044), yet such results might not survive multiple testing correction 55 . The ViDA trial did not find an effect of monthly vitamin D supplementation on the incidence of non-vertebral fractures (RR 1.19, 95% CI 0.94–1.50; non-significant) compared with no supplementation 56 . In participants with baseline vitamin D deficiency (<50 nmol/l), the HR for non-vertebral fractures was 0.94 compared with that in vitamin D-replete participants (95% CI 0.58–1.52). This conclusion was confirmed in the DO-HEALTH trial 18 .

A well-validated risk factor for fracture, such as BMD, might provide more information on the possible effects of vitamin D supplementation. In a subgroup of participants in the ViDA trial ( n  = 452) 57 , the loss of BMD during follow-up was about 0.5% lower in the vitamin D group compared with the control group. This difference was statistically significant for the femoral neck and total hip but not for the lumbar spine or total body BMD. However, in the small ( n  = 30) group of participants with a baseline serum 25OHD concentration of <30 nmol/l, BMD of the lumbar spine increased significantly by 3.1% compared with that in controls. These data indicate that correction of severe vitamin D deficiency might improve bone density, but not when given to vitamin D-replete people. A smaller RCT in Scottish adults confirmed that vitamin D supplementation (daily dose of 1,000 IU) increased BMD in individuals with a baseline serum 25OHD concentration of <30 nmol/l but not in people with a better vitamin D status at baseline 58 . These results are also in line with a RCT in US adults randomized to receive placebo, 800 IU of vitamin D or high-dose vitamin D (50,000 IU per day for 2 weeks followed by 50,000 IU per 2 weeks for 1 year), which concluded that neither low-dose nor high-dose vitamin D improved bone density in participants with a mean baseline serum 25OHD of 50 nmol/l (ref. 59 ). The same conclusion was drawn from a RCT of vitamin D supplementation in Black American women, as increasing baseline serum 25OHD concentrations of 55 nmol/l to concentrations above 75 nmol/l by vitamin D supplementation did not change the rate of bone loss during 3 years of follow-up 60 . Similarly, Finnish children below the age of 2 years who received 1,200 IU of vitamin D per day for ~2 years did not have better bone density (measured by peripheral quantitative CT (pQCT)) compared with children receiving the standard dose of 400 IU per day 61 . This finding is not totally unexpected, as the baseline serum 25OHD concentration was higher (80 nmol/l) than expected in this study due to the introduction of vitamin D supplementation of food in Finland.

The Calgary study was designed to evaluate the effect of long-term high-dose vitamin D on bone mass and quality. A daily dose of 400 IU, 4,000 IU or 10,000 IU of vitamin D for 3 years in Canadian adults did not increase BMD, but rather slightly decreased BMD, as measured by the best available methodology (high-resolution pQCT) 19 . Indeed, BMD at the radius and tibia significantly decreased by 3.5% and 1.7 %, respectively in the 10,000 IU per day group compared with the 400 IU per day group, whereas the decrease at both sites was not statistically significant in the 4,000 IU per day group compared with the 400 IU per day group. This study does demonstrate that vitamin D supplementation in vitamin D-replete adults (baseline serum 25OHD concentration of about 75 nmol/l) does not improve bone mass or quality. Moreover, very high doses might even have negative effects, as a small percentage of participants developed hypercalciuria or hypercalcaemia, which quickly resolved after adjustment of dosing. Of course, this finding might imply that regular follow-up is desirable when using such dosages 19 , 62 .

Many Mendelian randomization studies showed no causal effect of vitamin D status on a variety of bone traits in populations of European and non-European ancestry. An early Mendelian randomization study 63 found that genetically predicted one standard deviation increase in 25OHD was not associated with increased femoral neck BMD, lumbar spine BMD or estimated BMD change. Similar results were observed in relation to total body BMD 64 . A more powered Mendelian randomization analysis 65 (37,857 patients with fracture and 227,116 control individuals) also did not support a causal effect of 25OHD on fracture risk. However, a Mendelian randomization study in children 66 showed that haplotypes associating with low 25OHD were associated with low pQCT parameters (BMD, cross-sectional area and cortical density) in 2-year-old children. Finally, evidence from Mendelian randomization studies 67 refutes causal associations between predicted serum 25OHD concentrations and either BMD or bone metabolism markers found in 1,824 postmenopausal Chinese women (Supplementary Box  6 ).

Vitamin D and muscle function or falls

In mice, total deletion of VDR generates structural and functional consequences for skeletal and cardiac muscle 9 . Furthermore, humans with congenital CYP27B1 mutations or patients with severe combined deficiency of 25OHD and 1,25(OH) 2 D due to chronic renal failure develop severe muscle weakness that rapidly improves after treatment with 1,25(OH) 2 D 9 . Several meta-analyses have come to different conclusions regarding the consequences of vitamin D supplementation on muscle strength, with both positive 68 and null effects 69 . In addition, ample literature is available supporting a link between poor vitamin D status and increased risk of falls, but hesitance remains regarding causality 70 . High boluses of vitamin D, however, might transiently increase the risk of falls in older women 71 . High-dose continuous vitamin D supplementation to increase serum 25OHD concentrations to above 112 nmol/l might also induce an increased risk of falls in older men and women 72 , 73 , 74 . However, the large ViDA trial showed that monthly 100,000 IU doses of vitamin D did not reduce or increase the risk of falls. The hazard ratio for falls was 0.99 (95% CI 0.92–1.07) in the overall cohort who were treated with vitamin D compared with those receiving placebo and 1.07 (95% CI 0.91–1.25) in vitamin D-supplemented participants with baseline serum 25OHD concentrations below 50 nmol/l (ref. 56 ). The VITAL trial also looked at the effects of daily vitamin D supplementation on physical disability and falls in the SRURDY study 75 and found a non-significant (OR 0.97, 95% CI 0.91–1.25) effect of vitamin D supplementation on the risk of two falls or injurious falls requiring support from a doctor or hospital 76 . In further exploratory analysis, the same conclusion was reached when the baseline serum concentration of 25OHD was taken into account.

To our knowledge, no Mendelian randomization studies so far have examined the causal association between genetically estimated 25OHD levels and muscle traits or falls.

Vitamin D and musculoskeletal effects — summary

Of note, the 2017–2020 megatrials did not address the question of vitamin D supplementation and rickets, as there is consensus in all vitamin D guidelines from the past decade that serum 25OHD concentrations below 30 nmol/l are a risk factor for rickets or osteomalacia 12 . A daily vitamin D dose of 400 IU can prevent rickets and osteomalacia and increase serum concentrations of 25OHD well above 30 nmol/l (12 ng/ml) 77 . However, ~7% of the world population lives with severe vitamin D deficiency, with this percentage being much higher in the Middle East, North Africa and many countries in Asia 78 .

The role of vitamin D in the skeleton of adults and older adults is more disputed. The 2017–2020 megatrials were not designed to primarily evaluate the effect of vitamin D supplementation on fracture risk in older adults. These trials 15 , 16 recruited mostly vitamin D-replete adults with a fairly low risk of fracture. Even the DO-HEALTH trial in older, less vitamin D-replete, adults (compared with the other megatrials) did not find an effect on non-vertebral fractures 18 . However, the ViDA trial demonstrated that correction of severe vitamin D deficiency (<30 nmol/l) prevents age-related bone loss in adults. By contrast, the 2017–2020 megatrials demonstrate that vitamin D supplementation in vitamin D-replete adults does not improve bone mass, density or quality 16 .

Taken together, the findings indicate that supplementation with vitamin D only does not have a beneficial effect on fracture risk in vitamin D-replete, mostly white adults. However, combined calcium and vitamin D supplementation in older adults, especially those with poor vitamin D status and poor calcium intake, might decrease the risk of hip fractures and other major fractures by about 20% 51 . Therefore, most recent guidelines recommend a daily vitamin D supplement of about 800 IU of vitamin D combined with a good calcium intake (above 1,000 mg per day) in all older adults with a high risk or documented vitamin D deficiency. Of note, the Calgary study demonstrated that high daily doses of vitamin D (4,000 and especially 10,000 IU per day) might decrease BMD and bone quality 19 , 20 . Therefore, the optimal dose in vitamin D-deficient older adults should be at least 800 IU per day but not more than 4,000 IU per day.

Meta-analyses of older studies suggested a modest decrease in the risk of falls in older, mostly vitamin D-deficient, adults 79 . However, the ViDA trial did not confirm this finding as vitamin D supplementation did not change the risk of falls. The New Zealand population was younger and had a better vitamin D status than the participants in the older studies. There might also be a U-shaped relationship as very high vitamin status, especially due to high bolus doses, might increase the risk of falls 72 , 73 , 74 .

Lung function and respiratory effects

Vitamin d and respiratory infections or lung function.

The lung is increasingly recognized as an important target tissue for vitamin D. Observational data link poor vitamin D status with several inflammatory lung diseases or impaired lung function 80 , 81 , 82 . The most recent analysis published in 2019 (ref. 83 ) evaluated 10,933 participants in 25 RCTs and found a significant overall reduction in acute respiratory infections following vitamin D supplementation (OR 0.88, 95% CI 0.81–0.96) compared with no supplementation. The number needed to treat for benefit was 33. Subgroup analysis revealed that the greatest benefits were found in people with severe vitamin D deficiency (<25 nmol/l) at baseline (OR 0.58, 95% CI 0.40–0.82). Subgroup analysis revealed that intermittent (monthly or less frequent) doses of vitamin D did not generate protection, whereas daily or weekly vitamin D supplementation was more effective for preventing acute respiratory infections (OR 0.81, 95% CI 0.072–0.91). In the ViDA trial, however, no effects of vitamin D supplementation were found on acute respiratory infections in older adults 84 . This finding is not a total surprise as the lack of effects might be due to the intermittent dosing and/or adequate vitamin D status at baseline, and therefore might not contradict the findings of the 2019 meta-analysis 83 . In addition, the European DO-HEALTH trial did not show an effect on infections in general nor on upper respiratory infections 18 .

Several small-scale studies (eight RCTs) did not find an improvement in lung function (as measured in terms of forced expiratory volume in 1 s (FEV1)) in patients with chronic obstructive pulmonary disease (COPD) who were randomized to receive vitamin D supplementation 85 . A substudy of the ViDA trial, however, evaluated the effects of monthly vitamin D supplementation 86 in 442 adults treated for 1.1 years. Overall, in the ITT analysis, no significant effects were observed on FEV1. However, subgroup analysis revealed some beneficial effects, especially in subjects with existing lung problems such as asthma, COPD or a history of smoking (Table  2 ). To date, no Mendelian randomization studies have been performed that examined 25OHD levels, COPD and lung function.

Vitamin D and COVID-19

In view of the enormous health implications of the coronavirus disease 19 (COVID-19) pandemic caused by the worldwide spread of severe acute respiratory syndrome coronavirus 2, a possible link with poor vitamin D status and the risk or severity of COVID-19 has received great attention. Seven studies so far compared serum 25OHD concentrations in patients with COVID-19 compared with individuals without COVID-19 (ref. 87 ) and found a lower level (mean difference of about 12 nmol/l) in patients with COVID-19; however, in many studies the sampling did not take place at the same time in both groups. In addition, these studies were unable to control for confounding factors, a major problem due to the large number of similarities in the risk factors for vitamin D deficiency and COVID-19. About 31 studies looked at a possible link between vitamin D status and severity of the outcome of COVID-19. Lower serum concentrations of 25OHD were associated with greater mortality, greater need for intensive care treatment or increased severity of illness in general compared with better vitamin D status. However, this finding was based on observational studies. One placebo-controlled intervention study using a bolus dose of vitamin D (200,000 IU) did not reveal a beneficial effect in patients hospitalized with COVID-19 with a mean baseline 25OHD concentration of 50 nmol/l (ref. 88 ). However, one pilot study (which was not placebo-controlled) showed a marked reduction in the need for intensive care treatment in patients hospitalized for COVID-19 and treated with a high dose of 25OHD (calcifediol) at the time of admission 89 . Therefore, the link between vitamin D status and COVID-19 is unsettled so far, but many trials are ongoing that might clarify this question.

In 2021, a Mendelian randomization study assessed the causal role of serum 25OHD levels on COVID-19 susceptibility and disease severity 90 . Using data from 11,181 patients with COVID-19 and 116,456 control individuals from the Host Genetics Initiative, and six vitamin D SNPs that explain 2.5% of the variance in serum 25OHD levels, this study did not show any association between genetically decreased 25OHD and COVID-19 susceptibility or severity. These results were confirmed in a separate Mendelian randomization study using 81 25OHD SNPs that explain 4.3% of the variance in serum 25OHD levels, which also showed no effect of genetically determined 25OHD levels on risk of COVID-19-related hospitalization 91 .

Vitamin D and asthma

Research investigating the potential effects of vitamin D status on asthma has largely focused on a possible link between prenatal or maternal vitamin D status and wheezing or asthma in the offspring. A meta-analysis of four prospective studies and three RCTs concluded that vitamin D intake (~800 IU per day) by women during pregnancy is inversely related to wheezing or asthma in their offspring during up to 3 years of follow-up 92 . However, a longer follow-up did not confirm this conclusion: vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk of asthma 93 . Two Mendelian randomization studies have investigated the causal association between vitamin D and asthma. A large study (n > 160,000 children and adults) 94 found odds ratios of 1.03 (95% CI 0.90–1.19) for asthma and 0.95 (95% CI 0.69–1.31) for childhood-onset asthma per standard deviation of log-transformed decrease in serum 25OHD (Supplementary Box  6 ). These findings suggest that vitamin D levels probably do not have clinically relevant effects on the risk of asthma.

Vitamin D and respiratory effects — summary

The vitamin D endocrine system influences all cells and most cytokines of the immune system 9 . The innate immune system is stimulated by 1,25(OH) 2 D and this is in line with a decreased risk of upper respiratory infections with vitamin D supplementation in individuals with vitamin D deficiency 83 . Meta-analysis of intervention studies suggested a benefit of vitamin D supplementation of participants with severe vitamin D deficiency and COPD, asthma, or similar lung diseases, and on reducing the risk of acute upper respiratory infections in severely deficient individuals 83 . However, where tested, these findings have not been supported by Mendelian randomization studies 90 . According to the results of the LUNG-ViDA trial, vitamin D supplementation might modestly improve expiratory lung function 85 . If confirmed, such data would imply that the lung is a clinically relevant target issue for vitamin D. Of note, currently there are insufficient RCTs to evaluate the potential benefit of vitamin D or calcifediol supplementation on the risk or severity of COVID-19.

Autoimmune diseases

Observational studies have, in line with preclinical data, made a link between poor vitamin D status and increased risk of infection or risk of autoimmune diseases (such as multiple sclerosis (MS), inflammatory bowel diseases or type 1 diabetes mellitus) 95 . RCTs in humans dealing with infections have mainly focused on upper respiratory infections and an overview is presented in the previous section. Unfortunately, no major RCTs have addressed the possible primary or secondary prevention of the major human autoimmune diseases. So far, the 2017–2020 megatrials (Table  1 ) have not shown results related to autoimmune diseases.

Currently, strong evidence exists that supports a causal association between genetically low serum 25OHD levels and increased risk of MS 96 , 97 , 98 , 99 . The most recent Mendelian randomization study from 2020 evaluated data from The International Multiple Sclerosis Genetics Consortium discovery phase GWAS (14,802 MS and 26,703 controls from the USA, Europe, Australia and some Asian countries) 97 using six SNPs associated with serum levels of 25OHD and found that each genetically determined unit increase in log-transformed 25(OH)D 3 was associated with an odds ratio for MS of 0.57 (95% CI 0.41–0.81; P  = 0.001) (Table  4 ). This effect applies to adult-onset and childhood-onset MS.

Earlier Mendelian randomization evidence 100 did not support causality of predicted serum 25OHD levels in systemic lupus erythematosus or rheumatoid arthritis. Consistent null effects on rheumatoid arthritis were found in a 2020 Mendelian randomization study in participants from the UK Biobank, using ~220 vitamin D-associated SNPs as instruments 43 . Null effects of predicted serum 25OHD levels were also shown in Mendelian randomization studies on Crohn’s disease (odds ratio for 10 nmol/l higher 25OHD of 1.04, 95% CI 0.93–1.16) and ulcerative colitis (OR 1.13, 95% CI 1.06–1.21) 101 . Similarly, no effect on ulcerative colitis was found in participants from the UK Biobank 43 . The UK Biobank study also did not support a causal role of vitamin D on allergic rhinitis. Finally, Mendelian randomization 94 does not support causal effects of 25OHD on atopic dermatitis. A 2021 Mendelian randomization study on type 1 diabetes mellitus did not support causal effects of genetically lowered 25OHD levels on the risk of this disease 102 .

In summary, the adaptive immune system is downregulated by 1,25(OH) 2 D and therefore vitamin D deficiency might predispose to autoimmune diseases 9 . Observational studies have suggested this effect might apply to humans, but too few intervention studies have been conducted to evaluate this statement. Four independent Mendelian randomization studies agree, however, that individuals with genetically driven lower serum 25OHD concentrations have an increased risk of developing MS, either during adolescence or adulthood (Table  4 ).

Intervention studies as summarized in a Cochrane review from 2016 (ref. 103 ) dealing with 22 RCTs including 3,725 pregnant women, concluded that vitamin D supplementation significantly reduced the risk of pre-eclampsia (RR 0.48), gestational diabetes mellitus (RR 0.51) and low birthweight (<2,500 g; RR 0.55) compared with no supplementation. An update of these data 104 largely confirmed these observations. However, a large RCT in pregnant Bangladeshi women with severe vitamin D deficiency (baseline mean serum 25OHD about 25 nmol/l) supplemented from week 17–24 onwards with placebo or vitamin D (three groups receiving 4,200, 16,800 or 28,000 IU per week) until birth did not find a beneficial effect on fetal or neonatal parameters of length, weight or head circumference, either at birth or at one year of age ( n  = 1,164 infants) 105 .

To date only one Mendelian randomization study 106 has examined the causal effect of predicted serum 25OHD levels on gestational hypertension and pre-eclampsia. Overall, the evidence was weak supporting a causal effect of vitamin D status on gestational hypertension (OR 0.90, 95% CI 0.78–1.03) or pre-eclampsia (OR 0.98, 95% CI: 0.89–1.07) per 10% decrease in serum 25OHD (Supplementary Box  5 ).

In summary, pregnant women more frequently have a poor vitamin D status than non-pregnant women of the same age but the absolute and relative values vary from country to country. Several meta-analyses have suggested that vitamin D supplementation might modestly decrease maternal morbidity and improve the health of their offspring 103 , 104 . However, a 2018 large RCT in Bangladeshi women with severe vitamin D deficiency did not confirm this observation 105 . Therefore, the effects of poor vitamin D status during pregnancy on pregnancy outcomes for mother and infant remains unsettled.

Patients in intensive care

Patients with severe acute illness requiring intensive care frequently have low serum concentrations of 25OHD and this poor vitamin D status is linked with increased morbidity and mortality 107 , 108 . Two major RCTs so far in patients in intensive care units (ICU) have generated conflicting results. In the VITdAL-ICU trial, patients in the ICU were randomized to either placebo ( n  = 243) or high-dose oral vitamin D ( n  = 249) (starting dose 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months). Mean baseline serum 25OHD concentrations were low (33 nmol/l) and increased to ~82 nmol/l at day 3. Length of stay in the ICU or hospital, mortality in the ICU, in-hospital mortality and mortality at 6 months did not improve with the intervention. In a predefined subgroup with severe vitamin D deficiency who received the intervention (<30 nmol/l), hospital mortality (HR 0.56, 95% CI, 0.35–0.90) and 6-month mortality (HR 0.60, 95% CI, 0.39–0.93) were significantly decreased compared with patients with severe vitamin D deficiency who received placebo 107 . In the much larger Amrein ICU trial 108 , 1,059 patients in the ICU with vitamin D deficiency (<50 nmol/l) received either placebo or a single oral high dose of vitamin D (540,000 IU). This dose increased mean serum 25OHD concentration at day 3 to a mean concentration of 117 ± 58 nmol/l in comparison with the control group (mean concentration 28 ± 14 nmol/ml). The primary end point (90-day mortality) and other non-fatal outcomes were similar in the two groups. Although all patients in both studies were admitted to ICUs, the US patients in the VITdAL-ICU trial were probably less sick than those in the Amrein trial 107 as indicated by the percentage of patients requiring mechanical ventilation (32% in the US trial).

Effects of vitamin D supplementation on safety outcomes

In all vitamin D supplementation RCTs, some safety end points have been reported in addition to mortality (see next section). No effects were found on serum calcium or calciuria unless very high doses were used, such as 4,000–10,000 IU per day in the Calgary study. Even in these circumstances, hypercalcaemia was infrequent and occurred transiently after changes in treatment modality 19 , 62 . A modestly increased risk of kidney stones was observed in the WHI trial 109 , but this effect was not seen in the more recent 2017–2020 megatrials (that is, ViDA, VITAL and D2d; Table  1 ). Furthermore, no changes in kidney function were found in these large trials. Skeletal consequences were either null effects, slight (beneficial) increases in BMD in subgroups with poor vitamin D status at baseline, or a modest but significant decrease in BMD during high-dose (10,000 IU per day) therapy in the Calgary study 19 . An increased risk of fractures in patients receiving high intermittent bolus doses has been reported 71 , 110 . Similarly, an increased risk of falls has been reported when either high intermittent doses 71 or high continuous doses were used 72 , 73 . Importantly, the 2017–2020 megatrials (that is, ViDA, VITAL and D2d), with detailed evaluation of about 30,000 participants for 2–5 years, did not discover notable adverse effects. These findings indicate that a daily dose (or dose equivalent) of 2,000–4,000 IU can be considered as safe in an adult (even vitamin D-replete) population. High-dose vitamin D also did not modify arterial calcifications during a 3-year follow up in the Calgary study 111 .

Effects of vitamin D supplementation on mortality

Observational data have repeatedly linked poor vitamin D status with increased mortality. This effect was extensively documented in several NHANES studies based on representative samples of the US population and confirmed after validation of serum 25OHD concentrations according to standards generated by the US National Institute of Standards and Technology 112 . To decrease the possible effect of reverse causation, people who died within the first 3 years after 25OHD measurements were excluded from the analysis; however, the same association between poor vitamin D status and increased mortality remained 112 . Using a combination of several European prospective studies, mortality was also higher in the population with the poorest vitamin D status compared with the vitamin D-replete population 113 . A 2019 large long-term (>10 years) Finnish study concluded that people with the highest tertile of 25OHD concentrations (>50 nmol/l) had a mortality odds ratio of 0.77 (95% CI 0.71–0.84) compared with people with the lowest tertile of 25OHD concentrations, even in a multivariate model with correction of multiple co-variables 114 .

As nearly all long-term vitamin D supplementation trials include data on mortality, several meta-analyses have shown the effects of vitamin D supplementation on mortality. Extensive meta-analyses published in 2014 showed a modest decrease in overall mortality in participants randomized to vitamin D supplementation; based on 22 RCTs, the risk of death decreased by 11% 36 . A 2014 Cochrane analysis 29 evaluated 56 RCTs including 95,286 participants (mostly healthy women older than 70 years) with a mean follow-up of 4.4 years. Vitamin D supplementation significantly reduced all-cause mortality (RR 0.94, 95% CI 0.91–0.98; P  = 0.002) compared with no supplementation. This finding implies that vitamin D supplementation of 150 women for 5 years prevented one additional death. Vitamin D supplementation also decreased cancer mortality (RR 0.88, 95% CI 0.78–0.98; P  = 0.02) compared with no supplementation 29 .

In the 2017–2020 megatrials (that is, VITAL, ViDA and D2d), overall mortality was much lower than shown in the previous meta-analyses 29 , 36 and did not show an effect of vitamin D supplementation on overall mortality 15 . A new meta-analysis of 52 RCTs including a total of 75,454 participants concluded that vitamin D (either vitamin D 3 or D 2 ) supplementation did not change mortality (RR 0.98, 95% CI 0.95–1.02) compared with no supplementation 115 . A subanalysis, however, found that vitamin D 3 (instead of D 2 ) supplementation trials tended to reduce mortality (RR 0.95, 95% CI 1.90–1.00; P  = 0.06), whereas this was not the case for vitamin D 2 supplementation trials. These new findings conflict with the 2014 reports 112 . The difference could be partly because the 2019 meta-analysis did not include ten RCTs including ~50,000 participants using a combination of vitamin D and calcium supplementation. However, the 2019 meta-analysis did include two megatrials (VITAL and ViDA) that evaluated the effects of vitamin D supplementation in a younger population of mostly vitamin D-replete participants 115 .

In a large-scale population Mendelian randomization study (10,349 deaths in 95,766 total participants) 116 , the odds ratios for a genetically determined lower 25OHD concentration was 1.30 (95% CI 1.05–1.61) for all-cause mortality, 0.77 (95% CI 0.55–1.08) for cardiovascular mortality, 1.43 (95% CI 1.02–1.99) for cancer mortality and 1.44 (95% CI 1.01–2.04) for other types of mortality. Similar point estimates and effect sizes, whose 95% confidence intervals included the null, were found for all-cause mortality in two follow-up Mendelian randomization studies 46 , 117 . Nevertheless, both studies may have been underpowered to detect existing causal associations. Finally, evidence from Mendelian randomization 118 did not support an association between 25OHD concentrations and cancer mortality in a sample of 6,998 deaths from cancer. These data provide some evidence that genetically lowered vitamin D levels might increase overall mortality risks, but the results have not been consistent across studies, or across causes of mortality.

If vitamin D supplementation exerts beneficial effects on extra-skeletal health outcomes and major diseases, then it is likely to have some effects on mortality, especially in older adults with poor vitamin D status. Large meta-analyses dealing mostly with women older than 70 years 29 , 36 showed a 6–11% reduction in mortality; however, adding the newest 2017–2020 megatrials eliminated this effect, possible because these new trials recruited a younger population.

Discordance between studies

Preclinical data are mostly in line with the very large number of observational studies linking very poor vitamin D status with skeletal and extra-skeletal health effects (Fig.  1 ). However, Mendelian randomization studies and the majority of RCTs do not confirm the causality of these associations. Several possible reasons exist for this discrepancy. Most importantly, serum 25OHD levels are a highly confounded variable. Specifically, serum 25OHD levels are affected by a host of health behaviours, the presence of obesity, socioeconomic status and education levels. Although most observational studies have attempted to control for such confounding through multivariable adjustment, such approaches depend upon the degree of accuracy of measurement of the confounders, knowledge that such confounding takes place, and most often that the nature of the confounding relationship (linear versus nonlinear) is known. Furthermore, statistical adjustment for confounding variables can only be accomplished if the confounding variables are known.

The concordance between 25OHD Mendelian randomization studies and RCTs is striking and suggests that Mendelian randomization might be a more relevant way to begin to understand the effect of 25OHD levels on risk of disease than observational studies. Perhaps the vitamin D endocrine system only has a role in these extra-skeletal effects in people with prolonged and very severe vitamin D deficiency. Studies in countries or population groups with severe vitamin D deficiency who need improved vitamin D status anyway might be the ideal approach to better understand the effect of vitamin D supplementation in individuals with severe vitamin D deficiency. Most RCTs and Mendelian randomization studies have been undertaken in individuals from the general population in which the rates of severe vitamin D deficiency are low.

Of note, the available Mendelian randomization studies were not able to predict large variations in serum 25OHD concentrations (usually only about 5% difference or less). However, this low degree of variance would affect the statistical power of a study but not introduce bias. New techniques will soon enable us to use a much larger number of SNPs than used in current studies (usually based on less than six SNPs), thereby allowing much larger variations in serum 25OHD concentrations to be predicted. Most RCTs did not last longer than 3–5 years. In such short-term scenarios, answering the question of causality is extremely difficult. This fact implies that only very long-term improvements in vitamin D status might generate beneficial effects. However, Mendelian randomization studies provide estimates of the effect of a lifetime of genetically lowered vitamin D levels and such Mendelian randomization studies have generally produced null findings.

