The sunshine pathway: the vitamin-hormone we can't do without

Initial Note

This article was previously published and has been updated according to scientific and informative criteria. It is for informational purposes only and does not replace medical advice. The content summarizes available scientific evidence and indicates the limitations and uncertainties of research. For clinical or therapeutic decisions, always consult a healthcare professional.

IN BRIEF

• Vitamin D acts like a hormone: it is central to calcium absorption and maintains bone and muscle health.
• Most vitamin D is formed in the skin thanks to UVB rays; there are two main forms: D2 (ergocalciferol) and D3 (cholecalciferol).
• Observational evidence suggests associations between low vitamin D levels and an increased risk of infections or chronic diseases, but causality is not always proven.
• Supplementation can prevent fractures and reduce some respiratory infections in specific groups; clinical evidence on COVID-19 is limited and conflicting.

Abstract: what does science say?

Vitamin D is a substance with hormonal characteristics that contributes to calcium balance and musculoskeletal health. Most of its production comes from skin exposed to sunlight; some is introduced through food or supplements. Experimental studies show that many immune cells express the vitamin D receptor and the enzyme necessary for its activation, which justifies plausible immunomodulatory effects. However, clinical interpretation requires caution: observational studies report associations between low 25(OH)D levels and various conditions, while randomized clinical trials indicate clear benefits for fracture prevention and, in some subgroups, for respiratory infections. For acute conditions like COVID-19, trial results are heterogeneous and do not support generalized therapeutic recommendations. In summary, vitamin D is important for bones and muscles; it is worthwhile to recognize risk factors for deficiency and consider monitoring blood levels with a doctor, taking into account available evidence and methodological limitations of research.

The sun's path: how vitamin D is formed

Vitamin D is available in multiple chemical forms; the most relevant for humans are vitamin D3 (cholecalciferol), produced in the skin, and vitamin D2 (ergocalciferol), present in some plants and fungi. Cutaneous synthesis begins when UVB rays convert 7-dehydrocholesterol into previtamin D3, which then transforms into cholecalciferol. This process provides the predominant share of the requirement in the general population, provided there is sufficient and unscreened sun exposure [1].

Forms and practical differences

From a practical point of view, D3 and D2 are both converted into active forms, but controlled studies show differences in their ability to increase and maintain circulating levels of 25-hydroxyvitamin D: in some conditions, D3 is more effective than D2 in sustaining stable blood concentrations. This difference can influence the choice of form in supplementation, especially when the goal is to rapidly raise 25(OH)D levels. [2]

Factors that reduce cutaneous synthesis

With age, the skin loses some of its precursor content, and the ability to synthesize vitamin D decreases considerably, with a reduction observed even greater than 50% in the elderly compared to young people. Other factors that reduce cutaneous production include skin pigmentation, the use of sunscreens, clothing, latitude, and season. [3]

Biological functions and consolidated benefits

The routinely measured circulating form is 25-hydroxyvitamin D (25[OH]D); this concentration is the best marker of nutritional status. Vitamin D, once activated, regulates intestinal calcium absorption and bone remodeling, central elements for the prevention of rickets in children and osteoporosis in adults. Clinical guidelines compile recommendations on the diagnosis and treatment of deficiency and define reference thresholds for blood levels, while emphasizing the variability of measurement methods. [4]

Prevention of fractures and falls

Meta-analyses of randomized studies show that adequate vitamin D dosages can reduce the risk of fractures in older people, especially when supplementation reaches certain blood concentrations. The effect is influenced by the dose, combination with calcium, and baseline 25(OH)D level; not all trials show overlapping results, but overall, fracture prevention represents one of the interventions with the strongest clinical evidence. [5]

Vitamin D and the immune system: what we know

Many immune cells express the vitamin D receptor (VDR) and the enzyme that allows local conversion to the active form, justifying plausible immunoregulatory mechanisms. In vitro and in experimental models, vitamin D modulates the functions of macrophages, lymphocytes, and dendritic cells, with a reduction in inflammatory responses and promotion of more tolerant phenotypes. These mechanisms support the biological hypothesis that vitamin D status can influence the susceptibility and severity of infections or autoimmune diseases. [6]

Clinical evidence for respiratory infections

An individual participant data meta-analysis indicates that vitamin D supplementation modestly reduces the risk of acute respiratory tract infections at the population level, with more evident benefits in people with severe baseline deficiency and with regular dosing regimens (daily or weekly) rather than with single very high doses. These results support a protective role, but one that is not generalizable to all populations and conditions. [7]

Deficiency: signs, causes, and risk factors

Vitamin D deficiency often does not cause specific symptoms in the initial stages. When severe, it can manifest with signs of hypocalcemia (tingling, cramps), muscle weakness, asthenia, and an increased risk of falls and fractures. Diagnosis is based on measuring 25(OH)D in the blood; values below certain thresholds suggest deficiency, but it is important to remember the variability between laboratories and analytical methods. [4]

