Are there prophylactic effects of vitamin D among healthier adult patients? A systematic review of randomized controlled trials

Abstract

Introduction

In 2017, a study uncovered increasing trends in vitamin D supplementation, revealing that 18% of adults exceeded 1000 international units (IU) daily, and 3% surpassed the safe limit of 4000 IU, raising concern for severe hypercalcemia and associated pathological effects on the kidneys, heart, and vascular system. While vitamin D is well-established for prophylactic use against osteomalacia and osteoporosis, its extra-skeletal benefits for healthy individuals, such as improving insulin sensitivity and low-density lipoprotein, remain unclear. This study focuses on defining healthy adults and exploring the potential benefits and drawbacks of prophylactic vitamin D supplementation.

Methods

Using PubMed, EMBASE, and Scopus databases, 10,155 articles on vitamin D prophylaxis were identified. Randomized controlled trials targeting healthy patients receiving vitamin D for prophylaxis were included, with exclusions based on language, absence of reported outcomes, and patient history. Articles were screened and evaluated by Covidence and the Cochrane Risk of Bias tool, respectively. Dosage, form, frequency, duration, follow-up care, outcomes, and complications of included articles were recorded. This study protocol has been registered to PROSPERO: CRD42023446944.

Results

Out of 18 articles, 4,415 patients showed low bias risk by the Cochrane tool. Seven studies found significant improvements: protection against autoimmune reactions, elevated hematological and iron profiles, reduced influenza-like illness, and enhanced cognitive tasks. 5000 IU Vitamin D for four weeks significantly reduced cholesterol, unlike 1000 IU for 16 weeks. Conversely, 11 studies revealed no Vitamin D impact on outcomes including hemoglobin-A1c, lipoproteins, BMI, blood pressures, and respiratory infections.

Conclusion

Except for a few outcomes, most prophylactic Vitamin D supplementation was generally not found to have statistically significant benefits in the healthy adult population. Future directions can include additional prospective studies with larger sample sizes of healthy adults testing for benefits and adverse effects of prophylactic vitamin D use.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40795-025-01107-0.

Introduction

Vitamin D is a prohormone that is important for maintaining bone health and calcium levels. Vitamin D is found in two forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Studies have shown that vitamin D3 is more effective than vitamin D2 in raising serum 25-hydroxyvitamin D (25OHD), an established marker of vitamin D status [1]. Vitamin D3 deficiency is defined as < 30 nmol/l 25(OH)D, while adequate levels are generally defined as 50 nmol/l 25(OH)D or above. Levels above 125 nmol/l are considered too high and are linked to potential adverse effects. Deficiency in vitamin D3 results in hypocalcemia and defective bone mineralization [2]. In addition, vitamin D3 deficiency may be associated with increased risks for autoimmune diseases, chronic obstructive pulmonary disease, cancer, and metabolic syndrome [3]. A large consensus exists that vitamin D supplementation improves measures related to bone health, especially in individuals with poor vitamin D status, higher risk of osteoporosis, or insufficient exposure to sunlight. However, no relationship has been firmly established between vitamin D and other health outcomes, although extraskeletal effects have been suggested because of the wide expression of the vitamin D3 receptor in the human body, including in the immune, renal, nervous, and cardiovascular system [2, 4].

The recommended doses for vitamin D supplementation vary widely (from 200 IU to 2000 IU daily) and have changed as countries and scientific societies now recommend higher doses than before [5]. Correspondingly, the use of vitamin D3 supplements has increased, and recent data shows that vitamin D3 was the 65th most commonly prescribed medication in the United States in 2021, with more than 10 million prescriptions [6]. With the growing use of vitamin D by the general population, there is a need to examine the health effects of supplementation in vitamin D-replete patients. Although many studies have shown benefits of supplementation for the improvement of vitamin D3 deficiency and bone-related pathologies, far fewer have investigated the risks and benefits of supplementing vitamin D-replete adults. One such study found that supplementing vitamin D-replete adults demonstrated no overall health benefits on bone density, risk of falls, incidence of cancer, cardiovascular events, and type 2 diabetes mellitus [2]. Further research is necessary to definitively establish the effects of vitamin D supplementation in healthy individuals, especially as increased supplementation may pose a risk for exogenous hypervitaminosis D with various findings, such as hypercalcemia [3]. Thus, this systematic review aimed to discuss the efficacy and safety of vitamin D prophylaxis for diseases of the extraskeletal system in healthy adult patients.

Methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) Statement and Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. This protocol is registered in the PROSPERO database under the registration number CRD42023446944.

Search strategy

To complete this systematic review, articles were screened from several databases, including PubMed, Embase, and Scopus, using the Covidence Tool [7]. Key search criteria for article retrieval included terms related to vitamin D, prevention or prophylaxis, and randomized controlled trials. The full search algorithm utilized can be found in Appendix A. The initial search took place on June 28, 2023.

Article selection

A total of 10,155 articles, investigating vitamin D prophylaxis in healthy patients were selected. Two reviewers independently reviewed the title and abstract based on the eligibility criteria. If any systematic reviews met the inclusion criteria, their reference lists were added to the screening process and the systematic reviews were rejected. Any conflicts in screening were resolved via consensus. Next, the resulting full-text articles were screened independently by two reviewers and reasons for exclusion of an article were provided. Conflicts during the full-text screening were resolved by the lead authors and the gold standard reviewers: D.P., nephrologist, M.S., endocrinologist, Z.I., internist.

Eligibility criteria

Inclusion criteria included: healthy adult patients, randomized controlled trials (RCTs), all patients receiving vitamin D prophylaxis, peer-reviewed full-length articles, articles written in English, and outcomes are reported. Exclusion criteria included: patients with an ongoing history of hypercalcemia, patients with a diagnosis of bone pathology, patients that are considered unhealthy, and articles without outcomes. Pregnant patients were excluded, as the benefits of vitamin D on this population are well studied in literature. Eligibility criteria is further summarized in Table 1 using a Population, Intervention, Comparator, Outcomes, Timing, and Setting (PICOTS) framework.

Table 1.

PICOTS eligibility criteria

Population	Inclusion  ● Adults (> 18 years old) who are considered healthy  ● Patients are healthy (no history of chronic disease, end-organ damage, or pre-existing condition with proven benefits of vitamin D3 supplementation)  ● Peer-reviewed article Exclusion  ● Pediatric (< 18 years old) patients  ● Pregnant or postmenopausal patients  ● Patients had a history of ongoing hypercalcemia causing bone, kidney, gastrointestinal, or psychiatric related issues.  ● Patients had a diagnosis of rickets, osteoporosis, or osteomalacia  ● Patients who are unhealthy (have a history of chronic disease, end-organ damage, or pre-existing condition with proven benefits of vitamin D3 supplementation)
Intervention	Inclusion  ● All patients in the treatment arm received a prescription vitamin D3 prophylaxis. Exclusion  ● All patients in the treatment arm did not receive a vitamin D3 prophylaxis.  ● Vitamin D3 prophylaxis was non-prescription (i.e. Over-the-counter).
Comparator	● Only randomized controlled trials were included.  ● In general, the control group for eligible articles included patients receiving a placebo of equivalent route of administration rather than active vitamin D3. However, in the event that a placebo was not possible (i.e. UV-administered light) then the control group received no intervention.
Outcomes	Inclusion  ● Outcomes analyzed:   ○ Varied depending on the disease for which the vitamin D was intended, but included such things prophylactic trends, laboratory values, symptom complaints, confirmed diagnosis of infection, hospital admission, and/or changes to symptoms following vitamin D3 supplementation.  ● Articles without outcomes were excluded.
Timing	● Interventions with any timing, duration, and follow-up period were included.
Setting	● Interventions with any care setting (including in-patient or out-patient).