Reverse causality remains a valid rationale to explain the discordance between observational and intervention studies. The most plausible hypothesis states that individuals with any health problems are less likely to regularly engage in outdoor activity and less exposure to sunlight results in lower vitamin D status. Another mechanism of reverse causality might be that the activity of hepatic 25-hydroxylase is decreased in many major diseases and this decrease could cause low serum 25OHD concentrations. Indeed, data in mice demonstrate that diet-induced obesity, type 1 diabetes mellitus or T2DM, fasting and exposure to glucocorticoids substantially decrease the gene and protein expression of CYP2R1, thereby decreasing the overall 25-hydroxylase activity 119 , 120 , 121 . This finding implies that decreased 25OHD concentrations are the consequence of disease, rather than involved in the origin of these metabolic diseases. Of course, these data from mice need confirmation in humans. Finally, many diseases other than those described in this Review (including brain-related diseases) are linked with poor vitamin D status; however, causality is doubtful without adequate Mendelian randomization studies or RCTs.

Future Mendelian randomization studies

Improved understanding of the genetic determinants of 25OHD has helped re-assess the role of vitamin D in the aetiology of complex diseases through Mendelian randomization. Taken together, the evidence from over 60 Mendelian randomization studies published to date assessing the role vitamin D does not support a causal role for the large majority of studied outcomes. Despite this null data, in the few cases where the evidence from Mendelian randomization supported a causal role of vitamin D status, such as in the example of MS, these results had important clinical implications. For instance, clinical care guidelines for the use of vitamin D in preventing MS in those at risk were published by the MS Society of Canada 122 .

The earlier Mendelian randomization studies used, as instruments for 25OHD levels, SNPs within the four genes related to 25OHD synthesis and metabolism ( DHCR7 , CYP2R1 , GC and CYP24A1 ), which together explained 2.4% of the variance in 25OHD levels 123 . Later Mendelian randomization studies combined the aforementioned four SNPs with two SNPs in SEC23A and AMDHD1 (both genes without clear role in the vitamin D metabolic pathway), and thereby explained ~5.3% of the variance in 25OHD levels. The identification of over 150 25OHD-associated genetic variants in 2020, which explain a considerable portion of the variance in 25OHD levels (~10.5%) 43 , has enabled a deeper understanding of the genetic determinants contributing to variation in circulating 25OHD levels. These newly identified SNPs will probably enable improved instrumentation of vitamin D in Mendelian randomization studies. Moreover, with the emergence of large-scale GWAS in densely phenotyped biobanks, we anticipate that more powerful vitamin D Mendelian randomization studies will be published that utilize the optimized set of genetic instruments. Such new studies should revisit previously studied diseases and investigate new disease outcomes, to further aid causal effect estimation.

Conclusions

In conclusion, the data generated by the 2017–2020 megatrials of vitamin D supplementation in largely vitamin D-replete adults (Table  1 ) demonstrate that increasing the serum 25OHD concentration into the high normal range (based on the IOM and most recent guidelines published over the past decade 12 , in the range of 50–125 nmol/l or 20–50 ng/ml) does not generate benefits for global health or major diseases or medical events such as cancer, cardiovascular events, T2DM, falls or fractures. Therefore, no reason exists at present to recommend vitamin D supplementation of already vitamin D-replete individuals. These data do not contradict the causal link between severe vitamin D deficiency and rickets, or the need to correct severe deficiency at any age. Similarly, the 2017–2020 trials do not contradict the probable beneficial effects of combined supplementation of calcium and vitamin D in older adults with poor vitamin D and calcium status on their risks of fracture or falls.

A few hints have emerged that vitamin D supplementation might have some extra-skeletal benefits, especially in people with severe vitamin D deficiency (such as reduced progression to T2DM, decreased numbers of infections, increased lung function and decreased cancer or overall mortality) (Tables  2 , 3 ). These suggestions are largely based on subgroup or post hoc analyses and thus should not result in the systematic recommendation of vitamin D supplements in such populations but might guide the correct design of future studies.

Arguments have been put forward that daily doses of ≥4,000 IU of vitamin D convey some risks other than simple hypercalcaemia or hypercalciuria. Such doses, or the equivalent of serum 25OHD concentrations well above 112 nmol/l or 45 ng/ml bring no benefits, but might be harmful in some people (for example, in causing loss of BMD or increasing the risk of falls). The same is true for intermittent high-dose boluses of vitamin D. Unfortunately, about 3% of the US population as screened by NHANES use such high dose vitamin D supplements.

Over the past few decades, vitamin D has been a hot topic for scientists and lay people alike, who frequently suggest that vitamin D supplementation might generate a wide variety of health benefits. The data discussed in the present Review might well dampen such enthusiasm. However, a large number of intervention studies (and most probably Mendelian randomization studies) are still ongoing, and these might help provide a better understanding of who would benefit from vitamin D supplementation.

In conclusion, it seems that far too many people with severe vitamin D deficiency (~7% of the world population) do not take or even have access to normal doses of vitamin D. About a third of the world population lives with suboptimal (below 20 ng/ml) serum 25OHD concentrations 78 . However, many vitamin D-replete people take vitamin D supplements without clear benefits. In addition, a small percentage of the population takes higher doses than the upper limit of safe intake. Therefore, we recommend that vitamin D be used wisely and “giveth to those who needeth” 7 .

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Bouillon, R., Manousaki, D., Rosen, C. et al. The health effects of vitamin D supplementation: evidence from human studies. Nat Rev Endocrinol 18 , 96–110 (2022). https://doi.org/10.1038/s41574-021-00593-z

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• Summary of Recommendation
• USPSTF Assessment of Magnitude of Net Benefit
• Practice Considerations
• Update of Previous USPSTF Recommendation
• Supporting Evidence
• Research Needs and Gaps
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See the Figure for a more detailed summary of the recommendations for clinicians. See the Practice Considerations section for additional information regarding the I statement. USPSTF indicates US Preventive Services Task Force.

USPSTF indicates US Preventive Services Task Force.

US Preventive Services Task Force (USPSTF) Grades and Levels of Evidence

• USPSTF Review: Screening for Vitamin D Deficiency in Adults JAMA US Preventive Services Task Force April 13, 2021 This systematic review to support the 2021 US Preventive Services Task Force Recommendation Statement on screening for vitamin D deficiency summarizes published evidence on the benefits and harms of screening and interventions for vitamin D deficiency in asymptomatic, community-dwelling adults. Leila C. Kahwati, MD, MPH; Erin LeBlanc, MD, MPH; Rachel Palmieri Weber, PhD; Kayla Giger, BS; Rachel Clark, BA; Kara Suvada, BS; Amy Guisinger, BS; Meera Viswanathan, PhD
• USPSTF 2021 Recommendations on Screening for Asymptomatic Vitamin D Deficiency in Adults JAMA Editorial April 13, 2021 Sherri-Ann M. Burnett-Bowie, MD, MPH; Anne R. Cappola, MD, ScM
• Patient Information: Screening for Vitamin D Deficiency in Adults JAMA JAMA Patient Page April 13, 2021 This JAMA Patient Page summarizes the US Preventive Services Task Force’s 2021 recommendation that current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults (I statement). Jill Jin, MD, MPH
• USPSTF Still Finds Insufficient Evidence to Support Screening for Vitamin D Deficiency JAMA Network Open Editorial April 13, 2021 Erin D. Michos, MD, MHS; Rita R. Kalyani, MD, MHS; Jodi B. Segal, MD, MPH

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US Preventive Services Task Force. Screening for Vitamin D Deficiency in Adults : US Preventive Services Task Force Recommendation Statement . JAMA. 2021;325(14):1436–1442. doi:10.1001/jama.2021.3069

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Screening for Vitamin D Deficiency in Adults : US Preventive Services Task Force Recommendation Statement

• Editorial USPSTF 2021 Recommendations on Screening for Asymptomatic Vitamin D Deficiency in Adults Sherri-Ann M. Burnett-Bowie, MD, MPH; Anne R. Cappola, MD, ScM JAMA
• Editorial USPSTF Still Finds Insufficient Evidence to Support Screening for Vitamin D Deficiency Erin D. Michos, MD, MHS; Rita R. Kalyani, MD, MHS; Jodi B. Segal, MD, MPH JAMA Network Open
• US Preventive Services Task Force USPSTF Review: Screening for Vitamin D Deficiency in Adults Leila C. Kahwati, MD, MPH; Erin LeBlanc, MD, MPH; Rachel Palmieri Weber, PhD; Kayla Giger, BS; Rachel Clark, BA; Kara Suvada, BS; Amy Guisinger, BS; Meera Viswanathan, PhD JAMA
• JAMA Patient Page Patient Information: Screening for Vitamin D Deficiency in Adults Jill Jin, MD, MPH JAMA

Importance   Vitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.

Objective   To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.

Population   Community-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.

Evidence Assessment   The USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.

Recommendation   The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement)

See the Summary of Recommendation figure.

Quiz Ref ID Vitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. 1 - 3 Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency. According to the National Academy of Medicine, an estimated 97.5% of the population will have their vitamin D needs met at a serum level of 20 ng/mL (49.9 nmol/L) and risk for deficiency, relative to bone health, begins to occur at levels less than 12 to 20 ng/mL (29.9-49.9 nmol/L). 1 , 4 A report based on data from the 2014 National Health and Nutrition Examination Survey found that 5% of the population 1 year or older had very low 25-hydroxyvitamin D (25[OH]D) levels (<12 ng/mL) and 18% had levels between 12 and 19 ng/mL. 5

Quiz Ref ID The US Preventive Services Task Force (USPSTF) concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined ( Table ).

See the Figure , Table , and eFigure in the Supplement for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual. 6

Quiz Ref ID This recommendation applies to community-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency, such as bone pain or muscle weakness, or conditions for which vitamin D treatment is recommended. This recommendation focuses on screening (ie, testing for vitamin D deficiency in asymptomatic adults and treating those found to have a deficiency), which differs from USPSTF recommendation statements on supplementation.

Quiz Ref ID Although there is insufficient evidence to recommend for or against screening for vitamin D deficiency, several factors are associated with lower vitamin D levels. Low dietary vitamin D intake may be associated with lower 25(OH)D levels. 7 Little or no UV B exposure (eg, because of winter season, high latitude, or sun avoidance) and older age are also associated with an increased risk for low vitamin D levels. 8 - 12 Obesity is associated with lower 25(OH)D levels, 13 and people who are obese have a 1.3- to 2-fold increased risk of being vitamin D–deficient, depending on the threshold used to define deficiency. 8 , 9 , 13 , 14 The exact mechanism for this finding is not completely understood.

Depending on the serum threshold used to define deficiency, the prevalence of vitamin D deficiency is 2 to 10 times higher in non-Hispanic Black persons than in non-Hispanic White persons, likely related to differences in skin pigmentation. 7 - 9 , 14 However, these prevalence estimates are based on total 25(OH)D levels, and controversy remains about whether this is the best measure of vitamin D status among different racial and ethnic groups.

A significant proportion of the variability in 25(OH)D levels among individuals is not explained by the risk factors noted above, which seem to account for only 20% to 30% of the variation in 25(OH)D levels. 11 , 15

Vitamin D deficiency is usually treated with oral vitamin D. There are 2 commonly available forms of vitamin D—vitamin D 3 (cholecalciferol) and vitamin D 2 (ergocalciferol). Both are available as either a prescription medication or an over-the-counter dietary supplement.

The prevalence of vitamin D deficiency varies based on how deficiency is defined. According to data from the 2011 to 2014 National Health and Nutrition Examination Survey, which used the liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay to measure 25(OH)D levels, 5% of the population 1 year or older had very low 25(OH)D levels (<12 ng/mL) and 18% had levels between 12 and 19 ng/mL. 5 (To convert 25[OH]D values to nmol/L, multiply by 2.496.)

In some observational studies, lower vitamin D levels have been associated with risk for fractures, falls, functional limitations, some types of cancer, diabetes, cardiovascular disease, depression, and death. 16 , 17 However, observations of these associations are inconsistent. This inconsistency may be because of different studies using different cutoffs to define a low vitamin D level or because vitamin D requirements and the optimal cutoff that defines a low vitamin D level or vitamin D deficiency may vary by individual or by subpopulation. For example, non-Hispanic Black persons have lower reported rates of fractures 18 despite having increased prevalence of lower vitamin D levels than White persons. 7 - 9 , 14 Further, it is unknown whether these associations are linked to causality.

The goal of screening for vitamin D deficiency would be to identify and treat it before associated adverse clinical outcomes occur. Total 25(OH)D level is currently considered the best marker of vitamin D status. 4 , 19 A variety of assays can be used to measure 25(OH)D levels; however, levels can be difficult to measure accurately, and assays may underestimate or overestimate 25(OH)D levels. Additionally, the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community-dwelling adults.

Screening may misclassify persons with a vitamin D deficiency because of the uncertainty about the cutoff for defining deficiency and the variability of available testing assays. Misclassification may result in overdiagnosis (leading to nondeficient persons receiving unnecessary treatment) or underdiagnosis (leading to deficient persons not receiving treatment).

Quiz Ref ID A rare but potential harm of treatment with vitamin D is toxicity, which is characterized by marked hypercalcemia as well as hyperphosphatemia and hypercalciuria. However, the 25(OH)D level associated with toxicity (typically >150 ng/mL) 20 is well above the level considered to be sufficient. In general, treatment with oral vitamin D does not seem to be associated with serious harms.

The prevalence of screening for vitamin D deficiency by primary care clinicians in the US has not been well studied. Data suggest that laboratory testing for vitamin D levels has increased greatly over the last several years or longer. One study reported a more than 80-fold increase in Medicare reimbursement volumes for vitamin D testing from 2000 to 2010. 21

The USPSTF has published recommendations on the use of vitamin D supplementation for the prevention of falls 22 and fractures 23 and vitamin supplementation for the prevention of cardiovascular disease or cancer. 24 These recommendations differ from the current recommendation statement in that they address vitamin D supplementation without first determining a patient's vitamin D status (ie, regardless of whether they have a deficiency).

This recommendation updates the 2014 USPSTF recommendation statement on screening for vitamin D deficiency in asymptomatic adults. In 2014, the USPSTF concluded that the evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency. 25 For the current recommendation statement, the USPSTF again concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults.

To update its 2014 recommendation statement, the USPSTF commissioned a systematic review 26 , 27 of the evidence on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment. The review focused on asymptomatic, community-dwelling, nonpregnant adults 18 years or older who do not have clinical signs of vitamin D deficiency or conditions that could cause vitamin D deficiency, or for which vitamin D treatment is recommended, and who were seen in primary care settings.

Total 25(OH)D levels can be measured by both binding and chemical assays. Serum total 25(OH)D levels are difficult to measure accurately, and different immunoassays can lead to underestimation or overestimation of total 25(OH)D levels. 19 LC-MS/MS is considered the reference assay. However, LC-MS/MS is a complicated process and is subject to variation and error, including interference from other chemical compounds. 19

In 2010, the National Institutes of Health Office of Dietary Supplements, in collaboration with other organizations, initiated the Vitamin D Standardization Program. 28 , 29 The primary goal of the program has been to promote the standardized measurement of 25(OH)D levels. Most of the trials reviewed for this recommendation precede this standardization program. When previously banked samples have been reassayed using these standardized methods, both upward and downward revisions of 25(OH)D levels have been observed, depending on the original assay that was used. 19 , 30 , 31

The USPSTF found no studies that directly evaluated the benefits of screening for vitamin D deficiency. The USPSTF did find 26 randomized clinical trials (RCTs) and 1 nested case-control study that reported on the effectiveness of treatment of vitamin D deficiency (variably defined as a level <20 ng/mL to <31.2 ng/mL) on a variety of health outcomes, including all-cause mortality, fractures, incidence of diabetes, cardiovascular events and cancer, falls, depression, physical function, and infection. 26 , 27

Eight RCTs and 1 nested case-control study reported on all-cause mortality in community-dwelling adults. Study duration ranged from 16 weeks to 7 years. In a pooled analysis of the 8 trials (n = 2006), there was no difference in all-cause mortality in persons randomized to vitamin D treatment compared with controls (relative risk [RR], 1.13 [95% CI, 0.39-3.28]). 26 , 27 In the Women’s Health Initiative (WHI) Calcium–Vitamin D nested case-control study, there was no association between treatment with vitamin D and calcium and all-cause mortality among participants with baseline vitamin D levels between 14 and 21 ng/mL and among participants with baseline levels less than 14 ng/mL. 32 , 33

Six RCTs reported on fracture outcomes in community-dwelling adults. Study duration ranged from 12 weeks to 7 years. A pooled analysis of the 6 trials (n = 2186) found no difference in the incidence of fractures among those randomized to vitamin D treatment compared with placebo (RR, 0.84 [95% CI, 0.58-1.21]). 26 The USPSTF found only 1 trial reporting on hip fracture in community-dwelling adults. In that study, only 1 hip fracture occurred, leading to a very imprecise effect estimate. 34 In the WHI Calcium–Vitamin D nested case-control study, there was no association between treatment with vitamin D and calcium and clinical fracture or hip fracture incidence. 32

Five RCTs reported on incident diabetes. Study duration ranged from 1 year to 7 years. A pooled analysis of the 5 trials (n = 3356) found no difference in the incidence of diabetes among participants randomized to vitamin D treatment compared with placebo (RR, 0.96 [95% CI, 0.80-1.15]). 26

For several outcomes, the USPSTF found inadequate evidence on the benefit of treatment of asymptomatic vitamin D deficiency. Limitations of the following evidence include few studies reporting certain outcomes and, for some outcomes, variable methods of ascertainment, variable reporting of outcomes, small study size, or short duration of follow-up.

Two trials, the Vitamin D and Omega-3 Trial (VITAL) (n = 2001 in trial subgroup) 35 and the Vitamin D Assessment Study (ViDA) (n = 1270 in trial subgroup), 36 reported on cardiovascular events. Both trials observed no statistically significant differences in cardiovascular events between the treatment and placebo groups among the subgroup of participants with serum vitamin D levels less than 20 ng/mL at baseline. VITAL had 5.3 years of follow-up, while the ViDA trial had only 3.3 years of follow-up. The ViDA trial also used a heterogeneous definition of cardiovascular events, which included venous thromboembolism, pulmonary embolism, inflammatory cardiac conditions, arrhythmias, and conduction disorders.

Two trials, VITAL 35 and a post hoc analysis of the ViDA trial, 37 and the WHI nested case-control study 38 , 39 reported on the effect of vitamin D treatment on the incidence of cancer. Both trials reported no difference in cancer incidence between participants randomized to treatment and placebo among the subgroup of participants with serum 25(OH)D levels less than 20 ng/mL at baseline. The ViDA trial had only 3 years of follow-up, which may be a short period to detect an effect on cancer incidence. In the WHI Calcium–Vitamin D nested case-control study, the adjusted odds ratios (ORs) for incident breast or colorectal cancer over 7 years of follow-up did not demonstrate a statistically significant association between exposure to active treatment and incidence of cancer among participants with vitamin D deficiency at baseline. 38 , 39

Nine trials reported fall outcomes in community-dwelling adults. 26 , 27 Some trials reported only falls, others only the number of participants who experienced 1 or more falls (ie, “fallers”), and some trials reported both outcomes. A pooled analysis of 6 trials found no association between vitamin D treatment and number of fallers (RR, 0.90 [95% CI, 0.75-1.08]), while a pooled analysis of 5 trials found a significant association between vitamin D treatment and falls (incidence rate ratio, 0.76 [95% CI, 0.57-0.94]). 26 , 27 However, heterogeneity was high in both analyses, ascertainment methods for falls and fallers were variable across studies, and the variable reporting of falls, fallers, or both outcomes raises the possibility of selective outcome reporting. One trial reported on the incidence of 2 or more falls, a different definition of “fallers” than in the trials included in the pooled analysis above. It found no significant difference between participants randomized to vitamin D or placebo among the subgroup of participants with baseline vitamin D levels less than 12 ng/mL (adjusted OR, 1.03 [95% CI, 0.59-1.79]) or among those with levels between 12 and 20 ng/mL (adjusted OR, 1.13 [95% CI, 0.87-1.48]). 40

Three trials reported depression outcomes. One, VITAL-DEP (Depression Endpoint Prevention), was an ancillary study to the VITAL trial. Among the subgroup of participants with baseline serum vitamin D levels less than 20 ng/mL (n = 1328), there was no difference in the change in Personal Health Questionnaire Depression Scale scores between those randomized to vitamin D compared with placebo over a median follow-up of 5.3 years. 41 The other 2 trials were relatively small and of short duration. Both reported no significant difference in depression measures between vitamin D treatment and placebo. 42 , 43 Two trials reporting on physical functioning measures reported conflicting results. 44 , 45 An unplanned subgroup analysis of 1 trial conducted in persons with impaired fasting glucose found no difference in incidence of a first urinary tract infection in participants with vitamin D deficiency who were treated with vitamin D compared with placebo. 46

As noted, the studies comprising the body of evidence cited above did not uniformly define vitamin D deficiency. Different studies enrolled participants with vitamin D levels that ranged from less than 20 ng/mL to less than 31.2 ng/mL. For those outcomes with sufficient data (mortality, fractures, and falls), findings were similar between studies using a lower threshold and studies using a higher threshold. 26 , 27

The USPSTF found no studies that directly evaluated the harms of screening for vitamin D deficiency. The USPSTF found 36 studies that reported adverse events and harms from treatment with vitamin D (with or without calcium) compared with a control group. The absolute incidence of adverse events varied widely across studies; however, the incidence of total adverse events, such as gastrointestinal symptoms, fatigue, musculoskeletal symptoms, and headaches, and serious adverse events was generally similar between treatment and control groups. In the 10 trials that reported incidence of kidney stones, there was only 1 case. 26 , 27

A draft version of this recommendation statement was posted for public comment on the USPSTF website from September 22, 2020, to October 19, 2020. Some comments requested the USPSTF to evaluate the evidence on or make a recommendation regarding vitamin D supplementation. In response, the USPSTF wants to clarify that this recommendation focuses on screening for vitamin D deficiency. The USPSTF does have separate recommendations that address vitamin D supplementation (ie, providing vitamin D to all persons without testing, and regardless of vitamin D level) for a variety of conditions. 22 - 24 In response to comments, the USPSTF also wants to clarify that this recommendation applies to asymptomatic, community-dwelling adults. It does not apply to persons in institutional or hospital settings, who may have underlying or intercurrent conditions that warrant vitamin D testing or treatment. The USPSTF also wants to clarify that it did not review the emerging evidence on COVID-19, the disease caused by the new coronavirus SARS-CoV-2, and vitamin D.

More studies are needed that address the following areas:

More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex.

More research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.

When vitamin D deficiency is better defined, studies on the benefits and harms of screening for vitamin D deficiency will be helpful.

No organization recommends population-based screening for vitamin D deficiency, and the American Society for Clinical Pathology recommends against it. 47 The American Academy of Family Physicians supports the USPSTF 2014 recommendation, which states that there is insufficient evidence to recommend screening the general population for vitamin D deficiency. 48 The Endocrine Society 49 and the American Association of Clinical Endocrinologists 50 recommend screening for vitamin D deficiency in individuals at risk. The Endocrine Society does not recommend population screening for vitamin D deficiency in individuals not at risk. 49

Corresponding Author: Alex H. Krist, MD, MPH, Virginia Commonwealth University, 830 E Main St, One Capitol Square, Sixth Floor, Richmond, VA 23219 ( [email protected] ).

Accepted for Publication: February 22, 2021.

The US Preventive Services Task Force (USPSTF) members: Alex H. Krist, MD, MPH; Karina W. Davidson, PhD, MASc; Carol M. Mangione, MD, MSPH; Michael Cabana, MD, MA, MPH; Aaron B. Caughey, MD, PhD; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Chyke A. Doubeni, MD, MPH; John W. Epling Jr, MD, MSEd; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Douglas K. Owens, MD, MS; Lori Pbert, PhD; Michael Silverstein, MD, MPH; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD.

Affiliations of The US Preventive Services Task Force (USPSTF) members: Fairfax Family Practice Residency, Fairfax, Virginia (Krist); Virginia Commonwealth University, Richmond (Krist); Feinstein Institute for Medical Research at Northwell Health, New York, New York (Davidson); University of California, Los Angeles (Mangione); Albert Einstein College of Medicine, New York, New York (Cabana); Oregon Health & Science University, Portland (Caughey); University of Pittsburgh, Pittsburgh, Pennsylvania (Davis); University of North Carolina at Chapel Hill (Donahue); Mayo Clinic, Rochester, Minnesota (Doubeni); Virginia Tech Carilion School of Medicine, Roanoke (Epling Jr); George Mason University, Fairfax, Virginia (Kubik); University of Virginia, Charlottesville (Li); New York University, New York, New York (Ogedegbe); Stanford University, Stanford, California (Owens); University of Massachusetts Medical School, Worcester (Pbert); Boston University, Boston, Massachusetts (Silverstein); University of Missouri, Columbia (Stevermer); University of Hawaii, Honolulu (Tseng); Pacific Health Research and Education Institute, Honolulu, Hawaii (Tseng); Tufts University School of Medicine, Boston, Massachusetts (Wong).

Author Contributions: Dr Krist had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The USPSTF members contributed equally to the recommendation statement.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Authors followed the policy regarding conflicts of interest described at https://www.uspreventiveservicestaskforce.org/Page/Name/conflict-of-interest-disclosures . All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings.

Funding/Support: The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF.

Role of the Funder/Sponsor: AHRQ staff assisted in the following: development and review of the research plan, commission of the systematic evidence review from an Evidence-based Practice Center, coordination of expert review and public comment of the draft evidence report and draft recommendation statement, and the writing and preparation of the final recommendation statement and its submission for publication. AHRQ staff had no role in the approval of the final recommendation statement or the decision to submit for publication.

Disclaimer: Recommendations made by the USPSTF are independent of the US government. They should not be construed as an official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We thank Howard Tracer, MD (AHRQ), who contributed to the writing of the manuscript, and Lisa Nicolella, MA (AHRQ), who assisted with coordination and editing.

Additional Information: The US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms. It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision-making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

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Vitamin D toxicity due to self-prescription: A case report

Bhat, Javid Rasool; Geelani, Sajad Ahmed; Khan, Afaq Ahmad; Roshan, Reshma; Rathod, Santosh Govind

Department Clinical Hematology, SKIMS, Srinagar, Jammu and Kashmir, India

Address for correspondence: Dr. Santosh Govind Rathod, Department of Clinical Hematology, SKIMS, Srinagar - 190 011, Jammu and Kashmir, India. E-mail: [email protected]

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Apart from maintaining healthy bones, vitamin D is also required for cell differentiation, cell growth inhibition, and immune modulation. Vitamin D deficiency is common in the Indian subcontinent. Vitamin D presenting toxicity, leading to hypercalcemia, acute kidney injury, and altered sensorium is very rare. Here we present a case of a 65-year-old man who presented to emergency with persistent vomiting, altered sensorium, and acute kidney injury. The cause of which was an unchecked intake of vitamin D for non-specific musculoskeletal pain. When treated with intravenous fluid, diuretics, calcitonin, and steroids, the patient improved clinically. Therefore, for any patient presenting with persistent vomiting, altered sensorium, and hypercalcemia, with normal to low parathyroid hormone levels, a diagnosis of an overdose of vitamin D should be considered. Early treatment of this condition not only improves the symptoms but also prevents further kidney damage.

Introduction

Vitamin D is important for maintaining bone mineralization and serum calcium level. Vitamin D deficiency defined as serum [25-(OH) D] <20 ng/mL, and insufficiency concentration of 21-29 ng/mL. Vitamin D toxicity when the level >150 ng/mL.[ 1 ] Recent research work shows that vitamin D deficiency is associated with an increased risk of autoimmune disorder, chronic obstructive pulmonary disorder, cancer, and metabolic disease. There is growing awareness about vitamin D deficiency, and related health problems among general population. People are taking vitamin D orally or intramuscularly in mega doses as a supplement without adequate medical monitoring and indication. This leads to vitamin D toxicity causing hypercalcemia, acute kidney injury, and altered sensorium. Vitamin D is fat-soluble and remains in the body for long time and is released slowly. People are not aware of this phenomenon. The present case illustrates Vitamin D toxicity due to self-prescription of the drug without medical indication and its level monitoring.