Common causes of deficiency

Factors that increase the risk include: insufficient sun exposure (indoor living, latitude, season), advanced age with reduced cutaneous synthesis, high skin pigmentation, intestinal malabsorption (e.g., celiac disease, inflammatory bowel diseases), and some medications that alter vitamin D metabolism. For these reasons, specific groups may require targeted evaluation and interventions. [3][4]

Supplementation and clinical evidence: efficacy and limitations

Vitamin D supplementation is a widely studied strategy. For the prevention of fractures in the elderly, evidence from trials and pooled analyses indicates a benefit if the dose and compliance are adequate; the effect varies based on the dose, association with calcium, and the individual's baseline status. [5]

Dosages, regimens, and clinical results

Studies and guidelines propose reference thresholds for considering supplementation: in those with low 25(OH)D levels, it is reasonable to correct the deficiency with appropriate regimens under medical supervision. For the prevention of respiratory infections, the meta-analysis of individual data indicates a protective effect, especially in severely deficient subjects and with regular administrations over time. However, efficacy is not universal and depends on many variables. [7]

Experiences with COVID-19 and recent context

In acute conditions like COVID-19, randomized trials have explored the use of single high doses of vitamin D3: one randomized study showed no reduction in hospital length of stay after a single high administration, despite rapidly increasing blood levels. These results indicate that, in the context of acute diseases, the evidence does not support generalized therapeutic claims and that further studies with differentiated designs and populations are needed. [8]

What it means in practice

For most people, a combination of a balanced diet, reasonable sun exposure, and, when indicated, intelligent supplementation allows for maintaining adequate vitamin D levels. There are no universal recommendations valid for everyone: the assessment of vitamin status and the choice of any supplementation must take into account age, medical conditions, risk factors, and the measured 25(OH)D level. In at-risk subjects (elderly, malabsorption, very limited sun exposure), blood monitoring is useful for guiding decisions. If supplementation is considered, relying on professionals and following local guidelines reduces the risk of excess and ensures monitoring and dosage adjustment. [4][5]

Key points to remember

• Vitamin D is essential for calcium metabolism and musculoskeletal health.
• Most vitamin D is produced in the skin with sun exposure; food and supplements complete the intake.
• The correlation between low levels and diseases is often observational; the clinical effects of supplementation vary by condition and population.
• To prevent fractures and improve some infectious outcomes, there is evidence in selected groups; for acute treatments (e.g., COVID-19), the evidence is not sufficient to recommend routine high doses.
• Checking 25(OH)D blood levels with your doctor is the most prudent way to decide on personalized interventions.

Limitations of evidence

It is important to distinguish between observational associations and evidence of causality derived from randomized studies. Many studies showing links between 25(OH)D and diseases are observational and do not prove that deficiency directly causes the disease. Clinical trials provide more robust data, but they are often heterogeneous in terms of population, dose, form of vitamin D, and duration. Frequent methodological problems include variable baseline measures, non-homogeneous dosages, non-comparable administration times, and different outcomes. Furthermore, the effect may depend on the baseline level: those who are severely deficient may benefit more than those with normal levels. For these reasons, recommendations must be interpreted with caution and contextualized to the individual patient. [4][5][7]

Editorial conclusion

Vitamin D remains a key element for bone and muscle health and has plausible mechanisms of action in the immune system. Clinical evidence consolidates the benefit of correcting deficiency to reduce fractures and improve some health indicators, while the general efficacy of supplementation for the prevention of extra-skeletal diseases remains variable. For individual decisions, the clearest path is blood level monitoring and specialist medical consultation; choices must balance risks, benefits, and the clinical context. Research continues to clarify when and to whom supplementation brings net advantages.

Editorial note

The article has been updated according to criteria of scientific accuracy and transparency. The cited sources can be found in the final section. The content is informative and does not replace personalized medical advice.

SCIENTIFIC RESEARCH

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. https://doi.org/10.1056/NEJMra070553
2. Armas LA, Hollis BW, Heaney RP. Vitamin D2 Is Much Less Effective than Vitamin D3 in Humans. J Clin Endocrinol Metab. 2004;89(11):5387–5391. https://doi.org/10.1210/jc.2004-0360
3. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536–1538. https://doi.org/10.1172/JCI112134
4. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. https://doi.org/10.1210/jc.2011-0385
5. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367(1):40–49. https://doi.org/10.1056/NEJMoa1109617
6. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482–496. https://doi.org/10.1016/j.coph.2010.04.001
7. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. https://doi.org/10.1136/bmj.i6583
8. Murai IH, Fernandes AL, Sales LP, et al. Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. JAMA. 2021;325(11):1053–1060. https://doi.org/10.1001/jama.2020.26848