Data extraction/analysis

An abstraction form was developed to standardize data extraction (Appendix B). Two reviewers independently extracted data and did a study quality assessment for each study included using Covidence, and discrepancies were resolved through consensus. The Cochrane Risk of Bias tool [8] was employed to assess the potential for bias in each RCT included. Information collected included study name, number of patients, patient demographics, age, comorbidities, dose of vitamin D3, frequency, and duration of vitamin D3 dose. The main outcomes collected were prophylactic trends, laboratory values, symptom complaints, and changes to symptoms following supplementation. Reviewers also considered the change in outcomes over time, quantified the number of studies with similar methods, and assessed the extent of follow-up within each study. Due to significant heterogeneity, the extracted data was analyzed through narrative synthesis.

Results

Out of 10,155 articles screened on Covidence, 18 studies met our inclusion criteria of being a randomized control trial that gave prophylactic vitamin D to a healthy patient population. All included studies had an overall low risk of bias assessment (Table 2). Within the included articles, 4,415 participants, ranging from age 18 to 70 years old, were studied. Variable doses of vitamin D ranging from 200 IU to 200,000 IU were given prophylactically, and all studies were categorized based on the primary organ system investigated (Table 3). The main outcomes extracted from these studies were organized by organ systems and the dose of vitamin D supplementation given (Table 3). The PRISMA flow chart illustrates the process of selecting articles in Fig. 1.

Table 2.

Risk of bias of included studies

Study	Sequence Generation	Allocation Concealment	Blinding of Participants and Personnel	Blinding of Outcome Assessors	Incomplete Outcome Data	Selective Outcome Reporting	Other Source of Bias
Madar 2014	Low	Low	Low	Low	Low	Low	Low
Muldowney 2014	Low	Low	Low	Low	Low	Low	Low
Scragg 2014	Low	Low	Low	Low	Low	Low	Low
Fourouhi 2016	Low	Low	Low	Low	Low	Unclear	Low
Jastrzebski 2016	Low	Low	Low	Low	Low	Low	Low
Knutsen 2017	Low	Low	Low	Low	Low	Low	Low
Brisson 2017	Low	Low	Low	Low	Low	Low	Low
Barker 2012	Low	Low	Low	Low	Low	Low	Low
Chandler 2014	Low	Unclear	Low	Low	Low	Low	Low
Bock 2011	Low	Unclear	Low	Unclear	Low	Low	Low
Mielgo-Ayuso 2018	Low	Low	Low	Low	Low	Unclear	High
Knutsen 2014	Low	Low	Low	Low	Low	Low	Low
Pettersen 2017	Low	Low	Low	Low	Low	Low	Low
vanHelmond 2022	Low	Low	Unclear	Low	Low	Low	Low
Murdoch 2012	Low	Low	Low	Low	Low	Low	Low
Goodall 2014	Low	Low	Low	Low	Low	Low	Low
Li-Ng 2009	Low	Low	Low	Low	Low	Low	Low
Laaksi 2010	Low	Low	Low	Low	High	Low	Unclear

Table 3.