Case Report

A 65-year-old male, with no underlying co-morbid condition, was presented with vomiting for 2 days, and altered sensorium for 3 days. There was no history of fever, headache, seizure, and cough. On clinical examination, the patient was afebrile, drowsy, and disoriented with GCS-E3V4M5, 12/15. No neck rigidity was observed. The laboratory investigation showed the following results: hemoglobin 11.2 g/dL, white blood cell counts 7.2 × 10 3 /mm 3 , platelet count 242 × 10 3 /mL, blood urea nitrogen 95 mg/dL, creatinine 5.1 mg/dL, sodium 144 mEq/L, potassium 3.7 mEq/L, serum calcium 14.4 mg/dl, phosphorous 4.8 mEq/L, serum bilirubin 0.50 mg/dL, protein 6.2 g/dL, albumin 3.3 g/dL, globulin 2.7 g/dL, alanine transaminase 22 IU/L, aspartate transaminase 20 IU/L, alkaline phosphatase 67 IU/L, angiotensin-converting enzyme was 16.20 mg/dL, and intact parathyroid hormone was 3.20 pg/mL. Magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid study was normal with negative viral panel and cryptococcal antigen. Serum protein electrophoresis did not show an M band and whole-body MRI was normal. Bone marrow aspiration showed 2% plasma cells. Ultrasound of neck was unremarkable. Ultrasound scanning showed that both kidneys were normal as well as urine routine microscopy was normal too. However, vitamin D (25 hydroxy vitamin D) was 218 ng/mL [ Table 1 ]. The detailed history of the patient revealed that he was suffering from prolapsed intervertebral disc for which he had been prescribed vitamin D and calcium tablets. He was told to take injections of vitamin D 50000 IU per week for a total of 6 weeks. However, he lost to follow up and continued to take vitamin D injections every week for 1 year for non-specific musculoskeletal pain. This lead to the diagnosis of vitamin D toxicity. For hypercalcemia, he was treated with intravenous normal saline 3 L/day, diuretics, calcitonin, and dexamethasone. He showed clinical improvement. His serum calcium and creatinine levels were monitored regularly; they gradually decreased to normal levels in the next 10 days. The patient was discharged with a prescription of a calcium-restricted diet and advised not to take vitamin D supplementation, including the reduction of dietary intake, avoiding exposure to sunlight, and maintaining good hydration. After 1 month of follow up, the patient is doing well.

Vitamin D is an important prohormone. Fat-soluble in nature and plays an important function in the human body like bone mineralization, calcium levels, cell growth, and immunomodulator.[ 1 ] The recommended daily allowance of vitamin D is 800 IU/day and the upper limit of intake of vitamin D is 4000 IU/day as per guidelines by the Institute of Medicine and the Endocrine Practice Committee.[ 2 ] Vitamin D toxicity when level >150 ng/mL.[ 2 ] Being a fat-soluble in nature, vitamin D remains for a long time and is slowly released in the body.[ 2 ] There is growing awareness in the general population about the importance of vitamin D for normal functioning of the body and health-related problems due to its deficiency. It has led to aggressive intake of vitamin D without medical indication and monitoring its level in the body.

In our case, the patient took vitamin D injection 50000 IU per week for a period of 1 year because of non-specific musculoskeletal pain. Clinically, vitamin D intoxication presents with the following symptoms and signs like hypercalcemia, nausea, vomiting, polyuria, dehydration, altered sensorium, acute kidney injury, pancreatitis, and short QT interval.[ 3 4 5 ] In this present case patient presented with acute kidney injury, hypercalcemia, and altered sensorium.

The differential diagnosis of multiple myeloma, gastrointestinal, breast, lung malignancy, lymphoma, Sarcoidosis, vitamin D toxicity, and parathyroid adenoma considered.

In our case, there was no M band on serum electrophoresis. Bone marrow examination showed only 2% plasma cells only. Serum ACE level was normal. MRI of the whole body was normal. parathyroid hormone was reduced. However, vitamin D (25 hydroxy vitamin D) was 218 ng/mL.

Hypercalcemia due to Vitamin D toxicity results from increased concentration of vitamin D metabolites reaching the nuclear Vitamin D receptor and causing exaggerated gene expressions in dose depending manner. The mechanism behind this is the direct action of 25-OHD and other vitamin D metabolites on the l, 25-(OH) 2 D 3 receptor and the other is displacement of l, 25-(OH) 2 D 3 from D-binding protein by the high 25-OHD levels. This leads to an increase in the concentration of active, free l, 25-(OH) 2 D3 levels.[ 6 ] Vitamin D toxicity treated with vigorous hydration, diuretic, calcitonin, high dose steroid, and biphosonate. Dietary restriction calcium, avoiding sun exposure to light and discontinuation of vitamin D supplementation.[ 1 4 ]

Primary care physicians are the first point of contact to patients in the health system. Increasing awareness among primary care physicians regarding the toxicity of mega doses of vitamin D and cautious use of vitamin D supplements will prevent this condition, and spread awareness among the general population.

Physicians should keep the differential diagnosis of vitamin D toxicity when the patient comes to an emergency with persistent vomiting and hypercalcemia and altered sensorium in the presence of normal to suppressed parathyroid hormone. Promptly treatment of this condition improves symptoms and avoids further damage to the kidney.

• Vitamin D rarely causes hypercalcemia leading to acute kidney injury and encephalopathy.
• Being fat-soluble in nature it is slowly released into the body so a close monitoring of patients is needed.
• Primary care physicians should prescribe Vitamin D in medical indication, and monitor its level cautiously in order to avoid toxicity.

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Acute kidney injury; altered sensorium; hypercalcemia; PTH; vitamin D toxicity

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• Volume 15, Issue 7
• Vitamin D intoxication and severe hypercalcaemia complicating nutritional supplements misuse
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• http://orcid.org/0000-0003-0488-220X Alamin Alkundi 1 , 2 ,
• http://orcid.org/0000-0001-8412-0912 Rabiu Momoh 3 ,
• Abdelmajid Musa 4 and
• Nkemjika Nwafor 4
• 1 Diabetes and Endocrinology , East Kent Hospitals University NHS Foundation Trust , Canterbury , UK
• 2 Medical Education , Cardiff University , Cardiff , UK
• 3 Department of Intensive Care Medicine , East Kent Hospitals University NHS Foundation Trust , Ashford , Kent , UK
• 4 Department of Medicine , William Harvey Hospital , Ashford , Kent , UK
• Correspondence to Dr Rabiu Momoh; rabiu.momoh{at}nhs.net

This case report discusses an uncommon presentation of vitamin D intoxication and severe hypercalcaemia attributed to misuse of multiple nutritional supplements (˃20 active agents). A review of this case, supported by accumulated literature, lends room to further public health safety discussions. The multisystemic clinical manifestations of vitamin D toxicity can be debilitating, hence the need to prevent its occurrence.

• Calcium and bone

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bcr-2022-250553

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Patients often pursue unconventional or alternative therapy, the health outcomes of which remain controversial. An example is the use of over-the-counter nutritional supplements. Data on hypervitaminosis D or vitamin D toxicity are limited. This case report aims to contribute to the body of knowledge regarding this topic, which is of public health importance. Considering this topic, issues such as the potential interaction of over-the-counter and prescribed medications, market regulations of nutritional supplements, the misuse of these supplements in sports, and the potential harm among unsuspecting population groups (eg, children and the elderly) remain matters of public health significance that need to be addressed.

Case presentation

A middle-aged male was referred to the hospital by a general practitioner after complaining of recurrent vomiting, nausea, abdominal pain, leg cramps, tinnitus, dry mouth, increased thirst, diarrhoea, and weight loss (28 lbs (12.7 kg)). The patient had experienced the complaints for nearly 3 months, with onset noticed approximately 1 month after commencing a vitamin regimen therapy on the advice of a private nutritionist. The patient had been taking the following daily: vitamin D 15 0000IU (daily requirement: 10mcg (or 400IU per day)), vitamin K2 100mcg (daily requirement: 100–300 μg), vitamin C, vitamin B9 (folate) 1000mcg (daily requirement: 400 μg), vitamin B2 (riboflavin), vitamin B6, omega-3 2000mg twice daily (daily requirement: 200–500mg), selenium, bioactiver, zinc picolinate 15mg (daily requirement: 11mg), vitamin B3 50mg (daily requirement: 16mg), super-12 complex 1000 μg Lugol’s iodine drops 15% one drop, borax powder (sodium tetraborate decahydrate), l-lysine powder 500cmg (daily requirement of l-lysine: 1000–1500 μg) with NAC (N-acetyl cysteine) 600mg (daily requirement: 600–1800mg), wobenzym N 400, astaxanthin softgel 18mg, magnesium malate 1000mg, magnesium citrate 1480mg, pure taurine 1–2g per day, glycine powder 1g, high strength choline (+inositol) 100mg, calcium orotate 1000mg, probiotic, glucosamide and chondroitin complex, and sodium chloride.

The patient discontinued the intake of supplements on developing the above-listed symptoms, but his symptoms persisted. He had the following past medical history: bovine spinal tuberculosis, left vestibular schwannoma with hearing loss (operated by retro-sigmoid approach), hydrocephalus treated with a ventricular peritoneal shunt, bacterial meningitis, and chronic rhinosinusitis. On examination, he appeared cachectic with mild diffuse abdominal tenderness and no other significant finding on systemic examination. Vital signs were unremarkable.

Investigations

An initial set of blood tests performed by the patient’s general practitioner revealed elevated serum calcium (albumin adjusted) (3.9 mmol/L; reference (ref): 2.2–2.6 mmol/L), acute kidney injury with serum creatinine (166 µmol/L; ref: 64–106 µmol/L), and urea of 13.4 mmol/L; ref: 2.5–7.8 mmol/L). He presented a serum magnesium level of 1.04 mmol/L (ref: 0.7–1.0 mmol/L) and serum vitamin D of >400 nmol/L (ref: >50 (vitamin D sufficiency)). Further serial daily electrolytes results can be seen in table 1 .

• View inline

Serial serum electrolyte studies

No positive findings were detected on performing faecal bacteriology and parasitology tests. Table 2 presents results pertaining to serial vitamin D levels, normal serum thyroid function, a normal early morning cortisol level, normal serial parathyroid hormone level, and a negative coeliac screen result for the patient’s recurrent loose bowel.

Thyroid function test, serial vitamin D levels and parathormone levels, early morning cortisol levels, and coeliac screen results

Radiological imaging studies were performed to rule out malignancy as follows:

MRI of head: No obvious relapsed/recurrent acoustic neuroma and no hydrocephalous.

Positron emission tomography scan: An overt fluorodeoxyglucose (FDG)-avid malignancy was not identified. No overt sepsis focus was present. No systemic inflammatory process was identified.

CT chest/abdomen/pelvis: Calcified nodules were seen bilaterally in the upper lobes and were more pronounced in the right apex. No new lung consolidation, collapse, or endobronchial lesions were detected. The central airways were patent. No lymphadenopathy or pleural or pericardial effusions were observed. There was no cardiomegaly or mediastinal mass. Incidental pulmonary emboli were not observed. A notable paucity of intra-abdominal fat was observed. Focal hepatic lesions were not observed. A few calcified granuloma-type nodules were noted in the spleen. The kidneys and adrenal glands appeared normal. The prostate was enlarged. No significant bowel abnormalities were noted.

The patient was admitted to hospital for 8 days and rehydrated using intravenous fluid therapy. He underwent daily blood tests to monitor the progress of care. Oral bisphosphonate therapy was also initiated. During the hospital stay, he underwent dietetic and pharmacy service reviews. He was discharged after adequate counselling sessions and was recommended follow-up with regular blood tests. Oral bisphosphonates and antiemetics were continued post-hospital discharge.

Outcome and follow-up

After continued oral bisphosphonate treatment, the patient was followed up 2 months after hospital discharge at an endocrinology outpatient clinic. His corrected serum calcium level had dropped to 2.6 mmol/L, while the serum vitamin D level remained >400 nmol/L. A plan to monitor both parameters on an outpatient basis was established to track the declining levels to reference limits.

Compared with studies among the general population, nutritional supplement misuse or abuse has been extensively documented and reviewed among athletes. The present case describes the misuse of supplements with more than 20 active agents in a middle-aged man, who was not a professional athlete, with resultant vitamin D intoxication and hypercalcaemia.

Globally, there is a growing trend of hypervitaminosis D, a clinical condition characterised by elevated serum vitamin D3 levels. This term is often used interchangeably with vitamin D intoxication; however, some reports have described hypervitaminosis D as serum vitamin D3 level ˃250 nmol/L and vitamin D intoxication as levels ˃375 nmol/L. It has been reported that hypervitaminosis D is more likely to occur in females, children, and surgical populations. 1

Vitamin D is a fat-soluble vitamin in the body, along with vitamins A, E, and K. As a result, it undergoes widespread adipose tissue distribution. Recommended vitamin D requirements can be obtained from the diet (eg, wild mushrooms, oily fish), from sunlight through the skin (via ultraviolet-B-mediated conversion of 7-dehydrocholesterol), and are available as dietary supplements (in the form of pills). Given its slow turnover (half-life of approximately 2 months), during which vitamin D toxicity develops, symptoms can last for several weeks. 2

The manifestations of vitamin D intoxication (in terms of symptoms and signs) are often multisystemic and are largely derived from its resultant effects of hypercalcaemia. Neuropsychiatric features include drowsiness, confusion, apathy, psychosis, depression, stupor, and coma. Possible gastrointestinal features of vitamin D toxicity include anorexia, abdominal pain, vomiting, constipation, peptic ulcers, and pancreatitis. Hypertension and arrhythmias, such as shortened QT interval, ST-segment changes, and bradyarrhythmias, encompass cardiovascular signs of vitamin D intoxication. Renal system features of vitamin D intoxication include polyuria, polydipsia, dehydration, hypercalciuria, nephrocalcinosis, and renal failure. Other features such as keratopathy, arthralgia, and hearing impairment or loss have also been reported with vitamin D toxicity. 3

In a retrospective study assessing 38 children (aged 0.3 to 4 years) who had a diagnosis of vitamin D intoxication, Çağlar et al revealed that vomiting, loss of appetite, and constipation were the most common presentations among examined children (65.8%, 47.4%, and 31.6%, respectively). The authors also stated that the admission serum calcium level was 3.75±0.5 mmol/L and the admission vitamin D level was 396±110 ng/mL. Nephrocalcinosis was detected in 15% of the 38 cases reviewed. 4

Lam et al discussed the prevalence of non-prescription medications and dietary supplements among 45 residents at two assisted-living facilities in the USA. The authors revealed that participants used a mean of 3.4 products. Product classes used by residents, based on frequency, were nutritional supplements (32% of products), followed by gastrointestinal products (17%), analgesics (16.3%), herbal products (14.4%), topical agents (12%), and cold/cough products (8.5%). The potential misuse of products was detected among 51% of these participants. Duplication (70%), potential drug/disease/food interactions (20.8%), and other inappropriate use (9.1%) were misuse patterns documented. Approximately three-quarters of these participants believed that consuming these products helped maintain their health. Nearly 50% of participants wanted more product information. Almost half of the residents received product information from friends and family. Only 40% of these participants turned to their physicians and nurses for information, whereas 11% asked pharmacists for advice. 5

Known treatment modalities for vitamin D intoxication-related hypercalcaemia include discontinuation of vitamin D, hydration, establishing a low calcium-containing diet, steroids, and possible bisphosphonate therapy (agents that inhibit osteoclastic activities, thereby reducing serum calcium). Radiologic exclusion of complications, including nephrocalcinosis, should be undertaken. Further regulatory measures and education of the populace can help kerb the misuse of nutritional supplements to avoid untoward complications. 6

Learning points

Patients are encouraged to seek the opinion of their general practitioners regarding any alternative therapy or over-the-counter medications they may be taking or desire to initiate.

Nutritional causes of hypercalcaemia should always be excluded early in patients before investigating alternate pathological causes.

This case report further highlights the potential toxicity of supplements that are largely considered safe until taken in unsafe amounts or in unsafe combinations.

Ethics statements

Patient consent for publication.

Consent obtained directly from patient(s)

Acknowledgments

The authors thank their patient for granting consent towards this publication and thereby promoting medical knowledge. We would also like to thank Editage (www.editage.com) for English language editing.

• Sharma LK ,
• Sharma N , et al
• Tsiopanis G ,
• Marcinowska-Suchowierska E ,
• Kupisz-Urbańska M ,
• Łukaszkiewicz J , et al
• Tuğçe Çağlar H ,

Contributors AA identified this case as being suitable for possible reporting. He was also involved in the planning, patient’s consenting process, acquisition of data, analysis and interpretation of data. RM was involved in the planning sessions for this case report. He was also involved in data analysis and manuscript development. He is the submitting author for this case report and will be managing correspondence on behalf of other co-authors. AM was involved in the planning sessions for this case report. He was involved in obtaining the patient’s consent for this report. He also participated in the acquisition of data for this report. NN was involved in the planning for this case report, as well as in manuscript development.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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“This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like more pronounced effect after two years of supplementation for vitamin D,” said Karen Costenbader, senior author of the study.

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Vitamin D supplements lower risk of autoimmune disease, researchers say

Haley Bridger

BWH Communications

Study of older adults is ‘first direct evidence’ of protection against rheumatoid arthritis, psoriasis, other conditions

In a new study, investigators from Brigham and Women’s Hospital found the people who took vitamin D, or vitamin D and omega-3 fatty acids, had a significantly lower rate of autoimmune diseases — such as rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis — than people who took a placebo.

With their findings published Wednesday in BMJ , the team had tested this in the large-scale vitamin D and omega-3 trial (VITAL), a randomized study which followed participants for approximately five years. Investigators found the people who took vitamin D, or vitamin D and omega-3 fatty acids had a significantly lower rate of AD than people who took a placebo.

“It is exciting to have these new and positive results for nontoxic vitamins and supplements preventing potentially highly morbid diseases,” said senior author Karen Costenbader of the  Brigham’s Division of Rheumatology, Inflammation and Immunity.  “This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like more pronounced effect after two years of supplementation for vitamin D. We look forward to honing and expanding our findings and encourage professional societies to consider these results and emerging data when developing future guidelines for the prevention of autoimmune diseases in midlife and older adults.”

“Now, when my patients, colleagues, or friends ask me which vitamins or supplements I’d recommend they take to reduce risk of autoimmune disease, I have new evidence-based recommendations for women age 55 years and older and men 50 years and older,” said Costenbader. “I suggest vitamin D 2000 IU a day and marine omega-3 fatty acids (fish oil), 1000 mg a day — the doses used in VITAL.”

VITAL is a randomized, double-blind, placebo-controlled research study of 25,871 men (age 50 and older) and women (age 55 and older) across the U.S., conducted to investigate whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor fish oil, 1 gram) could reduce the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. Participants were randomized to receive either vitamin D with an omega-3 fatty acid supplement; vitamin D with a placebo; omega-3 fatty acid with a placebo; or placebo only. Prior to the launch of VITAL, investigators determined that they would also look at rates of AD among participants, as part of an ancillary study.

“Given the benefits of vitamin D and omega-3s for reducing inflammation, we were particularly interested in whether they could protect against autoimmune diseases,” said JoAnn Manson, co-author and director of the parent VITAL trial at the Brigham.

Participants answered questionnaires about new diagnoses of diseases, including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease, with space to write in all other new onset ADs. Trained physicians reviewed patients’ medical records to confirm reported diagnoses.

“Autoimmune diseases are common in older adults and negatively affect health and life expectancy. Until now, we have had no proven way of preventing them, and now, for the first time, we do,” said first author, Jill Hahn, a postdoctoral fellow at the Brigham. “It would be exciting if we could go on to verify the same preventive effects in younger individuals.”

Among patients who were randomized to receive vitamin D, 123 participants in the treatment group and 155 in the placebo group were diagnosed with confirmed AD (22 percent reduction). Among those in the fatty acid arm, confirmed AD occurred in 130 participants in the treatment group and 148 in the placebo group. Supplementation with omega-3 fatty acids alone did not significantly lower incidence of AD, but the study did find evidence of an increased effect after longer duration of supplementation.

The VITAL study included a large and diverse sample of participants, but all participants were older and results may not be generalizable to younger individuals who experience AD earlier in life. The trial also only tested one dose and one formulation of each supplement. The researchers note that longer follow-up may be more informative to assess whether the effects are long-lasting.

This study was funded by the National Institutes of Health grants R01 AR059086, U01 CA138962, R01 CA138962.

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This article has a correction. Please see:

• Errata - January 01, 2010

Vitamin D is a fat-soluble vitamin that plays an important role in bone metabolism and seems to have some anti-inflammatory and immune-modulating properties. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states. Low vitamin D levels are associated with increased overall and cardiovascular mortality, cancer incidence and mortality, and autoimmune diseases such as multiple sclerosis. Although it is well known that the combination of vitamin D and calcium is necessary to maintain bone density as people age, vitamin D may also be an independent risk factor for falls among the elderly. New recommendations from the American Academy of Pediatrics address the need for supplementation in breastfed newborns and many questions are raised regarding the role of maternal supplementation during lactation. Unfortunately, little evidence guides clinicians on when to screen for vitamin D deficiency or effective treatment options.

• Background and Physiology

Vitamin D is a hormone precursor that is present in 2 forms. Ergocalciferol, or vitamin D 2 , is present in plants and some fish. Cholecalciferol, or vitamin D 3 , is synthesized in the skin by sunlight. Humans can fulfill their vitamin D requirements by either ingesting vitamin D or being exposed to the sun for enough time to produce adequate amounts. Vitamin D controls calcium absorption in the small intestine and works with parathyroid hormone to mediate skeletal mineralization and maintain calcium homeostasis in the blood stream. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states, probably caused by its anti-inflammatory and immune-modulating properties and possible affects on cytokine levels.

Vitamin D 3 can be manufactured in the skin by way of ultraviolet (UV) B rays. UVB rays are present only during midday at higher latitudes and do not penetrate clouds. The time needed to produce adequate vitamin D from the skin depends on the strength of the UVB rays (ie, place of residence), the length of time spent in the sun, and the amount of pigment in the skin. Tanning beds provide variable levels of UVA and UVB rays and are therefore not a reliable source of vitamin D.

Vitamin D 3 is synthesized from 7-dehydrocholesterol in the skin. The vitamin D binding protein transports the vitamin D 3 to the liver where it undergoes hydroxylation to 25(OH)D (the inactive form of vitamin D) and then to the kidneys where it is hydroxylated by the enzyme 1 αhydroxylase to 1,25(OH)D, its active form. 1 This enzyme is also present in a variety of extrarenal sites, including osteoclasts, skin, colon, brain, and macrophages, which may be the cause of it's broad-ranging effects. 1 The half-life of vitamin D in the liver is approximately 3 weeks, which underscores the need for frequent replenishment of the body's supply.

Vitamin D and Mortality

Vitamin D may be a determinant of mortality because of its anti-inflammatory and immune-modulating effects. It has been used to treat secondary hyperparathyroidism in people on dialysis. Retrospective trials show that vitamin D supplementation is associated with decreased mortality in people on dialysis. 2 Low serum vitamin D levels are also related to increased mortality in most patients with chronic kidney disease before dialysis. 3 However, there have been no randomized prospective trials examining this relationship. 4

In patients not on dialysis, low vitamin D levels are associated with increased levels of inflammation and oxidative load. A prospective study of more than 3000 male and female patients scheduled for coronary angiography found a positive association between low vitamin D levels and cardiovascular as well as all-cause mortality. 5 Data analysis from the National Health and Nutrition Examination Survey III (more than 13,000 adults) showed that people with vitamin D levels in the lowest quartile had a mortality rate ratio of 1.26 (95% CI, 1.08–1.46). 6 A recent meta-analysis demonstrated that intake of a vitamin D supplement at normal doses also was associated with decreased all-cause mortality rates. 7 These data suggest that vitamin D may play a part in multiple causes of death, although causality has not been determined.

Vitamin D and Cardiovascular Disease

Vitamin D receptors are present in vascular smooth muscle, endothelium, and cardiomyocytes and may have an impact on cardiovascular disease. Observational studies have shown a relationship between low vitamin D levels and blood pressure, coronary artery calcification, and existing cardiovascular disease. A large cohort study that included more than 1700 participants from the Framingham offspring study looked at vitamin D levels and incident cardiovascular events. 8 During a period of 5 years, participants who had 25-OH D levels of <15 were more likely to experience cardiovascular events (hazard ratio, 1.62; 95% CI, 1.11–2.36). The relationship remained significant among people with hypertension but not among those without hypertension. 8

Vitamin D and Diabetes

Recent studies in animal models and humans have suggested that vitamin D may also play a role in the homeostasis of glucose metabolism and the development of type 1 and type 2 diabetes mellitus (DM). Epidemiologic data has long suggested a link between exposure to vitamin D early in life and the development of type 1 DM. 9 ,10 Vitamin D 3 receptors have strong immune-modulating effects. In some populations the development of type 1 DM is associated with polymorphisms in the vitamin D receptor gene. 11 ,12 There is also some evidence that increased vitamin D intake by infants may reduce the risk of the development of type 1 DM. 13

Vitamin D has recently been associated with several of the contributing factors known to be linked to the development of type 2 DM, including defects in pancreatic βcell function, insulin sensitivity, and systemic inflammation. Several physiologic mechanisms have been proposed, including the effect of vitamin D on insulin secretion, the direct effect of calcium and vitamin D on insulin action, and the role of this hormone in cytokine regulation. 9 ,12 ,13 Although most studies indicating this relationship are observational, one meta-analysis showed a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalence of type 2 DM or metabolic syndrome. The study concluded that the highest type 2 DM prevalence, 0.36 (95% CI, 0.16–0.80), among participants who were not black was associated with the lowest blood levels of 25-hydroxyvitamin D. In addition, metabolic syndrome prevalence of 0.71 (95% CI, 0.57–0.89) was highest among those with the lowest dairy intake. There was also an inverse relationship between type 2 DM and metabolic syndrome incidences and vitamin D and calcium intake. 14

Vitamin D and Osteoporosis

Osteoporosis is the most common metabolic bone disease in the world. A low vitamin D level is an established risk factor for osteoporosis. Inadequate serum vitamin D levels will decrease the active transcellular absorption of calcium.

Although combination calcium and vitamin D supplementation is associated with higher bone mineral density and decreased incidence of hip fractures, 15 the evidence for vitamin D supplementation alone is less clear. A recent evidence summary found that vitamin D supplementation at doses of more than 700 IU daily (plus calcium) prevented bone loss compared with placebo. 16 However, vitamin D supplementation (300 to 400 IU daily) without calcium did not affect fractures. 16 A Cochrane review found unclear evidence that vitamin D alone affected hip, vertebral, or other fracture rates but supported the use of vitamin D with calcium in frail, elderly nursing home residents. 17 A subsequent meta-analysis of trials looking at vitamin D and fracture rates concurred that calcium was also necessary to affect a significant difference. 18

The most recent meta-analysis of 12 randomized, controlled trials that included more than 42,000 people found that vitamin D supplementation of more than 400 IU daily slightly reduced incidence of nonvertebral fractures (rate ratio, 0.86; 95% CI, 0.77–0.96). 19 The effect was dose dependent and was not significant if doses were ≤400 IU daily.

Vitamin D and Falls among the Elderly

Vitamin D status is increasingly recognized as an important factor in fall status among elderly patients. Several trials have demonstrated that vitamin D supplementation decreases the risk of falling. One proposed mechanism is that higher vitamin D levels are associated with improved muscle function.

A randomized, controlled trial from Australia evaluated women with at least one fall in the preceding 12 months and with a plasma 25-hyroxyvitamin D level <24.0 ng/mL. 20 All women were given calcium 1000 mg per day and were randomized to receive either ergocalciferol 1000 IU per day or placebo. Women in the study group had fewer falls after 12 months, but this was not a significant difference (53% versus 62.9%; odds ratio, 0.66; 95% CI, 0.41–1.06). After correction for height difference in the 2 groups, the ergocalciferol group had a significantly lower risk of falling (odds ratio, 0.61; 95% CI, 0.37–0.99).

A dose of 800 IU daily significantly reduced the risk of falling compared with a placebo in a dose-stratified analysis of the effect of 5 months of vitamin D supplementation on fall risk (72% lower incidence rate ratio; rate ratio, 0.28; 95% CI, 0.10–0.75). Lower doses of vitamin D, however, did not significantly change the rate of fall incidence compared with placebo. 21

A review of 12 randomized, controlled trials studying the effect of vitamin D supplementation on fall risk among both nursing home residents and community dwellers found a small benefit of supplementation on fall risk (odds ratio, 0.89; 95% CI, 0.80–0.99), 9 an effect that was also shown in a review of randomized, controlled trials with strict inclusion criteria, which included 1237 men and women with a mean age of 70 years and supplementation for 2 months to 3 years. The pooled results showed a significant 22% decrease in fall risk among those treated with vitamin D versus placebo or calcium only. The number needed to treat from the pooled results was 15 to prevent 1 person from falling 22 Assessing vitamin D levels in a population at high risk for falling and supplementing with 800 to 1000 IU daily of vitamin D should be a part of any fall prevention program.

