Open research questions in Vitamin D Research Studies

What the literature leaves open

• Background: Vitamin D deficiency is linked to Parkinson disease (PD) pathogenesis; however, clinical trial results remain inconclusive.

  Effect of vitamin D supplementation on clinical outcomes of patients with Parkinson disease: A randomized controlled study · 2026 · DOI

• Future research should focus on multicentre studies involving larger and more diverse athletic populations to improve the generalizability of the findings. Long-term investigations evaluating the sustained effects of exercisebased rehabilitation on vitamin D status, musculoskeletal health, and sports performance are also warranted. Additionally, future studies should explore the influence of different exercise modalities, nutritional interventions, sunlight exposure, and genetic factors on vitamin D metabolism. Advances in wearable technologies and digital health platforms may facilitate continuous monitoring of physical activity and vitamin D status, thereby support rehabilitation programmes and individualized improve long-term athlete health.

  Influence of Exercise on the Rehabilitation of Vitamin D Deficiency among Athletes: A Study Protocol · 2026 · DOI

• Background/Objectives: Lower serum 25-hydroxyvitamin D [25(OH)D] is common in pediatric overweight and obesity, but it remains unclear whether direct adiposity assessment adds information beyond an age- and sex-adjusted model containing BMI z-score and season.

  DXA-Derived Total Body Fat Percentage and Serum 25(OH)D in Overweight and Obese Children: A Cross-Sectional Study · 2026 · DOI

• Background Prior investigations have suggested a relationship in which vitamin D may be linked to distal symmetric polyneuropathy (DSPN), but these results are inconsistent.

  Lower serum 25-hydroxyvitamin D levels predict higher risk of DSPN in type 2 diabetes, and exhibit a non-linear association with the severity of DSPN · 2026 · DOI

• Moreover, few studies have examined the linear relationship between vitamin D levels and the severity of DSPN and no definitive clinical threshold has been identified.

  Lower serum 25-hydroxyvitamin D levels predict higher risk of DSPN in type 2 diabetes, and exhibit a non-linear association with the severity of DSPN · 2026 · DOI

• Abstract Although vitamin D (VitD) exhibits anti-tumor activity in colorectal cancer (CRC) preclinically, its effects in the human tumor microenvironment (TME) remain unclear.

  Impact of vitamin D on the colon cancer immune microenvironment: results of a randomized clinical trial of preoperative vitamin D supplementation in patients with stage I-III colon cancer · 2026 · DOI

• Con- sequently, well-designed studies with larger sample sizes and more homogeneous patient groups are warranted to better elu- cidate whether 25-hydroxyvitamin D plays a meaningful role in determining grip strength in this patient population.

  The Effect of 25-OH Vitamin D Levels on Grip Strength in Myofascial Pain Syndrome · 2026 · DOI

• [10,11] Despite these mechanistic foundations, clinical research examining the vitamin D–muscle strength relationship has yielded conflicting results.

  The Effect of 25-OH Vitamin D Levels on Grip Strength in Myofascial Pain Syndrome · 2026 · DOI

• The main limitation of this study is its retrospective design. Additionally, by checking the hospital information system or pharmacy information system, the possibility of RRIs in the patient should be investigated. Furthermore, due to the observational nature of the study, causal relationships between vitamin D levels and the evaluated symptoms and clinical findings could not be established.

  Relationship Between Serum Vitamin D Levels and Clinical Findings: What We Know and Unknown in Pediatric Cases · 2026 · DOI

• Abstract Background This study was designed to inspect the effects of vitamin D 3 overdose on the submandibular salivary gland of Albino rats and to investigate the possible protective role of vitamin K 1 after one month, as few studies have addressed its histopathological effects.

  Histopathological effect of hypervitaminosis D3 on the submandibular salivary gland of albino rats and the possible protective role of vitamin K “histological & ultrastructural study” · 2026 · DOI

• Abstract Purpose Vitamin D deficiency (VDD) is common in older adults with osteoporosis, but its prevalence, determinants, and clinical impact in hip fracture (HF) patients remain incompletely defined.

  Prevalence, predictors, and clinical impact of vitamin D deficiency on 12-month outcomes in hip fracture patients · 2026 · DOI

• The most well- 17 established cause for the global prevalence of VD deficiency is insufficient exogenous intake combined with limited endogenous synthesis, a consequence of modern lifestyles associated with civilization development.