Vitamin D supplementation and patient outcomes

Article	Dose (IU)	Form	Duration	Patients (#)	Patient Outcomes
Cardiology
Muldowney et al. 2012	200	Capsule	22 weeks (wk)	470	No effect on parathyroid hormone, systolic and diastolic blood pressure, fasting lipids, glucose and insulin, HOMA-IR, high-sensitivity CRP, matrix metalloproteinase-9, tissue inhibitor metalloproteinase-1
I. Madar et al. 2014 II. Muldowney et al. 2012	400	I: Tablet II: Capsule	I: 16 wk II: 22 wk	I: 84 II: 470	I: No change to glycated hemoglobin (HbA1c), fructosamine, serum lipids, and body mass index II: No effect on biomarker risk
Muldowney et al. 2012	600	Capsule	22 wk	470	No effect on parathyroid hormone, systolic and diastolic blood pressure, fasting lipids, glucose and insulin, HOMA-IR, high-sensitivity CRP, matrix metalloproteinase-9, tissue inhibitor metalloproteinase-1
Madar et al. 2014	1000	Tablet	16 wk	84	No change glycated hemoglobin (HbA1c), fructosamine, serum lipids, and body mass index
Jastrzebski et al. 2016	5000	Droplet	4 wk	14	Significant decrease in total cholesterol
I. Scragg et al. 2014 II. Forouhi et al. 2016	100,000	I: Tablet II: Liquid	I*: 18 months (mo) II*: 4 mo	I: 161 II: 226	I: No effect on systolic BP, diastolic BP, and HR II: No effect on HbA1c with vitamin D2 or D3
Endocrinology
Knutsen et al. 2017	400	Tablet	16 wk	83	No effect on TPOab and autoimmune thyroid disease prevention
	1000	Tablet	16 wk	85	No effect on TPOab and autoimmune thyroid disease prevention
Gynecology
Brisson et al. 2017	1000	Tablet	12 mo	96	No reduction in breast density
	2000	Tablet	12 mo	99	No reduction in breast density
	3000	Tablet	12 mo	100	No reduction in breast density
Immunology
Barker et al. 2012	200	Not specified	28 days (d)	10	Prevented decrease in IL-5 response
Chandler et al. 2014	1000	Capsules	3 mo	81	No significant change in circulating levels of IL-6, IL-10, sTNF-R2, and CRP associated with treatment arms
	2000	Capsules	3 mo	83	No significant change in circulating levels of IL-6, IL-10, sTNF-R2, and CRP associated with treatment arms
I: Barker et al. 2012 II: Chandler et al. 2014	4000	I: Not specified II: Capsules	I: 28 d II: 3 mo	I: 10 II: 83	I: Prevented decrease in serum IL-5 II. No significant change in circulating levels of IL-6, IL-10, sTNF-R2, and CRP associated with treatment arms
Bock et al. 2011	140,000	Droplet	12 wk *	30	- No significant change to C-peptide mean value - Increase in mean percentage Tregs
Musculoskeletal
Knutsen et al. 2014	400	Tablet	16 wk	85	No significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo
	1000	Tablet	16 wk	84	No significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo
Mielgo-Ayuso et al. 2018	3000	Capsule	8 wk	18	- Prevented decline in hematological levels of hemoglobin and hematocrit, and improve transferrin - No changes to testosterone and cortisol profile
Neurology
Pettersen et al. 2017	4000	Tablet	18 wk	42	- Significant improvement on Paired Recognition Memory and nonverbal tasks - No significant difference in verbal memory tasks
Pulmonology
Laaksi et al. 2010	400	Tablet	6 mo	80	No significant difference in either the incidence, duration, or severity of upper respiratory tract infection (URTI) symptoms
Li-Ng et al. 2009	2000	Not specified	12 wk	78	No benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URTIs during winter
vanHelmond et al. 2022	5000	Capsule	9 mo	155	Significant reduction in influenza-like illness incidence
Goodall et al. 2014	10,000	Capsule	2 mo**	150	Significant reduction in URTI events
Murdoch et al. 2012	200,000	Tablet	18 mo***	161	No significant difference in URTI incidence

* Once monthly

** Once weekly

*** 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly

Fig. 1.

PRISMA Flow chart illustrating the process of selecting articles

Cardiology

Five out of the 18 studies studied the effects of prophylactic vitamin D on cardiovascular health. In three studies that assessed the effect of vitamin D supplementation on different biomarkers correlated with cardiovascular risk, there was no significant effect on hemoglobin A1c (HbA1c), fructosamine, and blood pressure in comparison to the placebo groups [9, 10] Scragg et al. [11], there was a transient decrease in systolic and diastolic blood pressure at five months. Ultimately, no significant difference in blood pressure and pulse rate at the 18 month end point between those that were supplemented with 100,000 IU daily and the placebo group. In contrast, Jastrzebski et al. [12] administered approximately 5000 IU of vitamin D daily for four weeks via a liquid form to determine its effect on total cholesterol levels and concluded a significant decrease in cholesterol levels in comparison to their placebo group. Notably, this study was limited by the study’s small sample size of 14 patients and lack of diet control. Forouhi et al. [13] was the only study to incorporate vitamin D2 for investigation (in addition to D3) and demonstrated a non-clinically significant reduction in arterial stiffness for both vitamin D2 and vitamin D3.