Vitamin D and Cancer

Both observational studies in humans and animal models support that vitamin D has a beneficial role in cancer prevention and survival. The mechanism of action is probably related to its role in the regulation of cell growth and differentiation. 23 In the Health Professionals Follow-Up study (a cohort study of 1095 men), each increment in 25(OH)D level of 25mmol/L was associated with a 17% reduction of total cancer cases. 24 However, the National Health and Nutrition Examination Survey of 16,818 men and women did not find a relationship between total cancer mortality and vitamin D level. There was an inverse relationship between vitamin D level and colorectal cancer, however. In this study, serum 25(OH)D levels of ≥80 nmol/L conferred a 72% reduction in risk of colorectal cancer compared with a level lower than 50 nmol/L. 25

A recent meta-analysis of 63 observational studies looked at the relationship between vitamin D levels and cancer incidence and mortality. 26 Twenty of the 30 studies looking at vitamin D and colon cancer showed that people with higher vitamin D levels had either a lower incidence of colon cancer or decreased mortality. Similarly, 9 of the 13 studies about breast cancer and 13 of the 26 studies about prostate cancer showed beneficial effects of vitamin D levels on cancer incidence or mortality (some of the studies included more than one type of cancer). 26

A population-based randomized, control trial found that postmenopausal women who were supplemented with calcium and vitamin D had a reduced risk of cancer after the first year of treatment (rate ratio, 0.232; 95% CI, 0.09–0.60). 27 There was not a group that was supplemented with vitamin D alone.

Vitamin D and Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative, T lymphocyte-mediated, autoimmune disease of uncertain etiology. Although genetic susceptibility may be involved, epidemiologic studies suggest environmental influence because the development of MS correlates most strongly with rising latitude in both the northern and southern hemispheres. 28 Migration studies show that risk can be modified at an early age from both low to high and high to low prevalence rates. 28 Exposure to sun in early childhood is associated with reduced risk of developing MS 29 and population-based studies about MS in Canada have also shown that birth timing is a risk factor for MS because there are statistically significantly fewer patients with MS born in November and more born in May compared with controls. 30 A birth-timing association suggests that seasonality and sunlight exposure may also have an effect on the developing fetus in utero. 30 ,31

Several studies have shown that vitamin D affects the growth and differentiation of immune-modulator cells such as macrophages, dendritic cells, T cells, and B cells. 32–34 This immune-modulatory effect has implications for a variety of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosous, type I DM, inflammatory bowel disease, and MS. 33

Despite the wealth of epidemiologic studies supporting a relationship between vitamin D and MS in humans, data showing a link between serum vitamin D levels and MS are only beginning to emerge. One prospective, nested, case-control study examined the serum samples of 7 million military veterans and compared serum samples of 257 MS patients before diagnosis with those of matched controls. 35 An inverse relationship between vitamin D levels and MS risk was found, particularly for vitamin D levels measured in patients younger than 20. Another case-control study compared the serum vitamin D levels of 103 MS patients with 110 controls and found that for every 10-nmol/L increase of serum 25(OH)D level the odds of MS was reduced by 19% in women, suggesting a “protective” effect of higher vitamin D levels. 36 In addition, a negative correlation was found between Expanded Disability Status Scale scores among female MS patients and 25(OH)D levels. Several other studies have supported the finding that lower levels of vitamin D in MS patients are associated with more severe disability. 37 Lower levels during relapses have also been reported in patients with relapse-remitting MS. 38–40

The potential effects of oral vitamin D intake have been observed in several different ways. A Norwegian case-control study found that fish and cod liver oil have a protective effect against the development of MS. 29 A large observational study in the United States that followed 2 large cohorts of women—the Nurses’ Health Study (92,253 women followed from 1980 to 2000) and the Nurses’ Health Study II (95,310 women followed from 1991 to 2001)—found that vitamin D supplementation in the form of a multivitamin seemed to lower their MS risk by 40%. 41 However, several methodological weaknesses in study design made the results inconclusive. 42

Despite the overwhelming amount of data describing the association between vitamin D and MS, there is a paucity of research describing the benefit of vitamin D supplementation to these patients. One small safety study of 12 patients taking 1000 μg per day (40,000 IU) of vitamin D for 28 weeks showed a decline in the number of gadolinium-enhancing lesions on magnetic resonance imaging per patient; this led to a 25(OH)D serum concentration of 386 nmol/L (158 ng/mL) without causing hypercalcemia, hypercalciuria, or other complication. 43

Vitamin D and Cognition

Observational studies have shown that people with Alzheimer dementia have lower vitamin D levels than do matched controls without dementia. 44 The biological plausibility of this relationship includes vitamin D's antioxidative effects and the presence of vitamin D receptors in the hippocampus, which has been seen in rats and humans. 44 A cross-sectional study of 225 outpatients diagnosed with Alzheimer disease found a correlation between vitamin D levels (but not other vitamin levels) and their score on a Mini Mental Status Examination. 45

Vitamin D and Chronic Pain

Because of the important role vitamin D plays in bone homeostasis, some have questioned whether vitamin D deficiency may also correlate with chronic pain syndromes, including chronic low back pain. Several case series and observational studies have suggested that vitamin D inadequacy may represent a source of nociception and impaired neuromuscular functioning among patients with chronic pain.

The data to support this conclusion are mixed. A recent review of 22 relevant studies found no convincing link between prevalence and latitude and no association between serum levels of 25-OH vitamin D in chronic pain patients and controls. Interestingly, though, there was a contrast in treatment effects between randomized, double-blind trials that minimized bias and those with studies known to be subject to bias. In those that blinded the vitamin D therapy, only 10% of patients were in trials showing a benefit of vitamin D treatment, whereas among those who did not blind the treatment 93% were in trials showing a benefit of vitamin D supplementation. 46

A second review examined the role of vitamin deficiency in patients from outpatient and inpatient rehab units. Fifty-one articles were reviewed and a direct correlation was noted between vitamin D deficiency and musculoskeletal pain. Treatment of vitamin D deficiency produced an increase in muscle strength and a marked decrease in back and lower-limb pain within 6 months. 47 Although these data were suggestive of a link between vitamin D and pain, the available evidence does not imply causality. The verdict on this topic will remain undecided until this is evaluated by double-blind, randomized, controlled trials stratified by baseline vitamin D level with defined treatments and comparison placebo groups.

• Vitamin D Supplementation for Infants and Breastfeeding Mothers

Breast milk is an ideal form of nourishment for a newborn. Because of most nursing mother's own vitamin D deficiency, however, and despite the mother taking a prenatal vitamin, breast milk alone is not sufficient to maintain newborn vitamin D levels within a normal range. 48 Many nursing mothers or their infants require vitamin D supplementation for optimal health. 49

In 2003, the American Academy of Pediatrics recommended that 200 IU of vitamin D be used as supplementation for all infants beginning during the first 2 months after birth. 50 More recently, in 2008 the recommendation has been increased to a minimum of 400 IU daily during the first days of life to prevent vitamin D deficiency that may lead to rickets. 48

A 2004 systematic review looked at 166 cases of nutritional rickets diagnosed between 1986 and 2004 in 17 states from the mid-Atlantic region to Texas and Georgia. A disproportionate number of rickets cases were found in African-American, breastfed infants. 51 In addition to rickets and the risk of developing type I DM, other pediatric and adult health conditions may be impacted by insufficient vitamin D levels in infants and their mothers. 52 Both bone mineral accrual in early childhood 53 and the risk of recurrent wheezing episodes in children at age 3 54 were linked to insufficient vitamin D intake by women during pregnancy. If a fetus or breastfeeding infant receives an inadequate amount of vitamin D from its mother it can have a direct impact on the baby's health as an adult. Because of these findings, in 2007 the Canadian Pediatric Society recommended 2000 IU of vitamin D 3 for pregnant and lactating mothers with periodic blood tests to check levels of 25 (OH)D and calcium. 52 The American Academy of Pediatrics recommendations focus on supplementing the infant and make no specific recommendations about universally supplementing breastfeeding mothers. 48

Supplementing the Newborn: 2008 Recommendations from the American Academy of Pediatrics

The American Academy of Pediatrics recommends supplementing all children who are exclusively breastfed with 400 IU of vitamin D from the first few days of life. Children who are fed by breast and formula or who are exclusively formula fed should also be supplemented until they are consistently ingesting 1 L of formula a day (approximately 1 quart). The supplementation should continue until 1 year of age, when children begin ingesting vitamin D-fortified milk. 48 All formulas sold in the United States contain at least 400 IU/L of vitamin D 3 ; therefore, 1 L per day would meet the vitamin D recommendations set by the American Academy of Pediatrics. 55

Preparations for Supplementation

There are many available preparations for newborns ( Table 1 ). Some companies make a single-drop preparation that contains 400 IU, but caution should be used when prescribing this product because of the ease of dispensing too much vitamin D to a newborn with just a few drops. 48

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Vitamin D Preparations for Newborns

Checking Serum Levels in Infants

Clinicians should obtain a serum vitamin D level (25-OH-D not 1,25-OH 2 -D) among infants with malabsorption disorders or who take anticonvulsants because they may need additional supplementation above 400 IU daily. Actual values of 25-OH-D that determine vitamin D insufficiency in children have not been defined. The ≥20 ng/mL of 25-OH-D that determines a sufficient vitamin D level for adults has been used for children. 48

Supplementing Breastfeeding Mothers

Mothers who were supplemented with 400 IU of vitamin D daily produced milk with vitamin D levels that ranged from <25 to 78 IU per liter. 48 Supplementing the mother alone with 400 IU—equivalent to a prenatal vitamin—produced inadequate vitamin D levels in the breastfed infants. 55 A randomized, controlled trial evaluated 19 breastfeeding mothers who were supplemented with 6000 IU of vitamin D 3 and a prenatal vitamin with 400 IU of vitamin D. The vitamin D levels found in their breast milk and in the exclusively breastfed infants themselves were found to be equivalent to the infants who received oral supplementation (300 IU per day). This level of maternal supplementation showed no toxic effects and provided adequate vitamin D to nursing infants without needing to supplement the infant. 56 Safety and efficacy of this dosing during pregnancy and lactation has not been confirmed. In the meantime, screening high-risk women is appropriate and supplementing breastfeeding women who are vitamin D 3 deficient is warranted. 57

• Testing for Vitamin D Deficiency

There are many causes of vitamin D deficiency, as listed in ( Table 2 ), 59 and despite growing attention to this deficiency, there are no established guidelines to help clinicians decide which patients warrant screening laboratory testing. The US Preventive Services Task Force does not comment for or against routine screening for vitamin D deficiency. One approach is to consider serum testing in patients at high risk for vitamin D deficiency but treating without testing those at lower risk.

Causes of Vitamin D Deficiency 58

An Australian working group issued a position statement itemizing groups of people at risk for vitamin D deficiency. The risk groups include: (1) older people in low- and high-level residential care; (2) older people admitted to hospital; (3) patients with hip fracture; (4) dark-skinned women (particularly if veiled); and (5) mothers of infants with rickets (particularly if dark-skinned or veiled). 58

If electing to test vitamin D status, serum 25-hydroxyvitamin D is the accepted biomarker. 60 Although 1,25-OH-D is the active circulating form of vitamin D, measuring this level is not helpful because it is quickly and tightly regulated by the kidney. True deficiency would be evident only by measuring 25-OH-D. Of note, questions have been raised regarding the need for standardization of assays. 61 A large laboratory (Quest Diagnostics) recently reported the possibility of thousands of incorrect vitamin D level results. 62 Sunlight exposure questionnaires are imprecise and are not currently recommended. 63

Controversy exists regarding the optimum level of serum 25-hydroxyvitamin D in a healthy population. Most experts agree that serum vitamin D levels <20 ng/mL represent deficiency. However, some experts recommend aiming for a higher minimum target level of 30 ng/mL of 25-hydroxyvitamin D 49 in a healthy population. Vitamin D intoxication can occur when serum levels are greater than 150 ng/mL. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and weakness probably caused by the resultant hypercalcemia. Of note, sun exposure alone cannot lead to vitamin D intoxication as excess vitamin D 3 is destroyed by sunlight.

Given concern about skin cancer, many patients and clinicians are cautious regarding sun exposure recommendations. However, exposure of arms and legs for 5 to 30 minutes between the hours of 10 am and 3 pm twice a week can be adequate to prevent vitamin D deficiency. 59

Natural dietary sources of vitamin D include salmon, sardines, mackerel, tuna, cod liver oil, shiitake mushrooms, and egg yolk. 58 Fortified foods include milk, orange juice, infant formulas, yogurts, butter, margarine, cheeses, and breakfast cereals. 59

Over-the-counter multivitamin supplements frequently contain 400 IU of vitamins D 1 , D 2 , or D 3 . Alternatively, over-the-counter vitamin D 3 supplements can be found in 400, 800, 1000, and 2000 IU strengths. Prescription-strength supplementation choices include vitamin D 2 (ergocalciferol), which provides 50,000 IU per capsule, and vitamin D 2 liquid (drisdol) at 8000 IU/mL. 59

To prevent vitamin D deficiency in healthy patients, the 1997 Institute of Medicine recommendations suggested a daily vitamin D intake of 200 IU for children and adults up to 50 years of age; 400 IU for adults 51 to 70 years of age; and 600 IU for adults 71 years or older. 64 The upper limit recommended was 2000 IU daily. However, some experts consider this to be too low and recommend that children and adults without adequate sun exposure consume 800 to 1000 IU daily to achieve adequate serum vitamin D levels. 59

Treatment recommendations vary depending on the cause of the deficiency. For example, patients with chronic kidney disease are recommended to have 1000 IU of vitamin D 3 daily. 59 The expected blood level response to a given vitamin D dose varies, probably because of differences in the cause of the deficit as well as the starting point for correction. A recent editorial reported that supplemental intakes of 400 IU per day of vitamin D increase 25(OH)D concentrations by only 2.8 to 4.8 ng/mL (7–12 nmol/L) and that daily intakes of approximately 1700 IU are needed to raise these concentrations from 20 to 32 ng/mL (50–80 nmol/L). 65 Responses to vitamin D supplementation or sun exposure may vary by patient, so clinicians may need to continue to monitor abnormal levels.

This article was externally peer reviewed.

Funding: none.

Conflict of interest: none declared.

• Received for publication February 27, 2009.
• Revision received July 10, 2009.
• Accepted for publication July 13, 2009.
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Vitamin d deficiency and depression in adults: systematic review and meta-analysis.

Published online by Cambridge University Press:  02 January 2018

• Supplementary materials

There is conflicting evidence about the relationship between vitamin D deficiency and depression, and a systematic assessment of the literature has not been available.

To determine the relationship, if any, between vitamin D deficiency and depression.

A systematic review and meta-analysis of observational studies and randomised controlled trials was conducted.

One case-control study, ten cross-sectional studies and three cohort studies with a total of 31 424 participants were analysed. Lower vitamin D levels were found in people with depression compared with controls (SMD = 0.60,95% Cl 0.23–0.97) and there was an increased odds ratio of depression for the lowest v. highest vitamin D categories in the cross-sectional studies (OR = 1.31, 95% CI 1.0–1.71). The cohort studies showed a significantly increased hazard ratio of depression for the lowest v. highest vitamin D categories (HR=2.21, 95% CI 1.40–3.49).

Our analyses are consistent with the hypothesis that low vitamin D concentration is associated with depression, and highlight the need for randomised controlled trials of vitamin D for the prevention and treatment of depression to determine whether this association is causal.

Depression is associated with significant disability, mortality and healthcare costs. It is the third leading cause of disability in high-income countries, Reference Lopez, Mathers, Ezzati, Jamison and Murray 1 and affects approximately 840 million people worldwide. 2 Although biological, psychological and environmental theories have been advanced, Reference Krishnan and Nestler 3 the underlying pathophysiology of depression remains unknown and it is probable that several different mechanisms are involved. Vitamin D is a unique neurosteroid hormone that may have an important role in the development of depression. Receptors for vitamin D are present on neurons and glia in many areas of the brain including the cingulate cortex and hippocampus, which have been implicated in the pathophysiology of depression. Reference Eyles, Smith, Kinobe, Hewison and McGrath 4 Vitamin D is involved in numerous brain processes including neuroimmunomodulation, regulation of neurotrophic factors, neuroprotection, neuroplasticity and brain development, Reference Fernandes de Abreu, Eyles and Feron 5 making it biologically plausible that this vitamin might be associated with depression and that its supplementation might play an important part in the treatment of depression. Over two-thirds of the populations of the USA and Canada have suboptimal levels of vitamin D. Reference Ginde, Liu and Camargo 6 , Reference Langlois, Greene-Finestone, Little, Hidiroglou and Whiting 7

Some studies have demonstrated a strong relationship between vitamin D and depression, Reference Wilkins, Sheline, Roe, Birge and Morris 8 , Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 whereas others have shown no relationship. Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 , Reference Pan, Lu, Franco, Yu, Li and Lin 11 To date there have been eight narrative reviews on this topic, Reference Barnard and Colon-Emeric 12 – Reference Humble 19 with the majority of reviews reporting that there is insufficient evidence for an association between vitamin D and depression. None of these reviews used a comprehensive search strategy, provided inclusion or exclusion criteria, assessed risk of bias or combined study findings. In addition, several recent studies were not included in these reviews. Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 , Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 , Reference Johnson, Fischer and Park 20 , Reference Zhao, Ford and Li 21 Therefore, we undertook a systematic review and meta-analysis to investigate whether vitamin D deficiency is associated with depression in adults in case–control and cross-sectional studies; whether vitamin D deficiency increases the risk of developing depression in cohort studies in adults; and whether vitamin D supplementation improves depressive symptoms in adults with depression compared with placebo, or prevents depression compared with placebo, in healthy adults in randomised controlled trials (RCTs).

Search strategy

We searched the databases MEDLINE, EMBASE, PsycINFO, CINAHL, AMED and Cochrane CENTRAL (up to 2 February 2011) using separate comprehensive strategies developed in consultation with an experienced research librarian (see online supplement DS1). A separate search of PubMed identified articles published electronically prior to print publication within 6 months of our search and therefore not available through MEDLINE. The clinical trials registries clinicaltrials.gov and Current Controlled Trials ( controlled-trials.com ) were searched for unpublished data. The reference lists of identified articles were reviewed for additional studies.

Eligibility criteria

The following study designs were included: RCTs, case–control studies, cross-sectional studies and cohort studies. All studies enrolled adults (age 18 years) and reported depression as the outcome of interest and vitamin D measurements as a risk factor or intervention. Cross-sectional and cohort studies were required to report depression outcomes for participants with vitamin D deficiency (as defined by each study, see Tables 1 and 2 ) compared with those with normal vitamin D levels. There was no language restriction. Eligibility criteria are detailed in online supplement DS2.

Our primary outcome for all studies was depression diagnosed using one of the following:

(a) a standardised psychiatric interview for the DSM diagnoses of depressive disorders (e.g. the Structured Clinical Interview for DSM Disorders) or ICD diagnoses of a depressive episode ordepression (e.g. the Composite International Diagnostic Interview); Reference Spitzer, Williams, Gibbon and First 22 , Reference Robins, Wing, Wittchen, Helzer, Babor and Burke 23

(b) a clinical diagnosis of a depressive disorder, depressive episode or depression not otherwise specified;

(c) a diagnosis of depression using an established cut-off point on a validated rating scale, such as a score of ⩾16 on the Center for Epidemiological Studies – Depression scale or ⩾8 on the Geriatric Depression Scale. Reference Orme, Reis and Herz 24 , Reference Yesavage, Brink, Rose, Lum, Huang and Adey 25

For RCTs that enrolled patients with depression our secondary outcome was change in depressive symptoms using a validated rating scale. This secondary outcome was not used for RCTs that enrolled non-depressed participants or other study designs because it was not meaningful in those contexts.

Study selection and data abstraction

Two authors (R.A. and Z.S.) independently reviewed all titles and abstracts identified by the search. Articles were selected for full-text review if inclusion criteria were met or if either reviewer considered them potentially relevant. Disagreements were resolved by discussion between the two reviewers, and a third author (S.M.) was available to determine eligibility if consensus could not be reached. Initial agreement was assessed using an unweighted κ value. Data were extracted by two authors (R.A. and Z.S.) independently using a form developed for this review, with disagreements resolved as above. We attempted to contact study authors for additional or missing information when needed.

Assessment of risk of bias

Two reviewers (R.A. and Z.S.) independently assessed the risk of bias using a modified Newcastle–Ottawa Scale (see online supplement DS3). Reference Wells, Shea, O'Connell, Peterson, Welch and Losos 26 In observational studies one of the main sources of bias is confounding. Known confounders can be statistically adjusted, but unknown confounders may still result in bias. It was decided a priori that studies that adjusted for factors shown elsewhere to affect vitamin D levels (chronic disease, body mass index, geographical location, season and physical activity) Reference Hanley, Cranney, Jones, Whiting, Leslie and Cole 27 , Reference Rosen 28 would be considered to have a low risk of bias, studies that adjusted only for other potential confounders would have an unclear risk of bias, and any studies that did not adjust for any confounders would have a high risk of bias. Publication bias was assessed using funnel plots.

Statistical analysis

Search results were compiled using citation management software (RefWorks version 2.0; ProQuest, http://www.refworks.com ). Statistical analysis was performed using Review Manager software (Revman version 5.1; Cochrane Collaboration, Oxford, UK), Epi Info version 6.0 (CDC, Atlanta, Georgia, USA) and PASW Statistics version 18.0 (SPSS, Chicago, Illinois, USA) for Mac.

Case–control studies

The standardised mean difference (SMD) of vitamin D levels between the participants with depression and the healthy controls was calculated. An SMD below 0.4 was considered small, 0.4–0.7 moderate and over 0.7 large. Reference Higgins and Green 29 Our protocol proposed pooling SMDs for meta-analysis using a random effects model.

Cross-sectional studies

Our protocol proposed examining adjusted odds ratios (ORs) of depression for those with or without vitamin D deficiency (as defined in each study) and the associated 95% confidence intervals. We planned to pool the adjusted ORs for meta-analysis. Unfortunately the cross-sectional studies used different reference categories of vitamin D concentration (either <50 nmol/l or the lowest and highest category) and presented data using different quartiles, tertiles or categories. After protocol development, but prior to analysing the data, we decided to use the adjusted OR of depression for the lowest v . highest vitamin D categories reported. The inverse variance method and random effects model were used for all meta-analyses. A random effects model was chosen because we anticipated heterogeneity among studies. Where ORs were reported for subgroups of patients within a single study, they were combined into a single OR for our analysis. Reference Nanri, Mizoue, Matsushita, Poudel-Tandukar, Sato and Ohta 30

Cohort studies

As with the analysis of cross-sectional studies, the variability in presentation of results of the cohort studies precluded the calculation of a pooled adjusted OR. We therefore contacted the authors of all three cohort studies to obtain the number of depressed participants and the person-years of follow-up in each category of vitamin D, and requested data using the cut-off point of 50 nmol/l. This allowed us to calculate hazard rates for each category, so that we could then account for losses to follow-up and variable follow-up periods; also, by assuming a constant hazard rate over time, we could pool hazard ratios using a cut-off point of 50 nmol/l. All authors provided some data, but one provided only data using the cut-off points of 37.5 nmol/l and 75 nmol/l. Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 We therefore performed a sensitivity analysis using these two cut-off points in a meta-analysis.

Additionally, we decided to analyse the cohort data using the highest v . lowest vitamin D categories in order to use the adjusted results and take confounding into account. For this analysis the adjusted hazard ratios were used; the adjusted OR from one study was converted first to a relative risk and then to a hazard ratio (HR). Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 Finally, we performed a third analysis in which we calculated the increase in the natural logarithm of the hazard rate (ln(HR)) of depression per 20 nmol/l decrease in vitamin D for each study. Reference Greenland and Longnecker 31 The mid-point of each category of vitamin D was calculated and half the width of the adjacent category was used to define the corresponding point for open-ended categories. The ln(HR) for each category was then regressed on the vitamin D mid-points (divided by 20) using a linear model, with the data weighted by the inverse variance of the ln(HR), to generate a coefficient that represented the change in ln(HR) per 20 nmol/l decrease in vitamin D and its associated standard error. The coefficients for each study were then pooled for meta-analysis.

Assessment of heterogeneity

Heterogeneity between the studies was measured using Cochran's Q statistic, with a probability value of P <0.05 (two-tailed) considered statistically significant. The I 2 statistic was used to quantify the degree of heterogeneity and we considered values below 25% to be low, 25–50% moderate and over 50% high. Reference Higgins, Thompson, Deeks and Altman 32

Subgroup and sensitivity analyses

We planned the following subgroup analyses a priori : gender, age ⩾65 years, prevalence of vitamin D deficiency, proportion of participants with a disease known to affect vitamin D, and adjustment for different confounders. We planned a priori to perform a sensitivity analysis excluding studies with a high risk of bias. For the cohort studies we performed a sensitivity analysis using the cut-off point of 37.5 nmol/l compared with 75 nmol/l for the one study that did not provide data using our standard cut-off point of 50 nmol/l. We also performed a sensitivity analysis for the cross-sectional studies excluding one study that had recruited participants aged 15–39 years Reference Ganji, Milone, Cody, McCarty and Wang 33 (our inclusion criteria specified adults aged 18 years).

Our primary search identified 6675 citations ( Fig. 1 ). No additional article or abstract was selected from other sources. After duplicates were removed 5484 citations remained for title and abstract screening. Of these, 35 were identified and retrieved for full-text screening; all were in English. After full text review, one case–control study, Reference Eskandari, Martinez, Torvik, Phillips, Sternberg and Mistry 34 three cohort studies, Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 , Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 , Reference Milaneschi, Shardell, Corsi, Vazzana, Bandinelli and Guralnik 35 and ten cross-sectional studies, Reference Wilkins, Sheline, Roe, Birge and Morris 8 , Reference Pan, Lu, Franco, Yu, Li and Lin 11 , Reference Johnson, Fischer and Park 20 , Reference Zhao, Ford and Li 21 , Reference Nanri, Mizoue, Matsushita, Poudel-Tandukar, Sato and Ohta 30 , Reference Ganji, Milone, Cody, McCarty and Wang 33 , Reference Hoogendijk, Lips, Dik, Deeg, Beekman and Penninx 36 – Reference Wilkins, Birge, Sheline and Morris 39 met eligibility criteria and were included (unweighted κ = 0.75). Figure 1 lists the reasons for excluding the other studies. Reference Humble 19 , Reference Reed, Laya, Melville, Ismail, Mitchell and Ackerman 40 – Reference Buell 58

Study characteristics

Baseline information on the case–control, cross-sectional and cohort studies is presented in Tables 1 and 2 . There were 31 424 participants in total. All studies were published between 2006 and 2011; study locations included the USA, Europe and East Asia. Seven of the ten cross-sectional studies included older adults.

Fig. 1 Study selection process.

Risk of bias in included studies

Case–control study.

The agreement between the reviewers in assessing the risk of bias for the case–control study across the nine points of the Newcastle–Ottawa Scale was 100%, with both reviewers assigning the same four points. There was potential for selection bias as participants were recruited through advertisements and were all premenopausal women; also, the study did not control for known confounders.

Agreement between the reviewers in assessing the risk of bias in cross-sectional studies was 95%, unweighted κ = 0.84. Four studies were thought to be unrepresentative of the general population: Johnson et al included only low-income older adults; Reference Johnson, Fischer and Park 20 Lee et al included only elderly men; Reference Lee, Tajar, O'Neill, O'Connor, Bartfai and Boonen 37 and the two studies by Wilkins et al included only elderly participants, half of whom in the 2006 study were purposely selected to have Alzheimer's disease, and in the 2009 study were purposely selected to include African Americans and European Americans in equal numbers. Reference Wilkins, Sheline, Roe, Birge and Morris 8 , Reference Wilkins, Birge, Sheline and Morris 39 Seven studies received a high risk of bias assignment for assessment of outcome because they used cut-off points on self-reported psychiatric rating scales. Two studies received an unclear risk of bias assignment for using administered surveys, which were felt to have an intermediate risk of bias between a self-report scale and clinician-administered standardised psychiatric interview. All studies adjusted for multiple confounders (online supplement DS4). The funnel plot (online supplement DS5) did not suggest significant publication bias.

