A comprehensive narrative review published in Cardiovascular Diabetology – Endocrinology Reports offers updated perspectives on the diagnosis, screening, and management of vitamin D deficiency. The study synthesizes current evidence from databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on studies published between January 2000 and December 2025. The authors, including Muhammad Ajmal Dina and colleagues, examine the clinical implications of vitamin D status, highlighting the need for standardized approaches to assessment and treatment. The review emphasizes that while vitamin D functions as a hormone crucial for calcium regulation and bone metabolism, its role extends to muscle function, immune modulation, and cardiovascular health. This synthesis aims to bridge gaps between heterogeneous evidence and clinical practice, providing a practice-oriented guide for healthcare providers.

Vitamin D deficiency remains a significant global public health concern, affecting individuals across all age groups and geographical locations. A pooled analysis of nearly eight million individuals from 81 countries, conducted between 2000 and 2022, revealed that 15.7% of participants had serum 25-hydroxyvitamin D [25(OH)D] levels below 30 ng/mL. Furthermore, 47.9% of participants had levels below 50 ng/mL, and 76.6% had levels below 75 ng/mL. The review notes that there is minimal variation in these prevalence rates over the two-decade span. Geographical factors significantly influence these rates, with the highest prevalence reported in the Middle East and South Asia, where over 30% of populations in some countries have levels below 30 ng/mL. In contrast, North America generally reports lower deficiency rates, with 2.6% of the U.S. population having levels under 25 ng/mL.

The definition of vitamin D deficiency continues to be a subject of debate, largely due to the use of non-standardized assays that yield inconsistent results. Serum 25(OH)D levels are commonly categorized as deficiency below 20 ng/mL, insufficiency between 20 and 29 ng/mL, and sufficiency at or above 30 ng/mL. However, the review highlights that establishing uniform guidelines has proven challenging, with a lack of consensus regarding the ideal serum level and the criteria for testing. The publication of more than 200 systematic reviews on vitamin D annually underscores the ongoing ambiguity in the field. Standardized reporting of 25(OH)D values in both ng/mL and nmol/L is essential to facilitate the accurate amalgamation of data from various studies and to aid researchers in reaching a consensus on deficiency definitions.

Routine screening for vitamin D deficiency is not universally advised, with experts advocating for a targeted strategy instead. The United States Preventive Services Task Force has examined the advantages and costs of extensive screening, finding that the evidence is inadequate to warrant routine testing for the general population. Research suggests that between 25% and 78% of vitamin D tests may be superfluous, with unnecessary testing representing up to 76.5% of all assessments in affluent regions. A targeted approach focuses on high-risk groups, including older adults, individuals with obesity, those with limited sun exposure, and people living in regions with low UV radiation. Identifying and addressing the needs of these specific populations is considered more practical and clinically meaningful than population-wide testing.

Cholecalciferol, or vitamin D3, is identified as the preferred formulation for supplementation due to its favorable pharmacokinetic profile. It is more effective at elevating and sustaining serum 25(OH)D levels compared to ergocalciferol, or vitamin D2. Cholecalciferol has a prolonged half-life of approximately 60 days, resulting in stable plasma concentrations over time. It also possesses a natural feedback mechanism during hepatic hydroxylation, which mitigates the risk of excessive vitamin D activity. This attribute makes weekly or monthly dosing, when converted to daily equivalents, both safe and effective. For patients with conditions that impair vitamin D metabolism, such as chronic kidney disease or severe liver disease, active forms or analogs may be preferred to bypass metabolic limitations.

The review discusses the economic considerations of vitamin D management, noting that supplementation is often more cost-effective than extensive screening. In some countries, the expense of testing can be as much as ten times greater than the cost of one year of supplementation. A study conducted in Ireland assessed vitamin D3 supplementation in adults aged 70 and older who were deficient, finding that the projected annual expenditure was €5.6 million, yielding 1,044 quality-adjusted life years. This translates to a cost per QALY of roughly €5,400. Daily supplementation with cholecalciferol at 800 IU in individuals aged 65 and older is associated with a modest but clinically meaningful reduction in the incidence of falls and hip fractures, particularly among those with low baseline 25(OH)D concentrations.

Clinical guidelines suggest that empirical supplementation can be initiated without prior serum testing for certain high-risk groups. This approach is practical and cost-efficient, minimizing the necessity for regular laboratory evaluations while still addressing the primary causes of deficiency. Initial replacement can be accomplished through the administration of oral cholecalciferol at a dosage of 4000 IU daily, which can be equally effective in weekly or monthly regimens. For continued maintenance beyond a six-month period, daily intakes of up to 2000 IU are typically adequate to ensure sufficient vitamin D concentrations. This strategy is endorsed by various expert organizations, including the American Geriatrics Society, for older adults with limited sun exposure.