Respiratory

Five of the included studies observed vitamin D supplementation in the prevention of respiratory infections and illness. Three of five studies observed the effects of varying doses of vitamin D supplementation in preventing upper respiratory infections (URIs). Goodall et al. [14] and Li-Ng et al. 15] administered 10,000 IU once a week for 2-months and 2000 IU daily for 3-months, respectively, yielding no statistical significance in the incidence of URIs. Similarly, Murdoch et al. [16] did not observe any significant reductions in URTIs or differences in duration or severity of the URTI episodes when they administered a loading vitamin D dose of 200,000 IU initially and at one month, and subsequent 100,000 IU monthly doses for a total of 18 months. Laaksi et al. [17] provided 400 IU of daily vitamin D supplementation and also reported no significant difference between the days those participants missed work due to a respiratory infection in comparison to their control group. However, Goodall et al. [14] noted a significant decrease in secondary outcomes, including lab confirmed viral illness and mean viral load. Notably, van Helmond et al. [18] demonstrated that supplementing their participants with 5000 IU of vitamin D daily for nine months helped to reduce incidence of influenza-like illness, with five patients experiencing adverse effects.

Immunology

Three studies focused on the effects of prophylactic vitamin D on different aspects of the immune system. Barker et al. [19] utilized vitamin D in the prevention of IL-5 decline and noted both the 200 IU and 4000 IU daily doses for 28 days prevented a decrease in IL-5 levels. Contrarily, Chandler et al. [20] supplemented their participants with 1000 IU, 2000 IU, and 4000 IU of vitamin D daily for three months reported that there were no statistically significant changes in levels of other interleukins and inflammatory markers, such as IL-6, IL-10, CRP, and soluble TNF-alpha receptor type 2 (sTNF-R2). Bock et al. [21] determined that short-term monthly dosage of 140,000 IU of vitamin D for three months resulted in a significantly increased regulatory T-cell (T-Reg) frequency, and suggested that it may be a useful therapeutic tool for certain autoimmune diseases.

Musculoskeletal

The effect of vitamin D supplementation on the musculoskeletal system was observed in two studies. Mielgo-Ayuso et al. [22] reported 3000 IU vitamin D supplementation for eight weeks, the decline in levels of hemoglobin and hematocrit were prevented. There were no notable improvements in the testosterone and cortisol levels compared to the control, providing evidence that supplementation did not enhance muscle recovery. Knutsen et al. [23] reported no significant effect on the degree, location, and frequency of muscle pain.

Gynecology

Breast cancer prophylaxis in conjunction with vitamin D supplementation was conducted by Brisson et al. [24] Specifically, doses ranging from 1000 to 3000 IU daily for one-year to determine any breast density reduction (previously correlated with a reduced risk of breast cancer). The 3000 IU daily dose of vitamin D resulted in less reduction in breast density in comparison to the placebo; however, the difference was not statistically significant.

Endocrinology

Vitamin D supplementation was utilized for autoimmune thyroid disease prophylaxis by Knutsen et al. [25] They tested the effect of a 400 IU or 1000 IU daily dose for 16 weeks on thyroid immunity. In comparison to the placebo, they found no prophylactic benefits for autoimmune thyroid disease as determined by no significant changes in levels of thyroid peroxidase antibody (TPOAb), free thyroxine (FT4), or thyroid stimulating hormone (TSH).

Neurology

In a study by Pettersen et al. [26], the effects of vitamin D supplementation on the prevention of cognitive decline were observed. The control group received 400 IU while the intervention group with 4000 IU daily dose of vitamin D for 18-weeks, and noted the intervention group had significantly improved non-verbal memory (visuospatial) memory. There were no significant differences between the two groups in other cognitive domains, such as verbal memory. Interestingly, an improvement in mood was observed in the high-dose group by 2.8 points, as assessed by the Beck Depression Inventory.