Agreement between the reviewers in assessing the risk of bias across cohort studies was 88%, unweighted κ = 0.61. Two studies Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 , Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 were considered unrepresentative of the general population, and the study by May et al was thought to be at high risk of bias for selection of the non-exposed cohort because vitamin D levels were obtained at the discretion of treating physicians, Reference May, Bair, Lappe, Anderson, Home and Carlquist 9 which may have biased whose vitamin D levels were observed. All studies included in this review adjusted for multiple confounders, but May et al did not measure or adjust for physical activity, body mass index or the presence of chronic diseases and therefore received an unclear risk of bias rating. Chan et al and Milaneschi et al used cut-off points on self-report scales to diagnose depression, Reference Chan, Chan, Woo, Ohlsson, Mellstrom and Kwok 10 , Reference Milaneschi, Shardell, Corsi, Vazzana, Bandinelli and Guralnik 35 which is less reliable than a clinical diagnosis, and therefore these studies were rated at high risk of bias. Although May et al used a clinical diagnosis of depression using ICD-9 codes, it was not clear whether all participants underwent a clinical assessment or whether record linkage was used; an unclear risk of bias was therefore assigned. May et al presented the average duration of follow-up period but did not otherwise describe loss to follow-up, and therefore this received an unclear rating. Because there were only three cohort studies the funnel plot was uninformative. Reference Sutton, Duval, Tweedie, Abrams and Jones 59 Further information on the risk of bias assessments is included in online supplement DS5.

Outcome evaluation and meta-analysis

A summary of the results from the cross-sectional and cohort meta-analyses including subgroup and sensitivity analyses is presented in Table 3 . Three cross-sectional studies did not report ORs, and the authors of these studies were contacted. Reference Johnson, Fischer and Park 20 , Reference Hoogendijk, Lips, Dik, Deeg, Beekman and Penninx 36 , Reference Wilkins, Birge, Sheline and Morris 39 One author replied and the OR provided was included in the meta-analysis; Reference Hoogendijk, Lips, Dik, Deeg, Beekman and Penninx 36 an unadjusted OR and 95% CI were calculated for another study using data provided in the paper and Epi Info version 6.0, Reference Wilkins, Birge, Sheline and Morris 39 but the third study could not be included. Reference Johnson, Fischer and Park 20

Table 1 Characteristics of included studies: case–control and cross-sectional studies

BDI, Beck Depression Inventory; CES-D, Center for Epidemiological Studies – Depression scale; CPBA, competitive protein binding assay; DIS, Diagnostic Interview Schedule; GDS, Geriatric Depression Scale; NA, not applicable; NR, not reported; PHQ, Patient Health Questionnaire; RIA, radioimmunoassay; SCID, Structured Clinical Interview for DSM-IV.

Table 2 Characteristics of included studies: cohort studies

CIA, chemiluminescent immunoassay; CES-D, Center for Epidemiological Studies – Depression scale; GDS, Geriatric Depression Scale; NR, not reported; RIA, radioimmunoassay.

a. Most of cohort (71%) ‘not evaluable’ at 500 days.

b. Mean follow-up period.

One study compared vitamin D levels in women with depression and healthy controls. Reference Eskandari, Martinez, Torvik, Phillips, Sternberg and Mistry 34 The mean difference between the groups was 17.5 nmol/l ( P = 0.002), with an SMD of 0.60 (95% CI 0.23–0.97). This represented a moderate difference, Reference Higgins and Green 29 which was also clinically significant. Meta-analysis could not be performed as only one study met our inclusion criteria.

The cross-sectional studies measured rates of depression and vitamin D in a population at a single point in time to determine whether there was an association between depression and vitamin D levels. Nine studies reported on depression for the lowest v . the highest vitamin D categories, with a pooled OR of 1.31, 95% CI 1.00–1.71 ( Fig. 2 ). There was substantial heterogeneity between studies ( I 2 = 54%, χ 2 = 17.24, P = 0.03). The only subgroup analysis that could be performed was of studies that had an average sample age of 65 years (online supplement DS5). When these studies were combined there was an increased – although non-significant – odds of depression with low vitamin D (OR = 1.54, 95% CI 1.00–2.40). A sensitivity analysis excluding the study by Ganji et al (online supplement DS6) had a minimal effect on our summary estimate (OR = 1.34, 95% CI 0.99–1.83, I 2 = 59%, χ 2 = 17.16, P = 0.02). Reference Ganji, Milone, Cody, McCarty and Wang 33

Three studies measured vitamin D levels at baseline in non-depressed individuals and followed them over time to determine whether vitamin D levels were associated with a risk of developing depression. There was a statistically significant increased risk of depression with low vitamin D (HR = 2.21, 95% CI 1.40–3.49) with non-significant heterogeneity ( I 2 = 21%, χ 2 = 2.52, P = 0.28) when the HRs for depression for the lowest v . highest vitamin D categories in the three cohort studies were pooled ( Fig. 3 ). The change in the ln(HR) of depression per 20 nmol/l change in vitamin D level was calculated for each study and pooled. There was a non-significant decreased ln(HR) of depression for each 20 nmol/l increase in vitamin D (β = −0.19, 95% CI −0.41 to 0.04; Fig. 4 ).

Table 3 Summary of results from the meta-analysis of cross-sectional and cohort studies of the relationship between vitamin D and depression

HR, hazard rate; OR, odds ratio.

Fig. 2 Cross-sectional studies: forest plot of the odds ratio (OR) of depression for the lowest v. highest vitamin D categories. Squares to the right of the vertical line indicate that low vitamin D was associated with increased odds of depression, squares to the left of the vertical line indicate that low vitamin D was associated with decreased odds of depression. Horizontal lines represent the associated 95% confidence intervals and the diamond represents the overall OR of depression with low vitamin D from the meta-analysis and the corresponding 95% confidence interval ( * OR provided by Dr B. Penninx, personal communication, 25 July 2011).

Fig. 3 Cohort studies: forest plot of the hazard ratio (HR) of depression for the lowest v. highest vitamin D categories. Squares to the right of the vertical line indicate that vitamin D deficiency was associated with an increased risk of depression, whereas squares to the left of the vertical line indicate that vitamin D deficiency was associated with a decreased risk of depression. Horizontal lines represent the associated 95% confidence intervals and the diamond represents the overall HR of depression with vitamin D deficiency from the meta-analysis and the corresponding 95% confidence interval.

The HRs of depression for those with and without vitamin D levels below 50 nmol/l from the studies by Chan et al and Milaneschi et al were pooled with the HR of depression for vitamin D below v . above 37.5 nmol/l from the study by May et al ( Fig. 5 ). The overall HR in this analysis was not significant (HR = 1.04, 95% CI 0.59–1.86). In the second analysis using cut-off points, the HR of depression for vitamin D below v . above 75 nmol/l from the May et al study was pooled with the other results ( Fig. 6 ). This also gave a non-significant HR of 1.31 (95% CI 0.97–1.77). Interestingly, using the cut-off point of 75 nmol/l compared with 37.5 nmol/l changed the direction of the effect in this study. This appears to result from the highest hazard rate, and largest number of participants, being in the 37.5–75 nmol/l category. Therefore, if this group is included in the vitamin D deficient group (cut-off point 75 nmol/l), the HR suggests an increased risk of depression with vitamin D deficiency. However, if this group is included in the normal vitamin D group (cut-off point 37.5 nmol/l), the HR suggests a decreased risk of depression with vitamin D deficiency. Therefore, the effect of vitamin D deficiency at levels below 50 nmol/l cannot be reliably determined from this study.

Fig. 4 Cohort studies: forest plot of the change in the natural logarithm of the hazard rate ln(HR) of depression per 20 nmol/l change in vitamin D using trend estimation. Squares to the right of the vertical line indicate a positive slope or increased risk of depression with increased vitamin D levels, whereas squares to the left indicate a negative slope or decreased risk of depression with increased vitamin D levels. Horizontal lines represent the associated 95% confidence intervals and the diamond represents the overall change in ln(HR) of depression per 20 nmol/l change in vitamin D from the meta-analysis and the corresponding 95% confidence interval.

Fig. 5 Cohort studies: forest plot of the hazard ratios (HR) of depression with vitamin D deficiency using cut-off points of 50 nmol/l and 37.5 nmol/l (see caption to Fig. 3 for explanation of symbols).

Fig. 6 Cohort studies: forest plot of the hazard ratios (HR) of depression with vitamin D deficiency using cut-off points of 50 nmol/l and 75 nmol/l (see caption to Fig. 3 for explanation of symbols).

No planned subgroup or sensitivity analysis could be performed because of insufficiently reported data and inability to obtain such data from authors.

Our systematic review identified one case–control study, ten cross-sectional studies and three cohort studies investigating the association between depression and vitamin D deficiency, but no randomised controlled trial. The single case–control study showed a moderate difference in vitamin D levels between women with depression and healthy controls. Meta-analysis of the cross-sectional studies demonstrated an increased but non-significant odds of depression for the lowest compared with the highest vitamin D categories (OR = 1.31, 95% CI 1.00–1.71, P = 0.05). Limiting the analysis to studies with an average participant age of 65 years or over did not substantially change the overall estimate or statistical significance. There was considerable variability in the vitamin D categories used in the cohort studies, and therefore three different meta-analyses were performed. Our pooled HR of the lowest compared with the highest vitamin D categories in the three cohort studies showed a significantly increased HR of depression with low vitamin D levels (HR = 2.21, 95% CI 1.40–3.49, P <0.001). The pooled change in ln(HR) of depression per 20 nmol/l change in vitamin D level across the three cohort studies also showed an increased hazard of depression with decreasing vitamin D concentration, although this was not significant (β–0.19, 95% CI −0.41 to 0.04, P = 0.1). Finally, we analysed the data using different cut-off points as provided in the studies, which yielded different but non-significant pooled HR: 1.04 (95% CI 0.59–1.86) v . 1.31 (95% CI 0.97–1.77). Overall, the summary estimates of all analyses suggest a relationship between vitamin D and depression, and all but one were close to being statistically significant.

Strengths and limitations

To the best of our knowledge this is the first systematic review or meta-analysis that has analysed the relationship between vitamin D deficiency and depression. We performed a transparent and methodologically rigorous systematic review of the literature. We developed a comprehensive search to identify articles and assessed their eligibility, extracted data and assessed risk of bias in each study in duplicate with a good level of agreement. Our protocol was developed a priori and any post hoc analyses were clearly identified. A particular strength was the method used and extensive analyses performed in an attempt to present the data in a uniform and consistent manner to allow for comparison and combination. We were also successful in obtaining supplemental information from several authors, which allowed us to include the majority of studies.

There are several limitations to our systematic review. As, at the time of our review, there was no RCT of vitamin D for depression our review was restricted to observational studies, which usually yield lower-quality evidence than RCTs. Reverse causality, in which patients with depression have less exposure to the sun and therefore lower vitamin D levels, cannot be ruled out in the cross-sectional studies. In addition there were potential biases across all study designs. Several cross-sectional studies had unrepresentative samples, used self-reports of depression and had small sample sizes. The study results were generally consistent, with the exception of those from Pan et al who reported a decreasedoddsofdepression withlow vitaminD. Reference Pan, Lu, Franco, Yu, Li and Lin 11 This was the only cross-sectional study conducted in China, and geographical differences in the nature and prevalence of vitamin D deficiency and depression might explain their discrepant findings. One small study could not be included in the quantitative analysis as insufficient information was available; it found an increased prevalence of depression with vitamin D deficiency Reference Johnson, Fischer and Park 20 and therefore it is unlikely that it would have significantly affected our findings. Most studies adjusted for multiple confounders; however, unadjusted data were used to generate an odds ratio for one study where an adjusted OR was not provided. Reference Wilkins, Birge, Sheline and Morris 39 All the cohort studies had problems with bias and the largest one had a high risk of bias. Publication bias could not be ruled out, and it is possible that additional cohort studies have measured vitamin D and depression but not reported negative results. The majority of the meta-analyses of the cross-sectional studies and cohort studies had significant heterogeneity and lacked precision. Studies used variable definitions of vitamin D deficiency, and therefore we performed analyses using the lowest v . highest vitamin D categories and different cut-off points rather than adhering to a strict definition of deficiency. As a result of these limitations the overall quality of the evidence from each study is low and therefore some uncertainty remains about the true association between vitamin D deficiency and depression.

Implications of the study

The importance of vitamin D to many brain processes including neuroimmunomodulation and neuroplasticity suggests that it might have a role in psychiatric illness such as depression. The biological plausibility of the association between vitamin D and depressive illness has been strengthened by the identification of vitamin D receptors in areas of the brain implicated in depression, Reference Eyles, Smith, Kinobe, Hewison and McGrath 4 the detection of vitamin D response elements in the promoter regions of serotonin genes, Reference Wang, Tavera-Mendoza, Laperriere, Libby, MacLeod and Nagai 60 and demonstration of interactions between vitamin D receptors and glucocorticoid receptors in the hippocampus. Reference Obradovic, Gronemeyer, Lutz and Rein 61 Given the high prevalence of both vitamin D deficiency and depression, an association between these two conditions would have significant public health implications, particularly as supplementation with vitamin D is cost-effective and without significant adverse effects. The observational studies to date provide some evidence for a relationship between vitamin D deficiency and depression, but RCTs are urgently needed to determine whether vitamin D can prevent and treat depression.

Acknowledgements

We thank Neera Bhatnager, librarian, McMaster University Health Sciences Library, for her assistance in developing the search strategy and Peter Szatmari for his critical review of the manuscript.

Declaration of interest

There was no dedicated funding to support this study. R.A. is supported by an Ontario Mental Health Foundation Research Training Fellowship Award, Z.S. is supported by Hamilton Health Sciences New Investigator Fund and S.M. is supported by a Canadian Institutes of Health Research New Investigator Award.

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• Volume 202, Issue 2
• Rebecca E. S. Anglin (a1) , Zainab Samaan (a2) , Stephen D. Walter (a3) and Sarah D. McDonald (a4)
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• Case Report
• Open access
• Published: 14 May 2009

Nutritional vitamin D deficiency: a case report

• Rachel L Stevens 1 &
• Corey Lyon 1  

Cases Journal volume  2 , Article number:  7000 ( 2009 ) Cite this article

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We present a 6-month-old African American male child with a chief complaint of failure to appropriately gain weight despite adequate caloric intake via breastfeeding. While he has met developmental milestones he appears small for age and is diagnosed with failure to thrive after crossing two major growth curve percentiles. After appropriate diagnostic workup, a diagnosis of nutritional vitamin D deficiency (rickets) was reached and supplementation was initiated with ensuing adequate catch-up growth.

Introduction

Rickets is often considered an "old" disease, a nutritional deficiency that has plagued communities for centuries. The re-emergence of vitamin D deficiency in westernized societies is thought to be multifactorial secondary to poor dietary intake, popularization of breastfeeding, and diminished exposure to sunlight. It is the most common metabolic bone disease in the world and is easily treatable as well as preventable with sun exposure and dietary supplementation [ 1 ].

Vitamin D is a prohormone essential for absorption of calcium from the intestines. Its supply stems from two well-known sources: exposure to sunlight and dietary intake, which accounts for less than 10% [ 2 ]. Vitamin D is primarily made in the skin after exposure to UV-B radiation (290 to 315 nm wavelengths) [ 2 ]. In rickets, decreased stores of this prohormone leads to low levels of ionized calcium, which initially stimulates parathyroid hormone release to initiate calcium resorption in the renal tubules (along with loss of phosphorous), and increase 1,25 dihydroxy vitamin D synthesis. A level of 25 hydroxy vitamin D (25-OH D) less than 12.5 nmol/L (5 ng/mL) is suggested for the diagnosis of rickets with a healthy maintenance level of approximately greater than 50 nmol/L (20 ng/mL) [ 1 , 2 ]. It should be noted that newer data suggests a lower limit of 80 nmol/L may be a more acceptable level in adults [ 1 , 2 ].

Case presentation

We present a 6-month-old African American male child with poor interval growth. His mother has noticed that though he is thought to be breastfeeding appropriately, as defined by feeding 4 ounces of pumped breast milk every 2-3 hours, and has been meeting developmental milestones, his weight and height are not as expected. He has been exclusively breastfed and his mother has not introduced solid foods as of yet to his diet.

He was a full term, spontaneous vaginal delivery without complications during the pregnancy or labor. He was in the 50 th percentile for both height and weight at his 2 month visit, but has fallen to below the 3 rd percentile for weight and is at the 3 rd percentile for height. He is on no medications, there are no other siblings with failure to thrive and his mother has no post-partum depression or substance abuse issues. There is no family history of malabsorptive conditions. His mother and father are of normal stature.

His review of systems is negative for emesis, diarrhea, fever, appetite changes, swallowing abnormalities, respiratory symptoms, apnea, repeated acute illnesses, or frequent injuries.

His weight at the four month well child visit was 6477 grams with a length of 63.5 cm increasing to only 6761 grams and a length of 66 cm by his six month well child visit. His vitals signs are otherwise stable. His physical exam is significant for an alert, playful, developmentally appropriate child, small for his age. His head/neck, cardiac, respiratory, gastrointestinal, genitourinary, musculoskeletal and neurological exams were within normal limits.

He is appropriately diagnosed with failure to thrive at this visit based on deviation across two major percentiles on standardized growth curves. His estimated weight needs were calculated to 0.33 kg/month and a follow up visit was established in one month with addition of solid foods and continued breastfeeding with the addition of formula to pumped breast milk for increased caloric intake. His mother was also instructed to keep a strict food diary.

Interval weight gain was not maintained with a weight of 7045 grams at follow up despite adequate caloric intake estimated based on his food diary and formula supplementation. Laboratory studies ordered were complete metabolic profile, thyroid stimulating hormone (TSH), lead level, and complete blood count (CBC). Electrolytes, kidney function, bilirubin, AST, ALT, protein, albumin, TSH, CBC, and lead were all normal. Alkaline phosphatase was elevated at 4280 (on repeat 6310). Normal should be less than 500 IU/L in neonates and 1000 IU/L in children up to age 9. Follow-up labs including gamma glutamyl transferase (which was normal, suggestive of boney resorption) [ 2 ], C reactive protein, T3, free T4, phosphate, parathyroid hormone, and 25-OH D were ordered. Phosphate was low at 2.9 (normal 3.0-4.5) and the vitamin D level was 11 (45-50 ng/mL).

A skeletal survey was ordered showing metaphyseal fraying and cupping of bilateral distal femurs, bilateral proximal and distal tibiae and fibulae, bilateral proximal and distal humeri, bilateral distal radii and ulni and the distal aspects of 2 nd through the 5 th metacarpals most consistent with rickets of the extremities, see radiograph 1 and 2. These classic findings may be paired with a separation of the periosteum from the diaphysis secondary to unmineralized osteoid when evaluating radiographic evidence of rickets [ 1 , 3 ]. Radiographic improvement should manifest within 3 months of appropriate treatment. Underlying malabsorptive conditions or noncompliance should be considered if this is not observed [ 2 ].

The diagnosis of rickets was made and the patient was started on 2000 IU of vitamin D and calcium carbonate 1000 mg daily. He was also started on iron sulfate 22 mg daily and Zinc 20 mg daily as recommended by pediatric endocrinology and nutrition staff. His catch-up growth has lead to a current weight (at 2 years of age) in the 45 th percentile and height in the 30 th percentile (Figure 1 ). Follow up labs (calcium, phosphorous, alkaline phosphatase) should be performed one month after therapy is initiated and again at 3 months along with magnesium, PTH, and 25-OH D [ 1 , 2 ]. Follow up labs in this patient indicated an improvement in vitamin D up to 29 ng/mL with ongoing supplementation continuing.

Growth Chart: Growth chart from birth to 20 months showing failure of appropriate growth and then his catch up growth after appropriate treatment . Radiograph Wrist/Hand: Metaphyseal fraying and cupping of distal radius and ulna and the distal aspects of the second through fifth metacarpals. Skeletal survey: Metaphyseal fraying and cupping involving bilateral distal femurs, bilateral proximal and distal tibiae and fibulae, bilateral proximal and distal humeri.

Infants and adolescents are predisposed to rickets secondary to increased flux in body composition and rates of rapid bone growth causing increased need/utilization of calcium and phosphate. Further increased risk is associated with dark-skinned individuals, lack of UV-B exposure, solely breastfed infants and prematurity. Screening should be considered for children with poor growth/development, seizure activity/tetany, and children with chronic malabsorptive states.

It is indisputable that breast milk is the ideal nutrition for infants, however, it only contains 15 - 50 IU/L of vitamin D [ 1 , 2 , 4 ]. There is limited prevalence estimates for vitamin D deficiency rickets in North America and the United Kingdom. Reported and published cases in the United States increased from 65 between 1975 to 1985 to 228 from 1986 to present [ 2 ]. This has led for the American Academy of Pediatrics (AAP) recommendation of vitamin D supplementation in all breast fed infants who do not consume 500 mL/day of vitamin D fortified formula and all non-breastfed infants that do not consume at least 500 mL/day of vitamin D fortified formula. It is recommended this begin in the first days of life and continue through childhood/adolescence [ 2 ]. The 2003 AAP breastfeeding guidelines suggest 200 IU/day to maintain a minimum level of 27.5 nmol/L, however this has been shown insufficient for prevention of all cases of rickets leading to controversy and newer recommendations for 400 IU/day, especially in deeply pigmented breastfed infants [ 2 , 5 ]. Despite appropriate breastfeeding technique and the appropriate amount of breast milk our patient was at risk for vitamin D deficiency secondary to the lack of oral vitamin D supplementation and his ethnicity.

The primary source of vitamin D (sunlight) is dependent on geographic location as well as outdoor exposure. To maintain a low normal level (>27.5 nmol/L) of vitamin D, a fully clothed child would have to spend two hours outside weekly and darker skinned individuals may require exposures up to 6-10 times this amount [ 1 , 2 ]. Sunscreen with an SPF of 15 reduces synthetic capacity by up to 98% [ 2 , 6 ]. The current AAP recommendation (to prevent sunburns and reduce skin cancer risk) is to keep infants less than 6 months of age out of direct sunlight and encourage the use of protective clothing/sunscreen again increasing the risk of vitamin D deficiency in this patient [ 2 ].

Because of this recommendation, management of vitamin D deficiency is via oral vitamin supplementation. Ergocalciferol (plant formulated vitamin D2) or Cholecalciferol (animal formulated vitamin D3) at >5000 IU daily for 2-4 months is suggested for toddlers greater than 12 months of age and up to 10,000 IU in adolescents. In younger infants (1-12 months) 1,000-5000 IU daily has been suggested. In infants <1 month old, 1000 IU daily is recommended [ 2 ]. Once laboratory values have normalized, maintenance of 400 IU per day is suggested [ 1 , 2 ]. If compliance is a concern a one time treatment with high dose oral formulation is appropriate (100,000-600,000 IU) over 1-5 days with a follow up dose in 3 months if necessary [ 2 ]. It is suggested that vitamin D3 may be up to 3 times as potent as D2 and may be preferable, especially when used in bolus form. Some formulations of vitamin D may contain propylene glycol, which is toxic at high doses so caution is advised [ 2 ].

Conclusions

While rickets is a disease that has plagued society for many centuries it is certainly still a significant cause for both skeletal and non-skeletal complications in today's culture. Despite recommendations for supplementation in all breast-fed infants and fortification of multiple household food items, it is still a relatively common nutritional deficiency. Education on proper nutrition during pregnancy and supplementation during breastfeeding is necessary to prevent its growing resurgence. Proper childhood maintenance visits with growth and development screenings are critical for early detection of this easily treatable condition.

Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images of radiographs and growth chart. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Abbreviations

American Academy of Pediatrics

Alanine Aminotransferase

Aspartate Aminotransferase

Complete blood count

Parathyroid hormone

Sun Protection Factor

Thyroid stimulating hormone

Ultra violet-B.

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RS provided care for this patient when he presented to her clinic at 6 months of age. RS completed the work-up, researched and initiated the treatment. CL provided assistance with the preparation of the manuscript

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Stevens, R.L., Lyon, C. Nutritional vitamin D deficiency: a case report. Cases Journal 2 , 7000 (2009). https://doi.org/10.1186/1757-1626-2-7000

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• Thyroid Stimulate Hormone
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• Adequate Caloric Intake
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Cases Journal

ISSN: 1757-1626

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Exogenous intoxication by non-prescribed use of vitamin D, a case report

• Ana Laura Teodoro de Paula 1 ,
• Wemerson Philipe Ferreira Gonzaga 1 ,
• Lucas Martins Oliveira   ORCID: orcid.org/0000-0002-7677-8076 1 ,
• Taciana Carla Maia Feibelmann 2 &
• Juliana Markus 3  

BMC Geriatrics volume  20 , Article number:  221 ( 2020 ) Cite this article

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This case report, unlike the current literature related to vitamin D intoxication, aims to highlight the risk of self-medication, and how publicity boosts the acquisition of vitamins for different purposes, increasing consumption with no professional indication or supervision. This practice can pose a serious health risk to the population.

Case presentation

Our patient, a brazilian retired 64-year-old female, presented to the emergency service with post-prandial food vomiting of undigested content and stabbing abdominal pain with worsening during palpation. Concomitantly, onset of sporadic frontal headache, fatigue, hyporexia, weight loss of 18 kg in the same period, severe pruritus, musculoskeletal pain in the limbs and nocturia. The physical examination showed hypertension (160/80 mmHg) and itchy macules in the lower limb. Initially, the main diagnostic hypotheses were multiple myeloma, hyperparathyroidism and pancreatitis secondary to hypercalcemia, osteolytic neoplasms and other neoplasms that present with hypercalcemia. However, blood count, parathyroid hormone, chest X-ray, immunoglobulins, myelogram and bone marrow biopsy were not compatible with these diagnoses. Meanwhile, 25 OH vitamin D dosage and diluted vitamin D test confirmed the diagnosis of hypervitaminosis D. Hypercalcemic crisis was managed with vigorous hydration (50 ml/kg in 2 h), furosemide, bisphosphonates and blood pressure control with amlodipine and atenolol. Subsequently, the patient was discharged from the outpatient clinic with complete remission of symptoms, weight gain, serum calcium values of 10.76 mg/dL and ionizable calcium values of 6.52 mg/dL.

Our report summarizes the possible consequences of using a vitamin compound without supervision of a competent professional, as these substances are mistakenly considered non-toxic. To add, little information is available about the supplements’ metabolism and their biological effects. Therefore, It is difficult to diagnose intoxication. This case report shows that even the self-administration of a product designed to bring health benefits can become a risky behavior. These vitamin and mineral supplements are supposed to bring patient empowerment and reduce government spending in health-care, but indeed represent a significant public health concern due to possible overdose and drug interactions.

Peer Review reports

This case report, unlike the current literature related to vitamin D intoxication, aims to highlight the risk of self-medication, and how publicity boosts the acquisition of vitamins for different purposes, increasing consumption with no professional indication or supervision. Therefore, this practice can pose a serious health risk to the population.

In the last years, speculations related to the possible extra-bone reactions of this hormone have been arising through controversial results of many different studies. These articles associate low levels of calcitriol with cancer, cardiovascular, metabolic, infectious and autoimmune diseases, beyond increased mortality. The proponents affirm that these associations establish a relation of cause and effect because there is biologic plausibility, since is well-known that the vitamin D receptor also regulates genes associated to immunity, cell differentiation and proliferation. The receptors can also be found in several tissues not involved with bone metabolism. However, none of the studies confirmed these presumptions [ 1 ].

In spite of non-conclusive evidences, population has been mistakenly informed that the use of supraphysiological doses of vitamin D can bring miraculous outcomes. Thereupon, the demand for its supplementation has increased either by prescriptions made by doctors or nutritionists, and also by frequent media orientations not based in scientific evidences [ 2 ].

Nevertheless, we must bear in mind that there are risk groups for hypovitaminosis D which require its supplementation. In these groups, dosing and supplementation is recommended to establish physiological body levels of cholecalciferol. The elderly, for example, are responsible for 43,4% of the outpatient cases and 71,2% of hospitalizations by lack of vitamin D, requiring supplements ingestion. Besides that, according to World Health Organization, newborn infants are at an elevated risk of vitamin D deficiency. Thus, vitamin D supplement to exclusive breastfed children is also highly recommended, aiming primary prevention of vitamin D deficiency and rickets [ 3 , 4 , 5 ].