  Environmental, biological and behavioral factors influencing vitamin D status · 2026 · DOI

• This study has several notable strengths. It is among the few investigations conducted in eastern Indonesia that specifically examines the relationship between serum vitamin D levels and hypertension, thereby providing valuable local epidemiological evidence in a tropical population. The study focused on government employees—a population group with a high prevalence of hypertension—making the findings relevant for targeted public health interventions. The use of the Enzyme Chemiluminescence Immunoassay (ECLIA) method ensured precise and reliable measurement of serum vitamin D levels, and the application of standardized diagnostic criteria based on the 2020 International Society of Hypertension 323 guidelines enhanced methodological rigor. Nevertheless, the study has certain limitations. Its cross-sectional design precludes establishing causality between vitamin D levels and hypertension, and the relatively small, occupation-specific sample may limit generalizability. Several potential confounders such as diet, physical activity, and sunlight exposure were not fully controlled, and secondary hypertension was not excluded through further diagnostic testing. Future research should employ longitudinal or interventional designs with larger and more diverse populations, incorporate biochemical and behavioral covariates, and explore genetic or environmental factors influencing vitamin D metabolism to clarify its causal role in hypertension.

  Difference of Serum Vitamin D Levels in Government Employees with Hypertension and Without Hypertension in Kupang City · 2026 · DOI

• Although this study focused on critically ill adults, the study population was diverse. For example, some patients suffered serious traumatic injuries, while others were taken to the surgical intensive care unit following an operation. Medical ICU patients suffering from sepsis, acute kidney injury, pneumonia, respiratory failure, or shock were included in certain trials. The selected studies varied greatly in terms of sample size. The majority of the trials included in our meta- analysis had small sample sizes, with only three large-scale RCTs (more than 200 patients) included (19, 20, 34). Our meta-analysis employed liquid chromatography–tandem mass spectrometry assay, the reference technique for measuring 25-hydroxyvitamin D levels. But not all of the included studies employed liquid chromatography– tandem mass spectrometry assay to measure the 25-hydroxyvitamin D concentration. The diverse analysis of 25-hydroxyvitamin D data may have introduced bias into the final results. We first evaluated 90-day mortality, followed by 28-day mortality and hospital mortality in included studies. We replaced alternative mortality rates for 90-day mortality, which may have added bias and should be considered with caution. The baseline 25-hydroxyvitamin D level, dosage and route of vitamin D supplementation, and illness severity of the recruited patients differed across the trials. Thus, the variability and evaluated confidence of the studies restrict the generalizability of the conclu- sions, which should be interpreted cautiously. Subgroup analyses of baseline vitamin D level (less than 20 ng/mL) are based on 16 studies. But subgroup analyses of baseline vitamin D level (less than 12 ng/ mL) are based on only two studies, and results should be interpreted with caution.

  Vitamin D supplementation and mortality among critically ill adults: a systematic review and meta-analysis · 2026 · DOI

• However, it must be emphasized that no standardized serum threshold, population-specific validation, or universally accepted predictive model currently exists; therefore, serum 25(OH)D should be regarded as a candidate—rather than an established—biomarker for SSNHL risk stratification.

  Vitamin D and sudden sensorineural hearing loss: emerging associations, mechanistic insights, and prospects for precision medicine — a review · 2026 · DOI

• Human studies suggest an association between blood vitamin D levels and blood cholesterol; however, the mechanistic impact of sustained elevation of 1,25(OH)2D3 (active vitamin D) on cholesterol flux remains unclear.

  Chronic elevation of 1.25(OH)2D enhances cholesterol excretion through coordinated regulation of hepatic and intestinal elimination pathways · 2026 · DOI

• Future research should address these gaps by prioritiz- ing studies that focus on cardiac autonomic endpoints to better define vitamin D’s role in autonomic regulation. While the evidence suggests a meaningful asso- ciation, further research is needed to confirm its impact on clinical outcomes.

  Shining Light on Dysautonomia: The Role of Vitamin D in Cardiac Autonomic Regulation · 2026 · DOI

• 5 Outcome measure limitations This study exclusively used EFS as the primary endpoint, failing to distinguish between local recurrence and distant metastasis, and did not evaluate overall survival, distant metastasis-free survival, treatment-related toxicities, or patient quality of life. While these findings are hypothesis-generating, trajectory-based vitamin D assessment remains investigational at this stage, and future studies are needed to confirm whether such monitoring can be effectively translated into routine clinical practice.

  Dynamic vitamin D trajectories and their prognostic value in breast cancer: a group-based trajectory modeling study · 2026 · DOI