Discussion

Although vitamin D has known therapeutic effects on bone health, there is a gap in knowledge about whether vitamin D supplementation can prevent diseases of the extraskeletal system. This systematic review analyzes 18 RCTs with 4,415 patients to further assess vitamin D prophylaxis in healthy adults from a multi-organ standpoint. Of the five cardiology-related articles included, 80% showed no preventative effect on cardiovascular biomarker risk, such as blood pressure, fasting lipids, and HbA1c, except for one study that found a significant decrease in total cholesterol. Vitamin D prophylaxis for URTI yielded mixed results, whereby 60% of the respiratory articles demonstrated no preventative effect with supplementation and 40% showed a significant decline in URTI incidence. While vitamin D had no significant impact on autoimmune thyroid disease and breast cancer prevention, there are promising benefits in terms of preventing immune, musculoskeletal, and neurological disease. Multiple studies found positive immune responses in 67% of the immune-related RCTs, improvement in hematological and iron metabolism profiles in 50% of musculoskeletal studies, and significant enhancement on memory and nonverbal tasks in one neurological study. Overall, this review found that vitamin D supplementation generally does not provide significant extraskeletal benefits among the healthier adult population and thus supports a personalized approach to physician prescription practices of vitamin D.

Cardiovascular

Interest in vitamin D’s potential association with cardio-metabolic health is on the rise, considering its relationship with cardio-metabolic markers like HbA1c, serum lipids, blood pressure, and several other factors. Overall, vitamin D supplementation has yet to demonstrate significant effects on a large-scale setting [27]. Concerning glycemic control, there are well-described mechanisms by which vitamin D and glucose metabolism are linked; however, data from randomized controlled trials are relatively rare and mainly in patients with type 2 diabetes or other underlying disease, overweight, insulin resistant, or vitamin D deficient, notably discussed in the D2d study by Bess Dawson-Hughes et al. [51] In this review, multiple studies have shown conflicting results when monitoring vitamin D’s effect on HbA1C, insulin resistance, and other diabetic markers (e.g. fructosamine). Previous studies have demonstrated positive effects through lowered LDL and increased HDL with the use of vitamin D3 supplementation [28]. Jastrzebski et al. [12] studied athletes who demonstrated a significant decrease in total cholesterol and HDL (p < 0.02 and p < 0.01, respectively), but non-significant decrease in LDL (p = 0.79) at 5000 IU supplementation [29]. Regular exercise has been associated with an improved lipid profile, where athletes tend to demonstrate lower total and LDL cholesterol and higher HDL concentration compared to non-athletes [30, 31]. However, Madar et al. [9] note that vitamin D supplementation may not induce clear effects on BMI or HbA1c in healthy individuals. Forouhi et al. [13] found minor effects on some lipid levels with mixed evidence for effects of vitamin D supplementation [32, 33]. For blood pressure, both Scragg et al. [11] and Muldowney et al. [10], indicate that long-term high or low dose vitamin D supplementation does not significantly lower blood pressure even at up to 100,000 IU supplementation. Forouhi et al. [13] reported a reduction in arterial stiffness, suggesting potential favorable effects on vascular health. However, the mechanisms behind this decline remain unclear and warrant further investigation. Thus, while there is significant interest in understanding the relationship between vitamin D and cardio-metabolic health, the current evidence from various studies yields mixed and inconclusive results. Notably, past trials with participants with high baseline levels of 25-hydroxyvitamin D were limited in meaningful effects. However, Wang et al. [52] found a nonlinear inverse relation in individuals with concentration below 20ng/mL and suggests focusing on populations with vitamin D deficiency to better evaluate benefits. Achieving and maintaining adequate serum 25(OH)D levels through supplementation may be associated with improved health outcomes [53, 54].

Respiratory

Five studies that examined the use of vitamin D supplementation to prevent respiratory illness showed mixed results. Four of the five respiratory-related articles demonstrated no significant differences to protection against URIs when given vitamin D supplementation at varying doses [14–16]. In particular, Li-Ng et al. [15], participants of 25(OH)D demonstrated levels > 20 ng/mL and supplementation did not affect URTIs. However, Goodall et al. [14] had significant decrease in viral illnesses and mean viral loads, which may suggest protective effects. While van Helmond et al. [18] demonstrated statistically significant reduction in respiratory infection, which was paralleled by Jolliffe et al. [34], who found that treatment with vitamin D significantly lowered acute respiratory infection incidence with an odds ratio of 0.92 (p = 0.018). The protective effects were especially prominent with daily dose regimens as opposed to single-dose or intermittent treatments. Throughout this research, significant improvements were reported after administering 5000 IU daily and 10,000 IU weekly. These findings suggest that a regimen with higher, more frequent doses may be more effective as vitamin D prophylaxis for respiratory illnesses and may be affected to a patient’s baseline 25(OH)D serum levels, but further investigation is required [55].