However, the supplementation should be avoided in the general population by lack of conclusive evidence about the benefits of this practice. As exceptions, we should cite specific places lacking sunlight or with reduced exposure to sunlight due to staying inside or wearing clothes, what happens specially during harsh winters. And even for those groups for which supplementation is recommend, It should be made under supervision. Unfortunately, in Brazil, this recommendation hasn’t been followed, since a study conducted in 2016 showed a prevalence of 16,1% in self-medication, mainly composed by substances for which over-the-counter sales are allowed, the case of vitamin D [ 6 ].

According to international guidelines, the necessary daily dietary value for people up to 50 years old is 5mcg, regardless of sun exposure. For people aged 50 to 70, in turn, the value is 10 mcg and for people over 71 years old the value is 15 mcg [ 7 ]. The target serum level of vitamin D for the healthy population up to 60 years old is 20 ng/ml and for risk groups it is 30 ng/ml up to 60 ng/ml. In the risk groups, we highlight pregnant and lactating women, elderly, people with rickets/osteomalacia, osteoporosis, history of falls and fractures, hyperparathyroidism, inflammatory diseases, autoimmune diseases, chronic renal injury and malabsorption syndromes. Values above 100 ng/ml constitutes high risk of toxicity and hypercalcemia [ 4 ].

In addition, it’s generally unknown to the general population that this vitamin is stored in fat tissue for long periods. Hence, its indiscriminate use can disrupt calcium metabolism, creating an aggressive hypercalcemia, which causes lots of adverse effects in almost every body system. Hypervitaminosis D can lead to clinical signs such as persistent vomiting, weight loss, dehydration, psychiatric disorders and, at levels generally greater than 150 ng/ml, hypercalcemic crisis with difficult to control hypertension and acute kidney injury, setting a medical emergency that can lead to death [ 8 ].

We report a case of severe vitamin D poisoning through self-medication, pointing to the importance of raising this hypothesis as a differential diagnosis of hypercalcemia. In addition, we warn about the risk of using high doses, either by prescription or not, based on media apology for the need to maintain supraphysiological levels, leading to indiscriminate consumption by the population.

A retired brazilian 64-year-old female started to present, 9 months ago, with postprandial vomiting of undigested content and stabbing abdominal pain. Those were constant symptoms that persisted for 12 months. Concomitantly, onset of lower limbs musculoskeletal pain, sporadic frontal headache, fatigue, hyporexia and weight loss of 18 kg in the same period. Few days after the onset of the abdominal and musculoskeletal pain, the patient reported nocturia, with 4 to 5 episodes each night with a foamy urine. The bowel habit alternated between constipated and normal, although there was no change in the appearance of the stool during the period of the disease.

The family history showed no significant informations beyond the low socioeconomic level. There were no significant past interventions related to the current symptoms.

In the investigation of the condition, laboratory tests were requested (complete blood count, electrolytes, calcium, magnesium and pancreatic enzymes). The results showed a significant hypercalcemia and the patient was hospitalized, as we can see in the Fig.  1 , which shows the disease timeline. At the time of admission, she was in good general condition, with diffuse cutaneous pallor, hypotrophic and eutonic muscles, discrete lower limb edema, capillary refill time of less than 3 s, anicteric, acyanotic and afebrile. She had a heart rate of 82 beats per minute, blood pressure of 160/80 mmHg and was eupneic. There were no abnormalities in the respiratory and cardiovascular examination. In the abdominal deep palpation, it was possible to notice mesogastric pain. It’s also important to take note of telangiectasias in the malleolar region of both limbs, and hypochromic and hyperchromic lower limb macules measuring up to 0.5 cm which, according to the patient, were local and severely itchy.

Timeline of the case

At the time, the main diagnostic hypotheses were multiple myeloma, hyperparathyroidism, pancreatitis secondary to hypercalcemia, osteolytic neoplasms and other cancers that present with hypercalcemia.

More laboratory tests were made, showing a normocytic and hypochromic anemia (Hb: 8.2 g/dL; Ht: 24.2%; MCV: 84.9 fL), leukocytes of 61,000/mm 3 and platelets of 23,600/mm 3 . Also a serum calcium of 11.67 mg/dL and ionizable calcium of 6.51 mg/dL. Parathyroid hormone (PTH) was decreased (13.58 pg/mL) and there were high levels of urea (101.7 mg/dL) and creatinine (3.97 mg/dL), setting up a framework of acute kidney injury (Fig. 1 ) which lasted 2 months, not requiring renal replacement therapy.

Following the investigation of multiple myeloma and other pathologies, it was found an unchanged chest radiograph, normal values of immunoglobulins (IgA, IgG, IgM and total IgE), a normal myelogram and bone marrow biopsy showing only dysplastic abnormalities, not consistent with multiple myeloma.

Not confirming the previous diagnostic hypothesis, the team decided to perform the 25-hydroxy vitamin D dosage, which showed high serum values (100 ng/dL), as well as the diluted vitamin D test, which also presented high values (374 ng/dl), confirming the diagnosis of hypervitaminosis D.

Despite denying the use of non-prescribed drugs, when asked specifically about vitamins, the patient reported taking various vitamin complexes, including cholecalciferol once daily for about 6 months. She had access to several of them through samples provided by a close relative. Thus, exogenous vitamin D intoxication was diagnosed to the team’s surprise.

The team maintained hypercalcemic crisis management with pharmacological measures, in addition to prescribed paroxetine hydrochloride (20 mg once daily) to relieve the patient’s anxiety. The procedures performed were mainly vigorous hydration (50 ml/kg in 2 h), furosemide, bisphosphonates and blood pressure control with amlodipine and atenolol. Related to hypervitaminosis, behavior measures were conducted, with immediate cessation of supplementation use.

In July (Fig. 1 ), the patient was discharged from hospital in remission of musculoskeletal and gastrointestinal symptoms, weight gain, serum calcium values ​​of 10.76 mg/dL and ionizable calcium values of 6.52 mg/dL. According to serum calcium, we could access the adherence to behavioral measures, with complete cessation of vitamin D use. However, she was discharged with permanent renal damage. A serum creatinine of 1,77 mg/dl for a period of more than 3 months was noted on follow-up, closing a diagnosis of chronic kidney disease class KDIGO 4.

Discussion and conclusions

Our report shows the case of a patient which suffered vitamin D toxicity by using a drug without a Dr. prescription and medical supervision. The investigation was prolonged by the variety of nonspecific symptoms presented by the condition and its rarity in relation to other more frequent pathologies such as neoplasms. These factor led to a delay in the beginning of adequate management. Another limitation of this case report consisted in the limited data contained in the medical records, which restricted our analysis. However, the case were strengthened by the social and political discussion about self-medication, its implications and causes.

Although a rare cause of hypercalcemia, vitamin D poisoning tends to become more prevalent as high doses of exogenous vitamin D are becoming available and increasingly prescribed by doctors. The wide variety of therapeutic uses to these products, allied to their profitable market, boost the publicity and, consequently, the consumption of vitamins for different purposes, such as anti-ageing, anti-stress, prevention of diseases and promotion of health. However, improper use, misrepresentation of the quantity of vitamins in packaging and lack of supervision pose a serious health risk to the population [ 9 ].

In the literature, there are many case reports of hypervitaminosis D due to several causes: manufacturing errors [ 2 , 10 , 11 ], overdosing by patients or prescribers [ 12 ], over-the-counter use [ 13 , 14 , 15 , 16 ] and many others, with possible combinations of the problems. What becomes clear is the lack of inspection related to labels and real dosages contained in the formulations, as well as misinformation and lack of information even by the doctors themselves. In the case reports above-mentioned, the presence of a dose many times higher than stated on the label was a frequent problem, that was discovered just with laboratory analyses made after the diagnostic hypothesis of intoxication.

Therefore, we strongly suggest that these medications should be tested prior to administration and the actual dosage should be assessed in comparison to the label information, since it is frequently unreliable. Such measures should be enforced through the law and strict inspection by regulatory agencies, since misinformation on the label can constitute fraud and a threat to public health. In addition, there is a clear need for educational campaigns aimed at doctors and the general public on the risks of vitamin D misuse, as well as the correct indications of its supplementation.

Even though there is no popular consensus on self-medication and consumption of these products, as they aren’t considered like drugs, the consequences can be equally harmful. The definition of self-medication encompasses, beyond the use of drugs without any professional guidance, the use of over-the-counter drugs and any industrialized mineral and vitamin supplements [ 17 , 18 ].

In this context, our report summarizes the possible consequences of using a vitamin compound without supervision of a competent professional, as these substances are mistakenly considered non-toxic. But we must alert: in high doses and/or consumed for long periods, many vitamins can be even lethal [ 19 ]. To add, little information is available about the supplements’ metabolism and their biological effects, making it difficult to diagnose intoxication [ 9 ].

Furthermore, three recent studies demonstrated that self-medication is more common among women, probably because they are more likely than men to recognise and express symptoms [ 18 , 20 ]. And this information is crucial for the promotion of awareness campaigns, especially, but not only, within this public.

Due to the lack of such policies, we then witnessed the effects of self-medication: chronically, hypercalcemia can cause several side effects, especially neurological, gastrointestinal, and renal ones. Hypercalcemia is deleterious to the function of excitable membranes, leading to musculoskeletal and smooth muscle fatigue. Effects on cardiac muscle include QT interval shortening and increased risk of cardiac arrest at very high calcium levels. Neurological sequelae include depression, irritability and, with sufficiently high levels, coma. Hypercalcemia rapidly exceeds the renal capacity for calcium resorption, and calcium leaks into the urine, causing nephrolithiasis. Beyond that, high levels of serum calcium can cause nephrocalcinosis and severely impair renal function, as it does to other soft tissues. Hypercalcemia also causes dehydration by inducing renal resistance to vasopressin, leading to nephrogenic diabetes insipidus. Dehydration, in turn, leads to a correspondingly greater increase in serum calcium concentration [ 2 , 8 , 21 ]. Concluding, we can see that our patient presented with most of these abnormalities.

Hence, we can highlight as most important take-away lesson from this case that the self-administration, without any medical guidance, even of a product designed to bring health benefits, can be framed as risky behavior and represents a significant public health concern due to overdose and drug interactions.

Patient perspective

On a follow-up interview, the patient described the experience of the disease like a real challenge, due to the long-time hospitalization and the initial hypothesis of because of the hypercalcemia and renal symptons. She also referred the received treatment as good and said she was happy about the outcomes.

One aspect that calls our attention is that she hasn’t showed any concern about the permanent renal damage, which lead us to think that even after all that time of hospitalization and several invasive interventions, she hasn’t understood the seriousness of the intoxication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Mean Corpuscular Volume

Parathyroid hormone

Chronic kidney disease

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Acknowledgements

The authors thank all partners for contributing in the development of this article, especially the Clinical Hospital of the Federal University of Uberlândia, an institution of tertiary level and of national reputation, besides being among the five federal hospitals with greater productivity in Brazil.

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All authors have read and approved the manuscript. The author ALTP contributed with the article by writing the paper (backgroung, discussion and conclusions) and translating it to english. WPFG helped write part of the background and manage the process of the ethicals approval. LMO was responsible for getting the patient’s history and building the timeline. He also made contributions over the construction of the paper and made the complete submission of the work. TCMF oriented the building of timeline and the clinical reasoning concerning the case. JM oriented the whole work from the process of getting the informations to building the history of the patient and the elaboration of the paper.

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de Paula, A.L.T., Gonzaga, W.P.F., Oliveira, L.M. et al. Exogenous intoxication by non-prescribed use of vitamin D, a case report. BMC Geriatr 20 , 221 (2020). https://doi.org/10.1186/s12877-020-01614-8

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Vitamin D deficiency and fatigue: an unusual presentation

• Kevin Johnson 1 &
• Maryam Sattari 1  

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Fatigue is a vague but common complaint that is poorly characterized by physicians as well as patients. While fatigue may result from a number of different etiologies, at the present time, a comprehensive approach to each patient with fatigue does not include routine measurement of serum vitamin D levels. A 61-year-old man was evaluated for excessive daytime fatigue. No features characteristic for depression, sleep apnea, or narcolepsy were present. A comprehensive work-up, including thyroid function tests and testosterone levels, did not reveal any abnormalities. However, serum 25-hydroxyvitamin D level was low, at 18.4 ng/mL. Vitamin D supplementation was initiated. At follow-up in 3 and 12 months, the patient reported complete resolution of daytime fatigue, corresponding to an increase in his vitamin D levels. Possible mechanisms for clinical improvement include effects of vitamin D on components of inflammatory cascades, including tumor necrosis factor-alpha and prostaglandin D2, which result in decrease in central nervous system homeostatic sleep pressure. While more research is needed to determine if patients presenting with fatigue should be routinely screened for vitamin D deficiency, clinicians should consider obtaining vitamin D levels in patients with unexplained fatigue, nonspecific musculoskeletal pain, and risk factors for vitamin D deficiency.

Fatigue is a vague but common complaint that is poorly characterized by physicians as well as patients. While fatigue may result from a number of different etiologies, at the present time, a comprehensive approach to each patient with fatigue does not include routine measurement of serum vitamin D levels. Vitamin D refers to a group of fat-soluble secosteroid hormones, and is typically ingested in dietary sources or manufactured in the skin after exposure to sunlight (Holick 2007 ). Increasing evidence suggests that vitamin D has many roles beyond its classically described effects on calcium homeostasis and bone health (Holick 2007 ). Research suggests possible associations between suboptimal levels of vitamin D and development of various diseases, including pulmonary disorders (Black and Scragg 2005 ; Sita-Lumsden et al. 2007 ; Camargo et al. 2007 ; Devereux et al. 2007 ; Litonjua and Weiss 2007 ) chronic rhinitis (Abuzeid et al. 2012 ), tonsillar hypertrophy, (Nunn et al. 1986 ; Reid et al. 2011 ), metabolic syndrome (Botella-Carretero et al. 2007 ), type 2 diabetes (Mattila et al. 2007 ), hypertension (Forman et al. 2007 ), cancers of the breast, colon, and prostate (Garland et al. 2006 ), poor stress resilience (Bracha et al. 2004 ), depression (Berk et al. 2007 ), and cognitive decline (Przybelski and Binkley 2007 ). Vitamin D appears to be necessary for skeletal muscle as well and its deficiency has been associated with nonspecific musculoskeletal pain (Plotnikoff and Quigley 2003 ), chronic pain (Turner et al. 2008 ), low back pain (Lotfi et al. 2007 ), and myopathy (Boltan et al. 2007 ; Goldstein 2007 ; Prabhala et al. 2000 ). Some researchers have even suggested a link between vitamin D deficiency and all-cause mortality (Giovannucci 2007 ).

Vitamin D also has immunomodulatory activities (Holick 2007 ). Deficiency of vitamin D might be associated with diseases of immune dysregulation, one manifestation of which could be excessive daytime sleepiness (Zitterman and Gummert 2010 ; Hoeck and Pall 2011 ). We present a case of daytime fatigue in an otherwise healthy male who was found to be vitamin D deficient.

Case presentation

A 61-year-old Caucasian man presented to primary care office with complaint of fatigue and daytime sleepiness, especially in the afternoons. His symptoms began gradually 2–3 months prior to presentation, insidiously worsening to the point that he began having functional difficulties with his normal tasks at work in the afternoons. He reported napping almost daily after work and even skipping some of his regular exercise sessions due to fatigue. He denied changes in his weight, new familial or occupational stressors, difficulty falling asleep, snoring, apnea, sleep disruptions, nocturnal awakenings, depression, or anxiety. In fact, his review of symptoms was only positive for chest pain that was worse in the afternoon when he felt tired. He reported good sleep hygiene and was able to get his customary 7–8 h of sleep each night. Before the onset of his symptoms, he had worked fulltime and exercised on an almost daily basis, without experiencing any difficulties. His past medical history was only significant for colon cancer, in remission since surgical resection and completion of systemic adjuvant chemotherapy in 2005 (7 years prior to presentation). He did not take any prescription medications and denied use of tobacco products, alcohol, or recreational drugs.

Physical exam revealed a pleasant male in no distress. Vital signs were within normal limits. His body mass index was 28. No significant abnormalities were detected on complete physical exam. Laboratory data, including thyroid stimulating hormone, liver function tests, and renal indices, were normal (Table  1 ). EKG and stress echocardiogram were normal. In absence of a common etiology explaining patient’s symptoms, serum 25-hydroxy vitamin D level was obtained and found to be low at 18.4 (normal range 30–80 ng/mL). Vitamin D replacement was initiated with ergocholecalciferol 50,000 international units (IU) weekly for 8 weeks, followed by vitamin D 1000 IU daily.

Patient reported improvement of his fatigue and daytime sleepiness within 2 weeks of initiation of vitamin D supplementation and complete resolution of his symptoms within 3 months of vitamin D initiation. In follow-up visit in 3 months, he reported being able to perform his previous daily routine without difficulty. In addition to working full-time, he had resumed his exercise routine (3 sessions of resistance training and at least 6 sessions of 30–60 min of cardiovascular training a week) without experiencing any limitations. He denied chest pain or daytime napping. He stated that—aside from initiating vitamin D supplementation—no other circumstances in his life had changed since his initial evaluation: there had been no interval changes in other medications, diet, social activities, caffeine use, stress level, or work. He continues to feel well and remains completely symptom-free to date. His repeat 25-hydroxy vitamin D levels were 27.2 ng/mL after 3 months of vitamin D supplementation and 32.2 ng/mL after 12 months (Table  2 ).

The exact mechanism for the improvement in this patient’s fatigue after identification and treatment of vitamin D deficiency is not known. To our knowledge, this is the second reported case of daytime fatigue and sleepiness resolving upon remediation of vitamin D deficiency. McCarty has previously reported a case of excessive daytime sleepiness and musculoskeletal pain in a 28-year-old African American female that improved with replacement of vitamin D (McCarty 2010 ). This patient underwent an overnight polysomnogram (PSG) before and after vitamin D repletion (McCarty 2010 ). While a full sleep evaluation before vitamin D repletion revealed the presence of heavy daytime napping and pervasive fatigue, the PSG did not show evidence of sleep disordered breathing or a sleep-related movement disorder (McCarty 2010 ). Post-replacement PSG did not show a decrease in episodes and duration of wake after sleep onset or an improvement in sleep continuity, but did reveal an interval decrease in stage N3 sleep, suggesting a reduction in homeostatic sleep pressure following vitamin D replacement (McCarty 2010 ).

McCarty postulated that vitamin D deficiency may contribute to symptoms of sleepiness via components of inflammatory cascades, including known sleep regulating substances (McCarty et al. 2012 ). For example, there is an inverse relationship between levels of tumor necrosis factor-alpha (TNF-α) and serum 25-hydroxyvitamin D (Fig.  1 ) (Peterson and Heffernan 2008 ). TNF-α has been implicated in the sleepiness associated with obstructive sleep apnea (Peterson and Heffernan 2008 ; Churchill et al. 2008 ). Vitamin D deficiency has also been associated with upregulation of nuclear factor kappa-B (NFĸB) (Jablonski et al. 2011 ), which is responsible for the regulation of numerous substances known to exert homeostatic sleep pressure, including prostaglandin D2 (Chen et al. 1999 ; Krueger et al. 2009 ). Prostaglandin D2 functions as a physiologic regulator of sleep and affects the central nervous system homeostatic sleep pressure (Fig.  1 ) (McCarty et al. 2012 ).

Proposed relationship between vitamin D and sleep regulation

Interestingly, the only identifiable potential risk factor our patient had for vitamin D deficiency was skin-protective behavior that consisted of sun avoidance and use of SPF protection. Though vitamin D deficiency is commonly understood to be disproportionately represented in underserved populations (Kakarala et al. 2007 ), patients residing in northern latitudes (Webb et al. 1988 ), individuals with darker skin tones (Matsuoka et al. 1991 , 1995 ), the elderly (Holick et al. 2005 ), the obese (Wortsman et al. 2000 ), and pregnant or lactating women (Lee et al. 2007 ), its prevalence among the general population is also increasing (Faiz et al. 2007 ; Zargar et al. 2007 ). In fact, vitamin D deficiency or insufficiency is estimated to affect over a billion persons worldwide (Holick 2007 ). Increased awareness of potential dangers of sun exposure, skin-protective behavior, and urbanization of the population are thought to be some of the factors underlying the increase in prevalence of vitamin D deficiency and insufficiency (Holick 2007 ). It is of note that this patient’s serum parathyroid hormone level was not checked and therefore, normocalcemic primary hyperparathyroidism cannot be ruled out as a contributing factor to his symptoms.

Conclusions

Our case lends support to the one presented by McCarty that vitamin D deficiency might be an unrecognized and easily reversible etiology of fatigue. Although a causal relationship cannot be confirmed by this case alone, the temporal relationship as well as biological plausibility makes this a possibility. While further study is needed to elucidate the possible mechanism for this association, and whether widespread screening for vitamin D deficiency among patients complaining of daytime sleepiness/fatigue is warranted, clinicians should consider obtaining serum vitamin D levels in patients who present with daytime sleepiness/fatigue, nonspecific musculoskeletal pain, and risk factors for vitamin D deficiency.

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Authors’ contributions

KJ drafted the manuscript. MS revised the manuscript critically for important intellectual content. Both authors read and approved the final manuscript.

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Johnson, K., Sattari, M. Vitamin D deficiency and fatigue: an unusual presentation. SpringerPlus 4 , 584 (2015). https://doi.org/10.1186/s40064-015-1376-x

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DOI : https://doi.org/10.1186/s40064-015-1376-x

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• Vitamin D deficiency
• Excessive daytime sleepiness

ORIGINAL RESEARCH article

New evidence that vitamin d prevents headache: a bidirectional two-sample mendelian randomization analysis.

• 1 Banan Hospital Affiliated to Chongqing Medical University, Chongqing, China
• 2 The First College of Clinical Medicine, Chongqing Medical University, Chongqing, China
• 3 Faculty of Pediatrics, Chongqing Medical University, Chongqing, China
• 4 The Second College of Clinical Medicine, Chongqing Medical University, Chongqing, China
• 5 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Background: Previous observational clinical studies and meta-analyses have yielded inconsistent results regarding the relationship between vitamin D and headache, and the causal relationship remains unclear. The aim of this study was to investigate the causal relationship between vitamin D and headache by bidirectional two-sample Mendelian randomisation (MR) analysis.

Methods: The relationship between high levels of vitamin D and headache was investigated by two-sample MR analysis using publicly available genome-wide association study (GWAS) data. The primary method was inverse variance weighting (IVW), and secondary methods were weighted median and MR-Egger methods. No heterogeneity or horizontal multidirectionality was found in the MR results. The robustness and validity of the findings were assessed using the leave-behind method.

Results: A significant causal relationship was found between high vitamin D levels and headache using the IVW method (OR = 0.848; p  = 0.007; 95% CI = 0.752–0.956). However, in a reverse analysis, no evidence of a causal relationship between headache and high levels of vitamin D was found using the IVW method (OR = 1.001; p  = 0.906; 95% CI = 0.994–1.006). Our MR analyses showed no significant horizontal multidimensionality or heterogeneity ( p  > 0.05). Sensitivity analyses confirmed that MR estimates were not affected by single nucleotide polymorphisms (SNPs). Confirmation that our results are robust and valid has been obtained by the leave-one-out method.

Conclusion: Our study suggests that high levels of vitamin D prevent the risk of headache. However, there is no evidence of a causal relationship between headache and high levels of vitamin D. Vitamin D may reduce the risk of headache.

Introduction

Vitamin D is a fat-soluble vitamin that plays several important roles in the body ( 1 ). It is mainly synthesised through the skin in the presence of sunlight and can also be ingested through food. Vitamin D promotes the absorption and utilisation of calcium and contributes to normal bone development and maintenance. It plays an important role in immune regulation, cell differentiation and inflammatory responses ( 2 – 5 ). In recent years, studies have increasingly focused on the role of vitamin D in neuropathic pain. Vitamin D receptors are widely distributed in the central and peripheral nervous system, suggesting that vitamin D may play a role in normal nervous system function and nociceptive modulation ( 6 ). Several studies have shown an association between vitamin D deficiency and the onset and exacerbation of headache, and that vitamin D supplementation can help alleviate the symptoms of headache ( 7 , 8 ).

Headache is a common neurological symptom that manifests as pain or discomfort in different areas of the head ( 9 ). Its etiology is complex and diverse, including intracranial lesions, vascular abnormalities, infection, inflammation, and metabolic disorders ( 10 ). Headache can be divided into two categories: primary and secondary; the former, such as migraine and tension headache, are mostly associated with genetic, endocrine, and environmental factors; the latter is caused by specific diseases, such as brain tumour and cerebrovascular disease. The severity, frequency of attacks and accompanying symptoms of headache vary from person to person and affect the daily life and work of patients ( 11 ).

Preliminary studies have investigated the correlation between vitamin D and headache. Some studies have shown that people with lower levels of vitamin D are at greater risk of headaches and have more severe pain ( 12 ). In addition, vitamin D supplementation appears to reduce headaches and improve patients’ quality of life ( 13 , 14 ). Although some relevant studies have shown a correlation between vitamin D and headache, it is difficult to establish a specific causal relationship between the two.

Mendelian randomization (MR) analysis is an emerging statistical method that uses genetic variation as an instrumental variable to explore potential causal relationships between exposure factors and disease. Mendelian randomisation analysis provides a classification effect similar to that of a randomised controlled trial (RCT) by randomly classifying genetic alleles during sperm-egg binding ( 15 ). However, MRI analyses provide stronger causal inferences than traditional observational studies and are effective in controlling for the effects of confounding factors ( 16 ). Furthermore, there is a lack of magnetic resonance studies exploring the potential causal relationship between vitamin D and headache, suggesting that further research is needed in this area.

The aim of this study was to investigate the potential causal relationship between vitamin D and headache. By integrating existing genome-wide association study (GWAS) data, we aimed to assess the effect of vitamin D levels on the risk of headache onset. This will provide a scientific basis for the development of targeted prevention and treatment strategies.

The study design

For MR analysis requires a valid instrumental variable (IV) that satisfies three key assumptions to obtain reliable results. Firstly, the IV must be strongly associated with the exposure. Secondly, the IV must be independent of any confounding factors that may affect the exposure and outcome. Finally, the IV must affect the outcome solely through the exposure ( 17 ). The study consisted of several core steps, including the use of multiple MR methods (IVW, WM, MR Egger), multiplicity assessment, and heterogeneity and sensitivity analyses. These steps were taken to select genetic IVs associated with exposure and to examine the association between vitamin D levels and headache. To further investigate the causal relationship between vitamin D and headache, a bidirectional two-sample MR study was conducted (see Figure 1 ). To reduce bias resulting from population stratification and racial differences, we only selected samples from the same racial group. Furthermore, this study followed the latest guidelines for MR in epidemiological studies (STROBE-MR) ( 18 ).

Figure 1 . Flowchart of Mendelian randomization.

Data sources

The genetic association data for this study were obtained from the IEU Open GWAS database. 1 The low level vitamin D dataset (ieu-b-4812) comprises 441,291 participants with a total of 16,668,957 SNPs. The dataset on headaches (finn-b-R18_HEADACHE1) was obtained from the Finngen Consortium and includes 13,345 cases and 172,999 controls.

The selection of IV

To fulfill the initial step of the first hypothesis, we identified single nucleotide polymorphisms (SNPs) that were significantly associated with exposure based on stringent criteria ( p  < 5 × 10 –8 ) and independence ( r 2  < 0.001, kb = 10,000) in order to select genetic IVs that are strongly associated with exposure. However, in a reverse MR analysis with headache as the exposure, no SNPs significantly associated with exposure at p  < 5 × 10 –8 were found. The significance level was set at p  < 5 × 10 –6 for the reverse MR analysis. Furthermore, all SNPs with palindromes and ambiguities were excluded to ensure consistent effect alleles between the exposure and outcome datasets. To evaluate the strength of the instrumental variable (IV), we calculated the F statistic value using the formula F  = ( N  − 2) * R 2 /(1 −  R 2 ) ( 19 ). An F value greater than 10 indicates a low risk of weak IV bias and avoids weak instrumental bias ( 20 ).