• Few RCTs have examined the effect of vitamin D3 supplementation during pregnancy on offspring cognitive functions.23,49 To our knowledge, this is the first RCT to assess cognitive functions among children older than 5 years using performance-based outcomes. The strengths of this study include the large sample size and the deep phenotyping of children enabled by their participation in the COPSAC2010 cohort. Furthermore, the cognitive test battery consisted solely of performance- based subtests covering a broad range of cognitive functions. ADHD diagnoses were based on clinical interviews.51 This study also has several limitations. It is a post hoc analysis of an RCT that was not prespecified, thus increasing the risk of spurious findings. The high preinterventional mean 25(OH)D level limits our ability to assess potential benefits among participants with low vitamin D status. The large number of cognitive measures included may have limited statistical power to detect significant group differences. The small number of children with ADHD reduces the power to detect subgroup- specific associations. The use of a single neurocognitive assessment at age 10 years may have limited insight into developmental patterns across childhood. Due to the timing of the supplementation, we had the opportunity to examine the potential association of high-dose supplementation only in late pregnancy. In the observational analyses, residual confounding cannot be ruled out. We lack data on parental intelligence and psychopathologic conditions, both of which are heritable.73-75 However, we do have data on income and educational level, which are known to be associated with intelligence,76 and adjusting for these factors did not substantially modify the results. Finally, the generalizability of the study is limited by the predominance of White participants with a high mean 25(OH)D level.

  High-Dose Vitamin D ₃ Supplementation During Pregnancy and Test-Based Cognitive Performance at Age 10 Years · 2026 · DOI

• The use of multivariable logistic regression enabled adjustment for potential confounders and the identification of independent predictors of hypovitaminosis D. However, because this was a hospital-based cross-sectional study, the findings may not be fully generalizable to the broader community. The relatively high absolute error (10%) used in sample size calculation resulted in a modest sample size. Berksonian bias may also have influenced the findings. Additionally, the cross-sectional design precludes causal inference regarding the relationship between vitamin D status and microvascular complications. Biochemical markers such as parathyroid hormone, serum calcium, phosphate, and inflammatory markers were not assessed, which limits mechanistic interpretation. Further multicentric studies with larger sample sizes are recommended to improve external validity and confirm these findings.

  Prevalence of Hypovitaminosis D Among Patients With Type 2 Diabetes Mellitus: Evidence From a Diabetes Clinic in Durgapur, West Bengal · 2026 · DOI

• Furthermore, vitamin D₃ plays a role beyond skeletal func(cid:415)on, including immunomodula(cid:415)on and an(cid:415)-inflammatory effects, which were not explored 36 in this study but remain cri(cid:415)cal in understanding systemic implica(cid:415)ons.

  Evaluation vitamin D3 and calcium in osteoporosis patients · 2026 · DOI

• Despite the strong mechanistic rationale and supportive preclinical evidence underlying the proposed VDR–RXR synergy hypothesis, several important limitations must be acknowledged. First, the framework is primarily hypothesis-driven and mechanistic, relying heavily on preclinical models, receptor biology, and molecular signaling logic rather than robust human clinical data. While animal models and in vitro systems are indispensable for mechanistic discovery, they do not fully recapitulate the biological, genetic, and environmental complexity of human neurodegenerative diseases. Translational failure is common in neurodegeneration research, and effects observed in rodent models frequently do not reproduce in clinical trials. Therefore, the proposed synergy between vitamin D₃ and vitamin A, although biologically plausible, remains speculative until validated in well-designed human studies. Second, VDR–RXR signaling is not a linear or isolated pathway. Nuclear receptor biology is inherently complex and context-dependent. Transcriptional outcomes are shaped not only by ligand availability but also by chromatin accessibility, epigenetic state, coactivator/ corepressor recruitment, receptor phosphorylation, metabolic status, and cellular redox environment. This means that RXR activation does not guarantee enhanced VDR transcriptional output in all biological contexts. In some conditions, RXR may preferentially dimerize with other nuclear receptors (e.g., PPARs, LXRs, FXR), potentially diverting signaling away from VDR pathways. This receptor competition introduces biological uncertainty into the assumption that RXR activation will consistently potentiate VDR-mediated neuroprotection. Third, the hypothesis assumes that vitamin A availability is a limiting factor in VDR–RXR signaling, yet this may not universally hold true. Endogenous dietary intake, retinoid metabolism, and brain retinoid homeostasis may already provide sufficient RXR activation in many individuals. In such contexts, additional vitamin A supplementation may offer minimal benefit or no added biological effect. This raises the possibility that combined therapy may only be beneficial in specific subpopulations (e.g., individuals with vitamin A deficiency, altered retinoid metabolism, or impaired RXR signaling), limiting the generalizability of the approach. Fourth, there are significant safety and dosing concerns, particularly regarding vitamin A. Unlike vitamin D₃, vitamin A has a narrow therapeutic window and well-documented toxicity (hypervitaminosis A), including hepatotoxicity, neuropsychiatric symptoms, and teratogenic effects. Chronic co-supplementation strategies would therefore require extremely careful dose optimization, monitoring, and risk stratification.

  Targeting VDR–RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy · 2026 · DOI

• The study was conducted in 2020 during COVID-19 pandemic mobility restrictions, which may have significantly limited patients' exposure to sunlight and confounded the results regarding typical vitamin D deficiency patterns.