Immunology

Vitamin D receptors are found on T-cells, mast cells and eosinophils, which are influenced by inflammatory cytokines, including IL-5 [35–38]. GATA binding protein 3 (GATA-3) transcription factor promotes IL-5 gene expression [39, 40]. Previous research have suggested suggest prophylactic effects on the immune system with vitamin D supplementation. Barker et al. [19] did not demonstrate an increase in IL-5 gene expression with 4000 IU supplementation and thought to be related to detecting errors within blood sampling protocols. Chandler et al. [20] and Muldowney et al. [10] found no significant impact on multiple proinflammatory markers with a range of 1000 to 4000 IU of vitamin D supplementation. However, Bock et al. [21] determined that 140,000 IU vitamin D supplementation over three months resulted in a significantly increased Tregs frequency (p ≤ 0.001), suggesting vitamin D3 may be a useful therapeutic agent in autoimmune diseases exerting immune modulatory effects involving stimulatory actions on Tregs; however, Bock et al. [21] reported only one-third of the subjects had incidentally been found to be vitamin D deficient (< 20 ng/mL). These conflicting results serve as a rationale for future trials with large populations and more stringent testing environments.

Musculoskeletal

One study measuring musculoskeletal pain and headaches observed that daily vitamin D supplementation of 400 or 1000 IU did not have a significant effect on patients [23], echoing similar trials. Other RCTs showed no significant pain reduction with vitamin D for chronic lower back pain [41] and knee pain in osteoarthritis patients [42, 43], while a study in fibromyalgia patients noted reduced pain, however, with limited power [44]. Contrarily, a study in male athletes revealed positive effects on hemoglobin (p = 0.009), hematocrit (p = 0.019), and transferrin (p = 0.007), potentially enhancing oxygen transport efficiency [22], supported by improved musculoskeletal performance in another study [45], suggesting that higher dosages may offer more pronounced benefits regardless of treatment duration. These results indicate that vitamin D may induce improvement primarily in hematological values rather than musculoskeletal pain and recovery in healthy adults.

Gynecology

Vitamin D’s association with breast cancer prevention and risk continues to be under investigation. Recent literature suggests that vitamin D signaling may have a protective effect against breast cancer risk, with an inverse association between vitamin D and breast cancer risk, especially for BRCA1 gene mutation carriers [46, 47]. Brisson et al’s [24] study did not demonstrate a significant decrease in breast density with medium to high doses of vitamin D supplementation for one-year. Rather, the 3000 IU dose showed less reduction in breast density. The serum 25(OH)D varied between intervention arms, and some < 20 ng/mol. Outside of our inclusion criteria, McDonnell et al. contradicted these findings when holding higher serum 25(OH)D concentrations of ≥ 40 ng/mL, which were associated with a significant reduction in cancer risk compared to lower levels [56]. Future research should explore the link between plasma vitamin D levels, calcium level changes, and breast cancer risk.

Endocrine

Vitamin D deficiency has been previously linked to autoimmune thyroid disease such as Hashimoto’s thyroiditis and Grave’s disease [48]. Yet, it is unclear whether supplementation of vitamin D can reduce thyroid autoantibody levels. One RCT tested this idea and showed that vitamin D supplementation did not have a significant effect on TPOAb, TSH, or free fraction of thyroxine levels in healthy adult patients [25]. These findings differ from another trial that conveyed a greater decline in TPOAb in a group of patients treated with both vitamin D and calcium compared to only calcium supplements (p = 0.028) [49]. This difference was particularly significant among those with baseline serum TSH of ≤ 10 mIU/L, suggesting that vitamin D supplementation may optimally benefit patients with newly diagnosed autoimmune thyroid disease. However, the advantages of supplementation were not replicated in Knutsen et al.’s [25] RCT included in this study. Because there are limited studies using vitamin D as therapeutic doses, more studies with healthy adult patients are necessary to identify the health effects of vitamin D on preventing thyroid autoimmunity.