Statistical analysis

This study used three methods, namely inverse variance weighted (IVW) and MR-Egger, weighted median (WM), to establish the causal relationship between vitamin D and headache. IVW is the dominant method and produces the highest statistical efficacy when all instrumental variables (IVs) are validated tools ( 20 ). Criteria for establishing causality include significant results in IVW analyses. The results of WM and MR-Egger analyses should align with those of IVW analyses ( 21 – 23 ).

For sensitivity analyses, we used the MR-Egger intercept to determine the presence of pleiotropy. Intercept values close to 0 and p -values greater than 0.05 indicate no horizontal pleiotropy ( 24 ). We then used Cochran’s Q -test to quantify the heterogeneity of the IVW estimates. A p-value greater than 0.05 indicates no heterogeneity ( 25 ). The results of the heterogeneity analysis are shown in Table 1 . Additionally, we ran the MR-PRESSO test to check for outliers (see Supplementary material ). If any outliers were identified, they were removed, and the MR effect was re-evaluated. To ensure the robustness of the results, we also conducted leave-one-out analyses to examine the impact of individual SNPs on the overall causal effect ( 26 ). Final funnel plots were used to assess the symmetry of the selected SNPs, while forest plots were used to evaluate the reliability and heterogeneity of chance estimates. Scatter plots were used to visualise the relationship between exposure and outcome. Please refer to the Supplementary material for additional details.

Table 1 . The heterogeneity and sensitivity of omega-3/omega-6 fatty acids and cerebrovascular disease after removal unqualified IVs.

The methodology used in the inverse MR analysis was the same as described above, which involved using SNPs associated with headache to investigate the causal effect of headache and vitamin D. The results of the inverse MR analysis were presented in RStudio. The entire analysis was conducted in R Studio (version 4.3.0) using the “TwoSampleMR” and “MRPRESSO” software packages.

Finally, we included 101 and 121 SNPs in the exposure and outcome datasets, respectively. Two and five SNP deleted due to palindromes, respectively. As shown in Table 2 , the results of IVW analysis indicated that high-level vitamin D were significantly associated with an decreased risk of headache (OR = 0.848; p  = 0.007; 95% CI = 0.752–0.956). This finding was also supported by WM and MR Egger. The forest plots of SNP effect sizes for each phenotype in the forward analyses are presented in Figure 2 . No horizontal pleiotropy was observed for any of the phenotypes (MR Egger intercept, p  > 0.05). After removing the palindromic SNPs, there was no heterogeneity observed among the exposure-associated SNPs. The MR-Egger intercept test results indicated no outliers or evidence of horizontal pleiotropy. Additionally, leave-one-out analyses revealed that no single SNP had a potential effect on MR estimates. The funnel plots were essentially symmetrical in both the forward and reverse MR analyses, suggesting no directional horizontal pleiotropy in the selected variables. The Supplementary material display scatter plots, funnel plots, and leave-one-out methods for forward analyses, which can demonstrate the absence of outliers that may affect causality.

Table 2 . Results of forward and reverse Mendelian randomization analysis.

Figure 2 . (A) Scatterplot of forward Mendelian randomization analysis. (B) Scatter plot of reverse Mendelian randomization analysis.

In the reverse MR analysis, none of the causal relationships between headache and vitamin D were significant when headache was considered as exposure (OR = 1.001; p  = 0.906; 95% CI = 0.994–1.006). Table 2 and Figure 2 provided further details. The statistical analysis indicated that there was no significant causal relationship between headache and vitamin D. The Supplementary material include scatterplots, funnel plots, and leave-one-out methods for inverse analyses.

This is the first study to explore a bidirectional causal relationship between vitamin D and headache using MR analysis. The results of the MR analysis showed that high levels of vitamin D significantly decreased the risk of headache. Furthermore, reverse MR studies did not find any evidence of a causal relationship between genetically predicted headache and vitamin D levels.

The relationship between vitamin D and headaches remains inconclusive, despite numerous studies exploring the topic. A case-control study conducted in Egypt found a significant vitamin D deficiency in migraine patients, which can significantly impact the character, duration, frequency, and severity of headache attacks ( 27 ). Similarly, a study in Turkish children also found a possible link between vitamin D deficiency and headaches ( 28 ). A cross-sectional descriptive study conducted in Norway confirmed that patients with headaches had lower average vitamin D levels compared to patients with other types of pain symptoms. Specifically, patients with headaches had a higher incidence of vitamin D deficiency ( 29 ). Quintero-Fabián et al. ( 30 ) found that vitamin D acts as an immunomodulatory hormone to reduce neuroinflammation and prevent headaches as a neurological disorder. Recent literature suggests that migraine sufferers may have a vitamin D deficiency, and taking vitamin D alongside conventional medication may reduce the frequency of migraine attacks ( 31 ). However, further verification of these results by other methods is necessary.

It is important to note that not all research findings support a link between vitamin D and headache. A randomized controlled trial conducted in Norway found that the use of vitamin D supplements did not have a significant effect on the occurrence and extent of pain or headache ( 32 ). Furthermore, a recent meta-analysis did not find any relationship between cluster headache and the three single nucleotide polymorphisms of the vitamin D receptor gene ( 33 ). The researchers also noted the lack of articles exploring the relationship between vitamin D and headaches. The relationship between vitamin D and headaches remains a controversial issue for objective reasons.

The varying results could be attributed to the fact that the majority of the studies were observational or meta-analyses and lacked the support of prospective randomized studies. Observational studies have inherent limitations, such as methodological flaws, selection bias, and insufficient adjustment for confounders, which make it difficult to establish a clear causal link. Mendelian randomization is a research methodology that can reveal the causal relationship between exposure and outcome by using genetic variation as an instrumental variable. This approach avoids the influence of non-heritable environmental factors. The study found a significant causal relationship between vitamin D and headache using two-sample MR analysis. A reverse MR study further confirmed this finding’s robustness. Our study did not find significant levels of pleiotropy or heterogeneity, which increases the credibility and reliability of our findings.

However, it is worth noting that MR studies have limitations. Firstly, existing databases lack data on different levels of vitamin D, making it difficult to explore the specific association between vitamin D levels and headache. Secondly, as our GWAS data is primarily derived from European populations, our findings may exhibit some racial or geographic bias and require further validation in other ethnic groups. It is expected that more high-quality studies and data will be published in the future to provide additional insight into the relationship between vitamin D and headache. Further research and technological advances may reveal the exact link between the two, leading to new ideas and approaches for preventing, testing, and treating headache.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary material .

Ethics statement

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/participants or patients/participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Author contributions

HiX: Funding acquisition, Investigation, Writing – original draft, Writing – review & editing, Methodology. RJ: Software, Writing – review & editing. LX: Investigation, Software, Writing – original draft, Writing – review & editing. JZ: Software, Writing – original draft, Writing – review & editing. XT: Investigation, Writing – original draft. JL: Methodology, Writing – original draft. XG: Data curation, Writing – original draft. SZ: Methodology, Writing – original draft. HoX: Formal analysis, Writing – original draft. JH: Writing – original draft. LL: Data curation, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing, Investigation.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Chongqing Science and Health Joint Medical Research Project (2021MSXM261).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2024.1423569/full#supplementary-material

SUPPLEMENTARY FIGURE S1 | (A) Forward Mendelian randomized leave-one graph. (B) Reverse Mendelian randomized leave-one graph.

SUPPLEMENTARY FIGURE S2 | (A) Funnel plot for forward Mendelian randomization. (B) Funnel plot for reverse Mendelian randomization.

SUPPLEMENTARY FIGURE S3 | (A) Forward Mendelian randomization of forest graphs. (B) Reverse Mendelian randomization of forest graphs.

1. ^ https://gwas.mrcieu.ac.uk/

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Keywords: vitamin D, headache, Mendelian randomisation study, single nucleic acid polymorphism, prevention

Citation: Xiong H, Jiang R, Xing L, Zheng J, Tian X, Leng J, Guo X, Zeng S, Xiong H, Huo J and Li L (2024) New evidence that vitamin D prevents headache: a bidirectional two-sample Mendelian randomization analysis. Front. Neurol . 15:1423569. doi: 10.3389/fneur.2024.1423569

Received: 26 April 2024; Accepted: 11 July 2024; Published: 26 July 2024.

Reviewed by:

Copyright © 2024 Xiong, Jiang, Xing, Zheng, Tian, Leng, Guo, Zeng, Xiong, Huo and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Letai Li, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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High-dose vitamin D supplementation in multiple sclerosis: a systematic review of clinical effects and future directions

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• Gbolahan Olatunji 2 ,
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Vitamin D deficiency is common in multiple sclerosis (MS) patients. This review explores the potential benefits and limitations of high-dose vitamin D supplementation in MS management. We reviewed relevant literature on the effects of high-dose vitamin D supplementation on relapse rates, disability progression, quality of life, and MRI markers of disease activity in MS patients. Additionally, we discussed the mechanisms by which vitamin D might influence MS, potential adverse effects, and future research directions. Studies suggest that high-dose vitamin D supplementation may reduce relapse rates and improve MRI markers of disease activity in MS. However, the evidence for its impact on disability progression and quality of life remains inconclusive. Vitamin D’s immunomodulatory properties are well-documented, and its potential for neuroprotection and neurogenesis warrants further investigation. High-dose vitamin D supplementation holds promise as a complementary or disease-modifying therapy for MS. However, further robust research is required to solidify its role in clinical practice. Exploring vitamin D’s multifaceted effects on the immune system, neuroprotection, and neurogenesis paves the way for novel therapeutic strategies to improve the lives of individuals with MS.

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Vitamin d and multiple sclerosis: a comprehensive review.

Vitamin D and Multiple Sclerosis

Vitamin D for the treatment of multiple sclerosis: a meta-analysis

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1 Introduction

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) characterized by autoimmune attacks on the myelin sheath [ 1 ]. This demyelination disrupts nerve impulses, leading to a wide range of symptoms that can vary depending on the affected areas of the brain and spinal cord [ 2 ]. The exact cause of MS remains unknown, but it is believed to be a complex interplay between genetic predisposition and environmental factors. Affecting over 2.8 million individuals worldwide, MS is the leading cause of non-traumatic neurological disability in young adults [ 2 ]. The disease course is highly variable, with symptoms ranging from mild fatigue and muscle weakness to severe paralysis, vision problems, and cognitive impairment [ 3 ]. The significant burden of MS on individuals and healthcare systems shows the urgent need for effective therapeutic strategies to manage disease progression and improve quality of life.

Vitamin D, a fat-soluble vitamin essential for bone health and calcium homeostasis, has emerged as a potential player in the immunomodulatory landscape [ 4 ]. Vitamin D exerts its effects through interaction with the vitamin D receptor (VDR), a ligand-activated transcription factor expressed in various immune cells [ 5 ]. Studies suggest that vitamin D can modulate immune function by suppressing T cell proliferation, promoting regulatory T cell activity, and influencing the production of inflammatory cytokines [ 6 , 7 ]. This immunomodulatory potential has sparked interest in exploring the role of vitamin D supplementation in MS, a disease with a well-established autoimmune component. This narrative review aims to examine the current evidence on the impact of high-dose vitamin D supplementation on MS.

2 Methodology

We searched PubMed, Google Scholar, Cochrane Library, and ScienceDirect, wielding a combination of keywords like “vitamin D,” “high-dose supplementation,” “multiple sclerosis,” and crucial outcomes like “relapses” and “disability progression.” (Fig.  1 ). Additionally, we employed the precision of Boolean operators (AND, OR, NOT). Our search focused on articles from 2000 to March 2024. Only studies investigating the effects of high-dose vitamin D supplementation (exceeding recommended daily intake) on people with MS, and employing human study designs (observational studies or randomized controlled trials), qualified for inclusion. Studies solely focused on vitamin D deficiency or insufficiency, or those utilizing animal models or in vitro experiments, were excluded.

Systematic literature search and study selection. Flow chart showing the selection of studies

Two independent reviewers (N.A and A.E.B) searched through titles and abstracts. Studies deemed potentially relevant were then retrieved for a deeper examination. Once the chosen studies were identified, we embarked on the critical task of data extraction. Due to the anticipated diversity in study designs, outcomes measured, and participant demographics, we opted for a narrative synthesis approach. This approach allows us to weave together the findings from both observational and RCT studies, critically evaluating their strengths and weaknesses.

3 Mechanisms of action of vitamin D in multiple sclerosis

Several potential mechanisms by which vitamin D might impact MS are under investigation. Table 1 . Vitamin D’s influence on MS pathogenesis likely hinges on its interaction with the vitamin D receptor (VDR), a protein expressed in various immune cells [ 8 , 9 , 10 ]. VDR acts as a molecular switch, and when vitamin D binds to it, a cascade of cellular responses is triggered [ 11 , 12 ]. These responses can modulate the immune system in several ways, potentially impacting MS development and progression [ 13 ]. One key area of influence is the regulation of T cells, the foot soldiers of the adaptive immune system [ 14 ]. Studies suggest that vitamin D-VDR interaction can suppress the proliferation and activity of Th1 and Th17 cells [ 15 , 16 ]. These T cell subsets are known to play a central role in driving autoimmune responses [ 16 ]. Vitamin D might offer a potential shield against the immune system’s attack on the myelin sheath in MS [ 17 ]. It achieves this by dampening the activity of specific T cells involved in the autoimmune response [ 18 ].

In contrast, vitamin D appears to support regulatory T cells (Tregs) [ 19 ]. These specialized T cells act as immune system moderators, actively suppressing the activity of other T cells and promoting immune tolerance [ 20 ]. Vitamin D supplementation holds promise for reducing the inflammatory response in MS by enhancing Treg function [ 21 ]. Tregs are regulatory T cells that act like immune system moderators, and boosting their activity could create a more balanced immune environment, potentially lessening the inflammation that characterizes MS [ 22 ]. Cytokines are signalling molecules that orchestrate communication between immune cells [ 23 ]. In MS, the production of pro-inflammatory cytokines, such as interferon-gamma and interleukin-17, is elevated [ 24 ]. These cytokines further activate immune cells and exacerbate inflammation. Evidence suggests that vitamin D might influence the production of these pro-inflammatory cytokines, potentially leading to a less inflammatory cytokine profile [ 25 , 26 , 27 ]. This shift in the cytokine landscape could contribute to a more subdued immune response in MS.

Epidemiological studies have observed a fascinating trend: individuals residing in regions with less sunlight exposure, and consequently lower vitamin D synthesis, tend to exhibit a higher prevalence of MS [ 28 ]. This geographic correlation, while not establishing a direct cause-and-effect relationship, certainly warrants further investigation. As discussed earlier, vitamin D possesses immunomodulatory properties [ 29 , 30 ]. Low vitamin D levels might lead to a state of immune dysregulation, characterized by an imbalance between pro-inflammatory and anti-inflammatory responses. This dysregulation could create a more susceptible environment for the development of autoimmune diseases like MS.

Sunlight exposure is the primary source of vitamin D synthesis in humans. Geographic regions with less sunshine may have a higher population burden of vitamin D deficiency [ 31 ]. However, these regions might also share other environmental factors, such as dietary habits or exposure to specific infectious agents, that could potentially contribute to MS risk [ 32 ]. Therefore, disentangling the independent effect of vitamin D deficiency from other environmental factors remains a challenge. Vitamin D’s immunomodulatory effects might also influence Epstein–Barr virus (EBV), a virus linked to MS development [ 33 ]. Vitamin D suppresses EBV replication and reactivation, potentially reducing its contribution to the autoimmune response in MS. However, further research is needed to understand how VDR polymorphisms might influence this specific mechanism [ 34 ].

The ability of vitamin D to modulate various aspects of the immune system, particularly those relevant to autoimmune responses, provides a compelling rationale for exploring its potential therapeutic role in MS [ 33 ]. While the exact mechanisms by which vitamin D might impact MS remain under investigation, these initial findings offer a promising avenue for future research [ 34 ].

4 Clinical evidence: high-dose vitamin D supplementation and MS outcomes

Mounting evidence explores the potential of high-dose vitamin D supplementation as a therapeutic strategy in MS management (Table 2 ).

4.1 Relapse rates

Several RCTs have yielded promising results regarding the impact of high-dose vitamin D supplementation on relapse rates in MS patients. Sotirchos et al. conducted a trial with 40 relapsing–remitting MS patients [ 1 ]. Their findings demonstrated that high-dose vitamin D3 supplementation (10,400 IU/day) significantly reduced annualized relapse rates compared to placebo (0.19 vs 0.41, p = 0.04) over an 18-month treatment period [ 1 ]. Similarly, Golan et al. reported a statistically significant association between high-dose vitamin D3 supplementation (20,000 IU/week) and a lower proportion of patients experiencing relapses compared to placebo (24% vs 37%, p = 0.03) in a study involving 229 patients over 96 weeks [ 19 ]. Supporting these observations, Essa et al. observed a significant decrease in annualized relapse rates with high-dose vitamin D3 (10,000 IU/day) compared to placebo (0.17 vs 0.41, p < 0.001) over 24 months [ 18 ].

However, some studies have yielded contradictory results. Hupperts et al. and Kampman et al. did not detect any statistically significant differences in relapse rates between high-dose vitamin D3 supplementation (14,000 IU/day and 20,000 IU/week, respectively) and placebo groups [ 20 , 22 ]. These inconsistencies highlight the need for further investigation to reconcile these findings and determine optimal dosages and treatment durations for high-dose vitamin D supplementation in reducing relapse rates for MS patients.

4.2 Disability progression

The evidence regarding vitamin D’s impact on disability progression in MS remains inconclusive. Essa et al. did not observe any significant differences in Expanded Disability Status Scale (EDSS) scores between the high-dose vitamin D3 and placebo groups [ 18 ]. Similarly, studies by Hupperts et al., Camu et al., and Kampman et al. reported no significant effect of high-dose vitamin D supplementation on disability progression as measured by EDSS scores [ 4 , 20 , 23 ]. Additionally, Dörr et al. did not detect a significant impact of high-dose vitamin D3 (20,000 IU/day) on EDSS scores over 96 weeks in their study with 229 patients [ 21 ]. These findings suggest that high-dose vitamin D supplementation might not significantly alter the course of disability progression in MS.

4.3 MRI outcomes

Several studies have assessed the effects of vitamin D on MRI markers of disease activity. Camu et al. found that high-dose vitamin D3 (100,000 IU/month) was associated with a lower number of new gadolinium-enhancing lesions compared to placebo (0.1 vs 0.6, p = 0.03) [ 4 ]. Similarly, Grimaldi et al. reported a significant reduction in new T2 lesions with high-dose vitamin D3 (20,000 IU/day) versus placebo (1.5 vs 4.1, p < 0.001) [ 24 ]. These findings suggest the potential benefits of high-dose vitamin D supplementation in reducing MRI activity, which might correlate with reduced inflammatory processes in the central nervous system. However, Hupperts et al. did not detect any significant differences in MRI outcomes between the high-dose vitamin D3 and placebo groups [ 20 ]. Furthermore, a trial by Stein et al. found that high-dose vitamin D3 (10,400 IU/day) significantly reduced new gadolinium-enhancing lesions compared to placebo (0.3 vs 1.5, p < 0.001) in 40 patients over 18 months [ 12 ]. These inconsistencies warrant further investigation to clarify the role of high-dose vitamin D on MRI outcomes in MS.

4.4 Quality of life

The impact of high-dose vitamin D supplementation on quality of life in MS patients remains a relatively unexplored area. While some RCTs have investigated this aspect, the evidence must be more conclusive. For instance, a trial by Rolf et al. involving 229 patients with MS found no significant difference in Multiple Sclerosis Impact Scale (MSIS-29) scores between the high-dose vitamin D3 (20,000 IU/week) and placebo groups over 96 weeks [ 25 ]. Similarly, Kampman et al. conducted a trial that evaluated the impact of vitamin D supplementation on quality-of-life measures but did not observe any significant differences between the high-dose vitamin D3 and placebo groups [ 23 ].

4.5 Factors influencing vitamin D status and response

Several factors influence a person’s vitamin D status and response to supplementation. Sunlight exposure remains the primary source of vitamin D for most individuals [ 26 ]. During sun exposure, ultraviolet B (UVB) radiation triggers the conversion of 7-dehydrocholesterol in the skin to previtamin D3, which isomerizes into vitamin D3 [ 26 ]. The amount of previtamin D synthesized depends on the duration and surface area of exposed skin. However, recommendations for sun exposure caution against overexposure and its associated risks. Optimal sun exposure involves short periods (5–30 min) most days of the week, without sunscreen, as sunscreens with SPF 8 or higher can significantly reduce UVB penetration and vitamin D synthesis [ 26 ].

Dietary sources contribute to vitamin D status, although to a lesser extent than sunlight exposure. Fatty fish, fish liver oil, and egg yolks are naturally rich in vitamin D [ 27 ]. Additionally, some food products are fortified with vitamin D, such as milk in the United States [ 27 ]. The recommended dietary allowance (RDA) for vitamin D in adults (19 years and older) is 600 IU daily for both men and women. This recommendation increases to 800 IU daily for adults over 70 years old [ 28 ]. In addition, immunomodulatory drugs, commonly used to manage autoimmune diseases like MS, can influence vitamin D status. These medications, such as azathioprine, methotrexate, and cyclophosphamide, modulate the immune system by altering antibody production [ 29 ]. While no interactions have been identified between azathioprine and vitamin D3 [ 30 ], other immunomodulatory drugs can affect vitamin D levels. For instance, cyclophosphamide, a chemotherapy drug sometimes used for MS, can increase the risk of severe vitamin D deficiency by accelerating vitamin D catabolism (breakdown) [ 31 ].

Variations in an individual’s genetic makeup, known as polymorphisms, can influence vitamin D status. Polymorphisms within specific genes can affect vitamin D metabolism. CYP24A1 is a gene that encodes an enzyme responsible for the hydroxylation (modification) of the active form of vitamin D (1,25-dihydroxyvitamin D3) [ 33 ]. While variations in CYP24A1 are believed to influence vitamin D levels, the exact relationship requires further investigation [ 34 ]. Also, certain medical conditions can predispose individuals to vitamin D deficiency or worsen existing deficiencies. Obesity is associated with lower vitamin D levels because the fat tissue in obese individuals acts as a reservoir for vitamin D, leading to lower serum (blood) concentrations [ 35 ]. Additionally, an inverse relationship exists between vitamin D levels and both systolic blood pressure and blood glucose levels. This means that higher blood pressure and blood sugar are associated with lower serum vitamin D concentrations. Notably, pre-diabetes may also be linked to vitamin D deficiency [ 35 ].

4.6 Optimal dosing strategies for achieving therapeutic vitamin D levels in MS

While vitamin D supplementation can be a valuable tool for managing MS, it is not a one-size-fits-all approach. Generally, older adults and those with underlying health conditions like obesity, high blood pressure, or pre-diabetes are more likely to benefit from supplementation due to their increased risk of vitamin D deficiency. Additionally, people on long-term steroids or with a history of fractures may also require supplementation to support bone health. However, there are some situations where vitamin D supplementation can be harmful. Individuals with hypercalcemia (excessively high blood calcium levels), hypervitaminosis D (vitamin D toxicity), impaired kidney function, or malabsorption syndrome (difficulty absorbing nutrients) should not take vitamin D supplements without close medical supervision.

The goal of supplementation is to achieve a therapeutic level of vitamin D in the bloodstream, typically considered above 75 nmol/L for MS patients. Doctors may initially recommend a high loading dose, such as 50,000 IU per week for up to 12 weeks, to rapidly reach this target level. Once achieved, a lower maintenance dose (usually between 2000 and 5000 IU daily) is typically prescribed for long-term management [ 36 ]. The Multiple Sclerosis Clinic of Canada suggests a more cost-effective approach: starting with a daily dose of 2000 IU for 4 months and then increasing to 3000 IU daily upon reaching the desired vitamin D level [ 37 , 38 ].

4.7 Adverse effects and safety considerations

Certain patient populations with underlying diseases such as lymphoma and granulomatous disorders may be more susceptible to vitamin D toxicity [ 39 ]. Toxicity from excessive cholecalciferol (vitamin D3) supplementation is primarily characterized by hypercalcemia (elevated blood calcium), hypercalciuria (excessive calcium in the urine), elevated serum 25(OH)D levels (> 150 ng/mL or > 375 nmol/L), and normal or slightly increased 1,25(OH)2D concentrations [ 40 ]. The vast array of clinical manifestations associated with vitamin D overdose is largely attributable to hypercalcemia and can affect various organ systems [ 39 , 40 ]. Known cardiovascular adverse effects include hypertension, shortened QT interval (ECG abnormality), ST-segment elevation (ECG abnormality), and bradyarrhythmia with first-degree heart block. Hypercalciuria is the earliest detectable renal manifestation, but polyuria (excessive urination), nephrocalcinosis (calcium deposits in the kidneys), and renal failure can also occur. Other reported symptoms of vitamin D toxicity caused by hypercalcemia include hearing loss, band keratopathy (corneal deposits), and painful periarticular calcinosis (calcium deposits around joints) [ 40 ]. A recent concern suggests that uncontrolled intake of ultra-high doses of vitamin D may mimic the progression of primary progressive MS, potentially causing a delay in diagnosis until the side effects become irreversible or even fatal [ 41 ]. This highlights the need for further research on the safety of high-dose vitamin D supplementation (exceeding 1000 IU/kg/day) in the context of MS management [ 42 ].

5 Clinical implications and future directions

Vitamin D plays a critical role in regulating the immune system, particularly by influencing T cell and dendritic cell function [ 43 ]. In MS, the disease pathology is driven by dysregulated immune responses targeting myelin antigens, the protective sheath around nerve fibres [ 44 ]. Several studies suggest a link between vitamin D deficiency and an increased risk of developing MS, as well as a more aggressive disease course [ 44 ]. Supplementation with vitamin D holds promise for modulating this immune dysregulation in MS patients.

Vitamin D’s potential extends beyond immunomodulation. Experimental evidence suggests its involvement in neuroprotection and neurogenesis, the generation of new neurons [ 45 ]. Studies have shown that vitamin D can promote remyelination (repair of damaged myelin), safeguard neurons from oxidative stress, and influence neurotrophic factors that support nerve cell growth and survival [ 45 ]. Given the progressive neurodegeneration characteristic of MS, these neuroprotective properties of vitamin D are particularly intriguing for long-term disease management.

Furthermore, vitamin D is a fat-soluble vitamin with well-established immunomodulatory properties [ 3 ]. It exerts these effects through binding to the Vitamin D Receptor (VDR) expressed on immune cells [ 4 ]. Polymorphisms potentially affect its function and how it interacts with vitamin D. These VDR polymorphisms can influence how individuals with MS utilize vitamin D. Some polymorphisms decrease the VDR’s ability to bind vitamin D, reducing its effectiveness in modulating the immune system in MS. For instance, the Taq I (T/C) polymorphism has been linked to a weaker response to vitamin D [ 46 ]. Studies suggest a potential link between VDR polymorphisms and MS risk and progression [ 47 , 48 ]. Certain polymorphisms, like FokI (C/T) variations, are associated with increased MS susceptibility [ 49 ]. Additionally, some research suggests that individuals with specific VDR genotypes respond better to vitamin D supplementation in terms of reducing relapse rates [ 50 , 51 ].

MS patients grapple with a variety of symptoms such as fatigue, spasticity, and cognitive decline, significantly impacting their quality of life [ 46 ]. While disease-modifying therapies (DMTs) target the underlying disease process, managing symptoms remains a crucial aspect of MS care [ 46 ]. The potential of vitamin D supplementation to alleviate some of these symptoms has been investigated, although current evidence is limited and inconclusive.

The current standard of care for MS includes DMTs like interferon-beta, glatiramer acetate, and newer monoclonal antibodies [ 47 ]. While DMTs are crucial for managing MS, some have unintended consequences on vitamin D levels or its metabolism in the body. For example, medications like glatiramer acetate (Copaxone) decrease intestinal absorption of vitamin D, while medications like interferon beta-1a (Avonex) affect enzymes involved in vitamin D metabolism [ 52 ]. Existing research suggests a potential interaction between DMTs and vitamin D levels in MS patients. Studies have shown that some DMTs, like fingolimod (Gilenya), may be associated with a decrease in serum vitamin D levels [ 33 ]. Due to this potential impact, it is crucial for MS patients receiving DMTs to have regular monitoring of their vitamin D levels. Early detection and treatment of vitamin D deficiency can help ensure optimal health outcomes.