  Vitamin D deficiency in elderly people in Ecuador · 2026 · DOI

• The novelty of this study lies in several key aspects. First, it applied a formative-designed SMART model intervention systematically to a specific population of female university students. Second, it employed staged, audience-centered social marketing rather than solely educational approaches. Third, it comprehensively assessed all TPB constructs as mediators of behavior change. Unlike many prior studies that focused solely on education or biochemical measurement, this study employed a structured, staged model tailored to students' real-life contexts [31]. However, several limitations warrant consideration. First, reliance on self- reported data may have introduced social desirability bias, potentially leading to over-reporting of supplement use. Although distribution logs were maintained to verify supplement receipt and weekly reporting intervals minimized recall bias, these measures confirm collection rather than actual consumption. Lack of objective biomarkers, such as serum vitamin D levels, limited independent verification of behavioral changes. Second, outcomes were assessed only one-month post-intervention, providing insufficient evidence regarding the long-term sustainability of behavior change. Third, the quasi-experimental design with convenience sampling and the restricted sample of female students residing in dormitories at a single medical university may have introduced selection bias and limited generalizability. Additionally, clustering effects were not adjusted for in the analysis. Several contextual factors may have enhanced intervention effectiveness in this population: being medical sciences students, participants likely had higher baseline health literacy and better understanding of vitamin D importance; ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT the female-only sample may perceive vitamin D deficiency risks, particularly for bone health, differently than males; and the dormitory setting provided a controlled environment where "Place" and "Price" strategies (easy access to free supplements) were more effectively implemented than would be possible in diverse community settings.

  SMART model-based social marketing intervention to improve vitamin d supplementation adherence in female university students: a quasi-experimental mixed-methods study · 2026 · DOI

• Conclusions A substantial proportion of individuals with ID, both children and adults, have increased total homocysteine (tHcy) plasma levels and insufficient VitD serum, but the clinical significance of these findings remains to be determined.

  Relationship between homocysteine levels, vitamin D and cognitive function in persons with intellectual disability · 2024 · DOI

Most-cited papers in Vitamin D Research Studies

• Fracture Prevention With Vitamin D Supplementation · JAMA · 2005 · 1,162 citations
• Effect of Vitamin D on Falls · JAMA · 2004 · 1,020 citations
• Vitamin D Supplementation and Total Mortality<subtitle>A Meta-analysis of Randomized Controlled Trials</subtitle> · Archives of Internal Medicine · 2007 · 861 citations
• Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey · Archives of Internal Medicine · 2009 · 764 citations
• Vitamin D deficiency and depression in adults: systematic review and meta-analysis · The British Journal of Psychiatry · 2013 · 675 citations
• Prevalence of Cardiovascular Risk Factors and the Serum Levels of 25-Hydroxyvitamin D in the United States · Archives of Internal Medicine · 2007 · 650 citations
• Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline · The Journal of Clinical Endocrinology & Metabolism · 2024 · 467 citations
• Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows · Endocrine Reviews · 2024 · 303 citations
• Prospective Study of Serum 25‐Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All‐Cause Mortality in Older U.S. Adults · Journal of the American Geriatrics Society · 2009 · 284 citations
• Hypovitaminosis D in Healthy Schoolchildren · PEDIATRICS · 2001 · 249 citations

Most recent work

• Calcium, vitamin D, or combined supplementation to prevent fractures and falls: systematic review and meta-analysis · BMJ · 2026
• High-Dose Vitamin D ₃ Supplementation During Pregnancy and Test-Based Cognitive Performance at Age 10 Years · JAMA Network Open · 2026
• Circannual prevalence of vitamin D insufficiency in older and minoritized ethnic adults in Northern Britain: screening outcomes from a clinical trial (ISRCTN13778806) · European Journal of Clinical Nutrition · 2026
• Is vitamin D the missing link in recurrent urinary tract infections in children? A prospective study · World Journal of Urology · 2026
• SMART model-based social marketing intervention to improve vitamin d supplementation adherence in female university students: a quasi-experimental mixed-methods study · Scientific Reports · 2026
• Vitamin D deficiency in elderly people in Ecuador · The Journal of Latin American Geriatric Medicine · 2026
• Differential and Dose-Dependent Redistribution of Vitamin D Metabolites After Acute High-Intensity Exercise in Mixed Martial Arts Athletes and Untrained Men: Pilot Study · Nutrients · 2026
• Samples for the Determination of Total 25-Hydroxyvitamin D Levels Were Stable at Ambient Temperature · The Journal of Applied Laboratory Medicine · 2026
• Targeting VDR–RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy · Frontiers in Neurology · 2026
• Paradoxical hypercalcemia in tuberculosis with concurrent vitamin D deficiency: mechanisms, clinical implications, and management strategies · Annals of Medicine & Surgery · 2026

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