Monitoring vitamin D levels is not universally necessary for all individuals but is essential in specific clinical scenarios. The most effective indicator for assessing status is the serum 25(OH)D level, which reflects the body’s response to supplementation. Evaluating both serum and urinary calcium is crucial for identifying early signs of imbalance or toxicity. Clinicians typically repeat these tests approximately three to four months after initiating therapy, providing sufficient time for levels to stabilize. Monitoring is particularly important for patients with varied responses due to medical conditions, medications, or other risk factors, such as those with renal disease, granulomatous disorders, or hyperparathyroidism, where the risk of vitamin D toxicity is increased.

The review highlights the importance of avoiding large bolus doses of vitamin D, as they can elevate fibroblast growth factor 23 [FGF23], leading to a reduction in 1,25(OH)2D levels. This can hinder calcium absorption, escalate bone turnover, and increase the likelihood of fractures and falls. Extremely high single doses, such as 300,000 to 500,000 IU, have been associated with a heightened risk of falls and fractures. While monthly or weekly regimens offer practical adherence benefits, daily cholecalciferol administration remains the preferred regimen when clinically feasible, particularly in older adults and individuals at risk of falls or fractures. The “bolus is bogus” principle suggests that intermittent high-dose administration may paradoxically increase fall and fracture risk due to transient elevations in FGF23.

The limitations of the current evidence include variability in study designs, definitions of vitamin D deficiency, and assay methods, which may affect comparability. Potential publication bias and the exclusion of non-English studies are also noted. The review concludes that future research should focus on standardized vitamin D measurement, defining population-specific optimal thresholds, and conducting high-quality trials to clarify long-term clinical outcomes. Adoption of harmonized thresholds will strengthen evidence-based decision-making and guideline alignment, ensuring that clinical practice is supported by robust, evidence-based strategies for vitamin D assessment and supplementation.

The review identifies specific clinical conditions where standard vitamin D activation pathways are impaired, necessitating alternative therapeutic approaches. Patients with chronic kidney disease, severe liver disease, hypoparathyroidism, or malabsorption syndromes may not respond effectively to standard cholecalciferol supplementation. In these cases, active forms or analogs such as calcifediol, calcitriol, alfacalcidol, or paricalcitol are preferred because they bypass metabolic limitations and ensure adequate biological activity.

Assessment of vitamin D status extends beyond simple concentration measurements to include functional indicators of deficiency. The vitamin D metabolite ratio, defined as the ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D, offers a clinical perspective on functional deficiency. Levels of 24,25-dihydroxyvitamin D falling below 3 ng/mL, or a ratio lower than 4%, are deemed indicative of deficiency.

Pharmacokinetic differences between vitamin D formulations influence treatment efficacy and monitoring requirements. Vitamin D binding protein exhibits a slightly weaker affinity for vitamin D2 metabolites compared to D3, resulting in a shorter half-life for 25-hydroxyvitamin D2, approximately 10% less than that of 25-hydroxyvitamin D3. Furthermore, most laboratory assays demonstrate greater accuracy in measuring D3 than D2. These factors contribute to the preference for cholecalciferol in general practice, as it provides more stable and sustained plasma concentrations.

The review also addresses the specific vulnerabilities of certain demographic groups, noting that dark skin tones are particularly susceptible to deficiency due to the absorption of UVB radiation by melanin, which hinders cutaneous synthesis. Additionally, obesity increases the risk of deficiency because vitamin D is stored in adipose tissue, reducing its bioavailability.

Subject of Research: Updated perspectives on vitamin D deficiency, screening, supplementation and clinical guidance

Article Title: Updated perspectives on vitamin D deficiency, screening, supplementation and clinical guidance

Article References: Dina, M. A., Hanif, A., Arshed, A., Karamat, A., Basit, M. S., Bhutta, M. A., & Ehsan, M. O. (2026). Updated perspectives on vitamin D deficiency, screening, supplementation and clinical guidance. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 30. https://doi.org/10.1186/s40842-026-00300-9

Image Credits: AI Generated

DOI: 10.1186/s40842-026-00300-9

Keywords: Updated, perspectives, vitamin, deficiency, screening, supplementation, clinical, guidance, scientific research