Neurology

Vitamin D supplementation may take over 16 weeks to show certain effects [50]. Petterson et al. [26] demonstrate 3000 IU vitamin D supplementation appears to improve cognition, especially nonverbal memory via Pattern Recognition Memory tasks and Paired Associates Learning Tasks (p = 0.043 and p = 0.044, respectively). This finding aligns with recent studies linking 25(OH)D levels and nonverbal memory, possibly due to the increased cognitive demands of visual memory [26]. This study also speculates that nonverbal, but not verbal memory, require increased cognitive demands and reliance on executive functioning processes of visual memory. Thus, Petterson et al. [26] suggest that higher levels of vitamin D supplementation may be more beneficial.

Limitations and future studies

Our findings can be considered in light of the following limitations. Included studies had inconsistent doses of vitamin D supplementation, differing follow up periods, unique outcomes, do not consider intake from diet and sun exposure, and some had limited sample sizes (< 500 participants), making a meta-analysis infeasible. In addition, there was also an inconsistency in duration between interventions from days-to-weeks-to-years, which introduced confounding factors between acute versus chronic use of supplementation. Recognition of these limitations can help future studies address these constraints to progress for a more comprehensive and articulate connection between vitamin D supplementation and [potential] health consequences. Future studies should consider studies with larger sample sizes of healthy adults testing for benefits and adverse effects of prophylactic vitamin D use, and adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels [57].

Conclusion

In summary, this systematic review evaluated 18 RCTs and 4,415 patients to explore prophylactic vitamin D supplementation in the healthy adult population. Out of the 18 studies, 11 demonstrated a positive response in at least one marker with supplementation, whereas seven found no significant effects. Overall, vitamin D prophylaxis generally was not found to have statistically significant benefits when considering seven extra-skeletal organ systems. Few adverse events (e.g. nausea, abdominal pain) were noted; however, no severe complications (e.g. hypercalcemia) or exacerbation of disease were observed. While certain studies, particularly the immune and neurological RCTs, hint at potential benefits, the extensive limitation of sample size, variable doses, inconsistent duration, and unaccounted for dietary or solar sources highlight the need for more rigorous research to establish a clearer understanding of the health consequences of vitamin D supplementation.

Electronic supplementary material

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Abbreviations

Vit D3

Vitamin D3

UVB

Ultraviolet B

PTH

Parathyroid hormone

Ca

Calcium

25(OH)D

25–Hydroxyvitamin D

1,25(OH)2D

1,25–Dihydroxyvitamin D

BMD

Bone mineral density

RCT

Randomized controlled trial

BMI

Body mass index

CI

Confidence interval

SD

Standard deviation

SE

Standard error

Author contributions

CG (co-author) - primary intellectual contribution of the project, set timelines and ensure all team members have adequate support to meet the deadlines, contribute to all aspects of data collection and will draft the discussion, assist in the results, and contributed to manuscript development. SL (co-author) - set timelines and ensure all team members have adequate support to meet the deadlines, contribute to all aspects of data collection and will draft the discussion, assist in the results, interpretation of data, and contributed to manuscript development. HZ - heavily contributed to acquisition and analysis, drafted results section.HP - contributed to acquisition and analysis, drafted introduction, assisted in results section drafts.BM - design of the work with methods, contributed to acquisition and analysis, substantively revised drafts. KA - contributed to acquisition and analysis, drafted methods section, assisted in results section drafts. MH - contributed to acquisition and analysis, substantively revised drafts, and contributed to references formatting and in-text citations.KT - contributed to acquisition and analysis; and revised drafts. MS - design of the work and provided direction towards purpose; substantively revised drafts. ZI - design of the work and provided direction towards purpose; substantively revised drafts. CL - provided inspiration to this project based on clinical experience, design of the work, and substantively revised drafts. DP - design of the work and provided direction towards purpose; substantively revised drafts; approved the submitted version; agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.