Moreover, these medications have limitations, including variable effectiveness, side effects, and high costs [ 47 ]. Vitamin D supplementation has been proposed as an adjunctive therapy to complement existing treatments and potentially enhance their efficacy [ 43 ]. Preclinical and clinical data suggest that vitamin D might work synergistically with DMTs to modulate immune responses and improve treatment outcomes [ 43 ]. Beyond its adjunctive role, vitamin D supplementation is being explored as a potential disease-modifying intervention in MS [ 43 ]. While current DMTs primarily target the immune system, vitamin D’s neuroprotective effects offer a unique opportunity to address the neurodegenerative aspect of the disease [ 45 ]. Additionally, the favourable safety profile and affordability of vitamin D make it an attractive candidate for long-term use as a disease-modifying agent [ 45 ].

Despite promising findings from observational studies and smaller clinical trials, there is a lack of strong evidence from well-designed randomized controlled trials (RCTs) [ 46 ]. Many existing studies have limitations such as small sample sizes, short follow-up periods, and heterogeneity in patient populations and vitamin D dosing regimens [ 46 ]. Large-scale RCTs with long-term follow-up are necessary to definitively assess the efficacy and safety of vitamin D supplementation in MS management.

The optimal dosing regimen for vitamin D supplementation in MS remains unclear [ 46 ]. While higher doses might be necessary to achieve therapeutic effects, concerns regarding potential toxicity and hypercalcemia exist [ 45 ]. Additionally, the optimal treatment duration to observe significant clinical benefits is not well-established [ 45 ]. Future research should focus on establishing individualized dosing strategies based on patient characteristics and disease stages.

MS is a heterogeneous disease with patients exhibiting variability in clinical presentation, disease course, and response to treatment [ 43 ]. Personalized approaches to therapy, including vitamin D supplementation, hold promise for optimizing treatment outcomes [ 43 ]. Genetic, environmental, and clinical factors may influence individual responses to vitamin D, necessitating personalized dosing strategies [ 45 ]. Identifying biomarkers that predict treatment response could help determine which patients are most likely to benefit from vitamin D supplementation.

The review explores various aspects of vitamin D supplementation in MS, including its impact on disease activity, quality of life, and potential as an adjunctive or disease-modifying therapy. While the review mentions existing clinical trials, it highlights the lack of strong evidence from well-designed RCTs.

6 Conclusion

Mounting evidence suggests a potential role for high-dose vitamin D supplementation in MS management. Studies have shown promising results regarding its impact on relapse rates and MRI markers of disease activity. However, the evidence for its effect on disability progression and quality of life remains inconclusive. While vitamin D’s immunomodulatory properties are well-established, its potential for neuroprotection and neurogenesis opens exciting avenues for further exploration. Despite the encouraging preliminary findings, limitations exist. The current evidence is largely based on observational studies and smaller clinical trials. Well-designed, large-scale RCTs with long-term follow-up are necessary to definitively assess the efficacy and safety of high-dose vitamin D supplementation in MS patients. Furthermore, establishing optimal dosing regimens tailored to individual characteristics and disease stages is crucial. Personalized medicine approaches that consider genetic, environmental, and clinical factors influencing vitamin D response hold promise for optimizing treatment outcomes.

High-dose vitamin D supplementation shows promise as a complementary or disease-modifying therapy for MS. However, further robust research is needed to solidify its role in clinical practice. Continued exploration of vitamin D’s multifaceted effects on the immune system, neuroprotection, and neurogenesis paves the way for the development of novel therapeutic strategies for improving the lives of individuals with MS.

Data availablity

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Code availability

Not applicable.

Abbreviations

Multiple sclerosis

Epstein–Barr virus

International Unit (of vitamin D)

Ultraviolet B (radiation)

Recommended dietary allowance

Cytochrome P450 family 24 subfamily A member 1 (a gene)

Randomized Controlled Trials

Disease-modifying therapies

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Nicholas Aderinto

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Aderinto, N., Olatunji, G., Kokori, E. et al. High-dose vitamin D supplementation in multiple sclerosis: a systematic review of clinical effects and future directions. Discov Med 1 , 12 (2024). https://doi.org/10.1007/s44337-024-00023-9

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Decreased serum levels of 25-OH vitamin D and vitamin K in patients with type 2 diabetes mellitus

Affiliation.

• 1 Department of Endocrine Metabolism, Huishan District Third People's Hospital, Wuxi, Jiangsu, China.
• PMID: 39076511
• PMCID: PMC11284023
• DOI: 10.3389/fendo.2024.1412228

Background: Insulin resistance and/or insulin secretion dysfunction are crucial causes of type 2 diabetes mellitus (T2DM). Although some studies have suggested potential roles for vitamins D and K in glucose metabolism and insulin sensitivity, there is limited and inconclusive research on their levels in T2DM patients and their relationship with blood glucose levels and insulin resistance. Additionally, there is a lack of large-scale clinical trials and comprehensive studies investigating the combined effects of vitamins D and K on T2DM.

Methods: A total of 195 participants with newly diagnosed T2DM were included in the research group, while 180 volunteers undergoing physical examinations in our hospital served as the control group. Fasting plasma glucose (FPG) was estimated using the glucose-oxidase technique, and fasting serum insulin (FINS) was evaluated by radioimmunoassay. FPG and FINS were used to calculate the homeostasis model assessment-insulin resistance (HOMA-IR). Serum vitamin D levels were measured using 25-hydroxyvitamin D, and vitamin K levels were evaluated using phylloquinone (VK1) and menaquinone (VK2) via ultra-high performance liquid chromatography and tandem mass spectrometry. Receiver operating characteristic (ROC) analysis was performed to assess the predictive value of these vitamins for T2DM.

Results: Circulating levels of 25-hydroxyvitamin D (25.95 ± 10.42 ng/mL), VK1 (1.24 ± 0.89 ng/mL), and VK2 (0.2 ± 0.21 ng/mL) in T2DM patients were significantly lower than in the control group (37.46 ± 13.95 ng/mL for 25-hydroxyvitamin D, 1.99 ± 1.39 ng/mL for VK1, and 0.33 ± 0.22 ng/mL for VK2; p<0.001 for all comparisons). ROC analysis indicated that 25-hydroxyvitamin D, VK1, and VK2 could predict the occurrence of T2DM, with AUC values of 0.75, 0.69, and 0.71, respectively. In T2DM patients, 25-hydroxyvitamin D levels were positively correlated with VK1 (r=0.43, p<0.001) and VK2 (r=0.40, p<0.001) levels. FPG and HOMA-IR in T2DM patients were negatively correlated with circulating levels of 25-hydroxyvitamin D (r=-0.57, p<0.001), VK1 (r=-0.44, p<0.001), and VK2 (r=-0.36, p<0.001).

Conclusion: Circulating levels of vitamins D and K are lower in T2DM patients and show significant correlations with blood glucose levels and insulin resistance. These findings suggest that measurements of 25-hydroxyvitamin D, VK1, and VK2 could have predictive value for T2DM, highlighting the potential roles of these vitamins in T2DM management.

Keywords: 25-hydroxyvitamin D; serum; type 2 diabetes mellitus (T2DM); vitamin D; vitamin K.

Copyright © 2024 Yang.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Comparisons of serum 25-hydroxyvitamin D…

Comparisons of serum 25-hydroxyvitamin D (A) , vitamin K1 (B) and K2 (C)…

ROC analysis of serum 25-hydroxyvitamin…

ROC analysis of serum 25-hydroxyvitamin D (A) , vitamin K1 (B) and K2…

Spearman correlation analysis was carried…

Spearman correlation analysis was carried out to measure the correlations between 25-hydroxyvitamin D…

Spearman correlation analysis was carried out to measure the correlations between fasting plasma…

Spearman correlation analysis was carried out to measure the correlations between HOMA-IR with…

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Article Versions Notes

Di Maso, M.; Augustin, L.S.A.; Jenkins, D.J.A.; Crispo, A.; Toffolutti, F.; Negri, E.; La Vecchia, C.; Ferraroni, M.; Polesel, J. Adherence to a Cholesterol-Lowering Diet and the Risk of Pancreatic Cancer: A Case–Control Study. Nutrients 2024 , 16 , 2508. https://doi.org/10.3390/nu16152508

Di Maso M, Augustin LSA, Jenkins DJA, Crispo A, Toffolutti F, Negri E, La Vecchia C, Ferraroni M, Polesel J. Adherence to a Cholesterol-Lowering Diet and the Risk of Pancreatic Cancer: A Case–Control Study. Nutrients . 2024; 16(15):2508. https://doi.org/10.3390/nu16152508

Di Maso, Matteo, Livia S. A. Augustin, David J. A. Jenkins, Anna Crispo, Federica Toffolutti, Eva Negri, Carlo La Vecchia, Monica Ferraroni, and Jerry Polesel. 2024. "Adherence to a Cholesterol-Lowering Diet and the Risk of Pancreatic Cancer: A Case–Control Study" Nutrients 16, no. 15: 2508. https://doi.org/10.3390/nu16152508

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Vitamin D deficiency mediates the relationship between dietary patterns and depression: a case–control study

Gity sotoudeh.

1 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran

Firoozeh Raisi

2 Department of Psychiatry, Roozbeh Hospital and Psychiatry and Psychology Research Centre, Tehran University of Medical Sciences, Tehran, Iran

Maryam Amini

3 Department of Nutrition Research, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Reza Majdzadeh

4 Knowledge Utilization Research Center and Community Based Participatory Research Center, Tehran University of Medical Sciences, Tehran, Iran

Mahdieh Hosseinzadeh

5 Department of Nutrition, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Fatemeh Khorram Rouz

6 Student Research Committee, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Maryam Khosravi

7 Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Vakilabad Blv. Azadi Squre, Mashhad, Iran

8 Department of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran

Associated Data

The datasets produced and analyzed during the current study are not publicly available, but they are available from the corresponding author on reasonable request.

Depression is a major contributor to disability-adjusted life years (DALY) lost in the world. Dietary patterns are widely used to investigate diet–disease relations. In the current study, the relationship between dietary patterns and depression was investigated. Besides, the role of serum vitamin D, zinc, magnesium, and total antioxidant capacity as potential mediatory variables was studied.

It was an individually matched case–control study in which 330 depressed and healthy subjects were recruited for the extraction of dietary patterns; psychiatrists diagnosed major depressive disorder, using the criteria of the Diagnostic and Statistical Manual of Mental Disorders. Serum vitamin D and aforementioned biomarkers were measured for a number of randomly selected depressed and healthy individuals. We conducted mediatory analysis by regression models.

Healthy and unhealthy dietary patterns were associated with the lower and higher odds of depression (OR 0.39, CI 0.17–0.92 and OR 2.6, CI 1.04–6.08), respectively. A significant relationship between serum vitamin D with depression after adjusting for potential confounders was observed as well (OR 0.93, CI 0.87–0.99). According to the mediatory analysis the unhealthy dietary patterns were related to depression via altering the serum vitamin D concentration.

This study showed that vitamin D deficiency mediates the relationship between unhealthy dietary patterns and depression. However, to get a clearer result further prospective studies are required.

Depression is a common heath problem all over the world which currently affects 264 million people [ 1 ]. It is a leading cause of disability worldwide and is a major contributor to DALY lost in the world [ 2 ]. Depression is highly prevalent in developed and developing countries. In the USA, it has been estimated that 6.3% of adult population are depressed [ 3 ]. Depression ranks the forth contributing factor for burden of disease and is anticipated to rank the second until 2020. In Iran, depression constitutes 35% to 45% of mental illnesses and about 8% to 20% of the population suffer from it [ 4 ]. There are some medications for treatment of depression such as drugs that increase serotonin concentration as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and serotonin-specific reuptake inhibitors (SSRIs) which are reported to have either side effects or not to be effective enough [ 5 ].

Diet has long shown to contribute to the treatment of depression. Prior studies on diet–depression associations have mostly focused on nutrients [ 6 – 8 ], foods [ 9 ] and food groups [ 10 ] rather than dietary patterns. Due to the complex interactions between nutrients and foods, nutritional epidemiologists have suggested to deploy dietary pattern approach in investigating diet–disease relations [ 11 ]. This approach can provide a more comprehensive and new insight toward the diet–mental health relations [ 12 ]. Some studies have assessed the association between dominant dietary patterns and risk of depression [ 13 – 15 ] which most of them have been driven from food questioners and not biochemical assessment. Some potential biomarkers like 25(OH) D, total antioxidant capacity (TAC), zinc (Zn), and magnesium (Mg) in serum are reported to be significantly related to depression. For example, low levels of serum 25(OH) D were associated with depressive symptoms [ 16 ], and in a large cohort study it was concluded that hypovitaminosis D may increase vulnerability for depression [ 17 ]. According to another study vitamin D-deficient people had higher risk for depression [ 18 ] which was confirmed by a meta-analysis [ 19 ]. It is documented that vitamin D has some receptors in the hypothalamus [ 20 ], and plays an important role in brain development [ 21 ]. Furthermore, case–control studies have shown TAC concentration is lower in depressed people compared with their healthy counterparts, as well as a negative dose–response relation observed between depression severity and TAC [ 22 ]. According to several studies a negative relationship was seen between zinc and depression [ 23 , 24 ], and magnesium showed to have a protective effect in treatment of depression via glutamate system [ 25 ], neurotransmitter metabolism [ 23 ] and psychomotor function [ 26 ].

So far it is not established if biochemical ingredients mediate the relation between dietary patterns and depression. So, in the current study we aimed to investigate the mediatory role of all above-mentioned biomarkers in the relation of dietary patterns and depression.

We acknowledge that the paper has been compliance with STROBE checklist.

Participants and study design

A total of 110 depressed patients and 220 healthy individuals participated in this individually matched case–control observational study. Serum vitamin D, zinc, magnesium, and total antioxidant capacity were considered as potential mediatory variables, when evaluating the relationship between dietary patterns and depression. The patients were selected from two psychiatric clinics in Tehran. For recruitment of controls, we reached each patient’s residential area, and invited eligible people to participate in the study.

According to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV, the patients’ diseases were diagnosed by the psychiatrist as major depressive disorder [ 27 ]. No one in the case and control groups did not have history of depression in the past year. Individual matching between two groups was done, based on sex, age, and residential area. Each people with depression was matched with two people as control within 10-year age categories.

For evaluating the relationship between biochemical markers and depression, the sample size was calculated for each quantitative biochemical marker separately and the highest obtained sample size was 43 matched cases and controls (86 depressed and healthy people out of total cases and controls). They were randomly selected for biochemical analysis including serum levels of 25(OH) D, TAC, Zn, and Mg. It is notice worthy that in this study biases were minimized by matching, considering precise criteria for inclusion and exclusion, correct selection of the case and control participants and using new cases.

Inclusion criteria

People aged 18–65 years, residing in Tehran, having major depressive disorder with a maximum period of 3-month intervals from onset of five symptoms of depression to the beginning of the study were included in the case group. For inclusion of the control group, the criterion was the absence of major depressive disorder, based on Beck Depression Inventory questionnaire (BDI-II), standardized in Iran [ 28 ].

Exclusion criteria

People who suffered from cognitive impairment or other psychotic illnesses diagnosed by a psychiatrist; those who had severe depression or lacked ability to cooperate and answer the questions; took any anti-depression drugs or treatments; suffered from hormonal disorders like Addison’s, Cushing’s disease; had hyperthyroidism, hypothyroidism, and hyperparathyroidism; suffered from chronic diseases like cancer, heart disease, diabetes, stroke, fibromyalgia, kidney or liver failure, multiple sclerosis and Parkinson disease; had history of trauma, cuts, fractures, bleeding, burns, accidents and other similar events in the past 3 months that resulted in unconsciousness and hospitalization; suffered from chronic and infectious diseases like HIV, mononucleosis, tuberculosis, viral hepatitis and pneumonia in the past 2 weeks; people who were addicted to alcohol and/or drug at the time of the study or in the past 3 months; had BMI ≥ 40 kg/m 2 , pregnancy and lactation at the time of the study or in the past year, any type of special diet in the past 2 months, any type of special diet for more than 2 months in the past year; took vitamin D more than once in the last 6 months; took Zn and Mg within at least 2 previous months; and people who took other nutritional supplements continuously, by injection or orally in the past month.

After describing the aim of the study, the written informed consent form was signed by all the participants. The study protocol was approved by the Ethics Committee of Tehran University of Medical Sciences. The ethics code was 19374-161-03-91.

Assessment of covariates

A demographic questionnaire was employed to collect general information and some confounders. Anthropometric measurements were obtained from all subjects with a precision of 100 g for weight and 0.5 cm for height. Dietary intakes of the subjects in the last 12 months were assessed using a valid and reliable semi-quantitative food frequency questionnaire (FFQ) [ 29 ]. Physical activity was measured by a valid questionnaire in Iran [ 30 ]. The questionnaire consisted of nine levels of activity from rest and sleep (MET = 0.9) to vigorous activity (MET ≥ 6), based on the metabolic equivalent task hours per day (MET-h/day). An M.Sc. holder in nutrition collected data of physical activity. Depression was diagnosed based on the fourth edition of DSM criteria by a psychotherapist. For quantitative measurement of anxiety as a confounder, the Iranian standardized Beck Anxiety Inventory or BAI-II [ 31 ] was utilized. We used standardized Beck Depression Inventory questionnaire or BDI-II [ 28 ] for screening controls.

Assessment of serum biomarkers

Blood samples were collected before patients took any antidepressant drugs. To measure biomarkers, 5 ml blood samples were collected from the subjects who fasted for 12 h, between 7 and 10 AM and transferred into tubes with no anticoagulant. After centrifuging for 20 min at 1500 g in room temperature, the serum was separated and stored at − 70 °C. Serum 25(OH) D was assay by Enzyme immunoassay (EIA) method (IDS, UK). We measured serum total antioxidant capacity (TAC) with 3-ethylbenzothiazoline-6-sulfonic acid as a peroxidase substrate suitable for using in ELISA procedures. Serum Mg and serum Zn were measured with colorimetric assay (0.05–5 mg/dl pars azemun) and chemistry methods (Selecta E, Vitalab, Netherland in µg/dl), respectively.

Statistical analysis

“Kolmogorov–Simonov test was applied to analyze the normality of covariates, followed by t test or Mann–Whitney test to compare variables in two groups. To compare qualitative variables Chi square was used. The exploratory factor analysis/principal component analysis was applied to determine the dietary patterns. According to the nutrient profiles and culinary recipes, food items of the FFQ were classified into 26 food groups. Food groups with factor loadings ≥ 0.3 were considered as important contributors to a dietary pattern. The factors were orthogonally converted using varimax rotation to improve interpretability. To identify whether a factor should be retained, the study factors were naturally interpreted in conjunction with eigenvalues that was equal to 1.5 and the scree plot was determined. The factor score for each person was calculated by summing the intakes of food groups weighted by his/her factor loading. The derived factors (two dietary patterns) were labeled based on our interpretation of the data and of the earlier literature. To identify the association of dietary patterns with other dependent variables, the calculated scores for each individual in each pattern were used as independent variables.

Finally, two dietary patterns, healthy (high in fruits, cruciferous, yellow, green leafy and other vegetables, low-fat dairies, whole grains, nuts, and olives) and unhealthy (high in refined grains and breads, high-fat dairy, solid oils, liquid oils and mayonnaise, pickles, snacks, soft drinks, industrial fruits and juice, red meats, poultry, processed meats, and sweets), were defined [ 32 , 33 ].

Then, dietary patterns were used to evaluate the association of depression with dietary patterns and to adjust the confounders in multiple logistic regression. Multiple logistic regression models were used to assess the mediatory role of blood biomarkers related to depression. The following criteria were used to seek mediatory role of a variable [ 34 ]:

• Significance of the relationship between dietary pattern(s) and depression;
• No longer significance of the relationship between dietary pattern and depression after adding the mediatory variable to the model. In other words, after adding the mediatory variable(s) into the model, the relationship between dietary pattern(s) and depression had to transfer into the relationship between the mediatory variable and depression. Therefore, a third model had to be designed for ensuring the significant relationship between the mediatory variable(s) and depression.
• Significance of the relationship between the mediatory variable and depression.

The mediatory analysis was performed after adjusting some confounding variables such as job, education, marital status, children number, energy intake, and so on. The mentioned covariates were related to both dietary patterns (as the independent variables) and depression (as the dependent variable) which indicated they were confounders. In this way, the mediatory variables were in the causal path of dietary pattern and depression [ 35 ].

All statistical analyses were carried out using SPSS (version 20; Chicago, IL).

According to Table  1 for some important variables including weight, height, age, energy intake, smoking, and hookah, there was not a significant difference between case and control group indicating the matching had been done correctly.

Table 1

Baseline characteristics of study population in case and control groups

Data were presented as frequencies and percentages for categorical variables and mean ± SD, median (Q1–Q3) for normally and non-normally distributed variables, respectively

* p values calculated by Chi square for categorical values and Independent samples t test or Mann–Whitney test for continuous values

Based on our published results [ 33 ], the healthy dietary pattern significantly was related to the lower odds ratio of depression (OR 0.39, CI 0.17–0.92), and the unhealthy dietary pattern significantly was related to the higher odds ratio of depression (OR 2.6, CI 1.04–6.08).

We observed a significant relationship between serum vitamin D (OR 0.93, CI 0.87–0.99) and TAC (OR 2.08, CI 1.17–3.72) with depression after adjustment for some potential confounders. However, there was no significant association between serum zinc and magnesium, and depression (Table  2 ).

Table 2

Compare of some serum biochemical factors in case and control groups

p < 0.05 values are in italic

a Total antioxidant capacity

c Magnesium

d Multiple logistic regression after adjusting for job, education, marital status, children number, smoking and hookah, depression history, unemployment history in past 5 year, tragic events in past 6 months, energy expenditure, and physical activity

e Multiple logistic regression after adjusting age, sex, non-depression drugs, smoking and hookah, history of depression, body mass index, energy expenditure, and physical activity

In addition, in mediatory analysis unhealthy dietary pattern was inversely related to depression via changing the serum level of vitamin D after adjusting for job, education, marital status, children number, smoking and hookah, depression history, unemployment history in past 5 year, tragic events in past 6 months, energy intake, and physical activity (Table  3 ).

Table 3

Logistic regression model for mediation analysis in the pathway of the relation of dietary patterns with depression

p ≤ 0.05 values are in italic

Model 1: Logistic regression model for studying of relationship between depression and dietary patterns

Model 2: Logistic regression for studying of relationship between healthy dietary pattern and depression with mediation variables

Model 3: Logistic regression for studying of relationship between mediation variables and depression

All of three models adjusted for job, education, marital status, children number, unemployment history in past 5 year, tragic events in past 6 months r, smoking and hookah, depression history, energy expenditure, and physical activity

* Confidence intervals and p values for Hosmer and Lemeshow test that is the criterion of the goodness-of-fit for Logistic regression were nonacceptable

Model 1 in Table  3 illustrates the significant relation between dietary patterns and depression. For hypothesis testing of mediatory role, vitamin D was added in regression in model 2 (the same Table). By adding this variable, the significant relation between both dietary patterns and depression eliminated. In other words, the relationship between dietary patterns and depression moved to the relationship between the mediatory variable and depression. Therefore, it can be concluded that vitamin D is an intermediate variable. For confirmation of the idea, we examined the relation of vitamin D with depression (Table  3 —model 3). This mediatory role could be established by the significant results of the latest model. It was concluded that only unhealthy dietary pattern is related to depression via the intermediary role of vitamin D. In other words, people who had an unhealthy diet, if their vitamin D was increased by one unit, their odds of depression would be reduced by 11%.

Complete mediation in which other exposures no longer affects outcome after intermediary variable was controlled. Based on the results, vitamin D was a complete mediator because after serum vitamin D had been entered the relationship between unhealthy dietary pattern and depression disappeared [ 36 ].

We repeated testing the model for TAC (Table  3 ) because TAC was significantly related to depression (Table  2 ). However, the goodness of fit for the logistic regression model (based on confidence intervals and p value for Hosmer and Lemeshow test), was not valid (Table  3 ). There was no significant association between depression and serum zinc and magnesium. Hence, we did not do mediatory analysis for them.

In our study, there was a significant relationship between depression and serum vitamin D as well as between the unhealthy dietary pattern and depression after adjustment for some potential confounders. There was also a mediatory role for vitamin D in the pathway between unhealthy dietary pattern and depression. Therefore, we concluded that if people on an unhealthy diet try to raise their serum vitamin D levels by consuming more vitamin D, the chance of depression will be reduced among them. To the best of our knowledge, it is the first study that evaluates mediatory role of serum vitamin D in the associations between dietary pattern and depression.

According to our findings hypovitaminosis D resulted in higher odds of depression. In accordance with the present study, Eyles et al. [ 37 ] showed that in rats whose mothers were vitamin D deficient their brain in terms of gross morphology, cellular proliferation, and growth factor signaling as well as expression of nerve growth factor was not developed properly. In contrast with the mentioned study, in a cross-sectional study conducted in middle-aged and elderly Chinese, depressive symptoms were not associated with 25(OH) D concentrations [ 38 ].

Several mechanisms have been proposed to explain the association between vitamin D and depression. Effects of active form of vitamin D (1, 25 dihydroxycholecalciferol) in brain tissue have been established by the detection of vitamin D receptors (VDR) in different parts of the brain [ 10 , 39 ] such as amygdale as the center of the limbic system that affects behavior and emotions [ 40 ]. Vitamin D has also several neuroprotective functions, for example calcitriol regulates concentrations of calcium in neurons that could decrease toxicity resulted from excess calcium [ 13 , 15 , 18 ]. However, more studies are needed to examine the long-term effect of vitamin D depletion on the brain.

We could not establish the mediatory roles of TAC in the pathway of the relationship between the dietary pattern and depression because the goodness-of-fit criterion for the Logistic regression models was not acceptable (logical confidence intervals and p values for the Hosmer–Lemeshow test). Similar to the current study, Gonoodi et al. [ 41 ] did not find any significant relation between serum Zn levels and depression score in 408 adolescent girls aged 12–18 years. There were other studies which reported serum Zn concentrations did not differ between depressed patients and healthy group that support our results [ 42 – 44 ]. A randomized clinical trial demonstrated the efficacy of zinc supplementation in treatment of depression [ 45 ]. Moreover, one meta-analyses confirmed an inverse association between serum Zn concentration and depression [ 46 ]. All depressed patients in our study were new cases and it is the probable reason we could not observe any relationship in this regard. In other words, there was not enough time for reduction of zinc in the newly recognized patients. Another possible cause can be justified by the fact that the populations in different studies were not the same.

Results concerning evaluating serum magnesium concentrations in depressive disorders were inconsistent. Some authors found higher levels of serum Mg in depressed patient compared to healthy group [ 47 , 48 ] which are in contrast to our finding. On the other hand, several studies reported an inverse association between serum Mg levels and depression [ 49 – 52 ]. However, it seems serum Mg levels may not be a proper indicator of depressive disorders [ 52 ].

Strengths and limitations

In the current study we recruited new cases of depression. In addition, we conducted mediatory analysis, considered all inclusion and exclusion criteria precisely and minimized selection bias in the control group by going to the residential area of each patient.

The most important limitation of our study goes back to the nature of case–control studies in which the chance of recall bias is high, as well as the temporal relationship between depression and dietary patterns cannot be realized in such studies. Another limitation was related to financial restrictions which forced us not to do biochemical measurements for all the participants.

Recommendations

Some oxidative stress biomarkers such as albumin, HDL cholesterol, and uric acid are likely to be associated with depression. Therefore, we highly recommend future studies which evaluate the mediatory role of the mentioned biomarkers in the relationship between dietary pattern and depression.

This study showed that Vitamin D deficiency mediates the relationship between unhealthy dietary patterns and depression. However, to confirm the finding further prospective studies are suggested.

Acknowledgements

We are appreciated Research Deputy of Tehran University of Medical Sciences.

Authors’ contributions

GS has made substantial contributions to conception and design. She revised the manuscript critically as well. FR has made substantial contributions to conception and recruitment. MA has made substantial contributions to revise the manuscript in all of terms to satisfy your valuable comments and criticisms. MH has made substantial contributions to interpretation of data, and has been involved in the drafting of the manuscript. RM has made substantial contributions to design and statistical analysis. FK has been involved in the drafting of the manuscript. MK has made substantial contributions to conception and design, recruitment, biochemical analysis, interpretation of data, and the drafting of the manuscript. All authors read and approved the final manuscript.

The Research Deputy of Tehran University of Medical (19374-161-03-91) supported financial resources of the study.

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