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Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.

Vitamin D enhances calcium absorption and bone mineralisation, promotes maintenance of muscle function, and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction, and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25-hydroxyvitamin D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that consider different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity, optimal intake of vitamin D, vitamin D supplement alone as a strategy to prevent fractures and falls, recommended sun exposure at different latitudes and for different skin pigmentations, and the extra skeletal effects of vitamin D.

Low plasma levels of vitamin D causes bone mineral change that can precipitate osteopenia and osteoporosis and could aggravate autoimmune diseases, hypertension and diabetes. The demand for vitamin D supplementation becomes necessary; however, the consumption of vitamin D is not without risks, which its toxicity could have potentially serious consequences related to hypervitaminosis D, such as hypercalcemia and cerebral alterations. Thus, the present study describes the electroencephalographic changes caused by supraphysiological doses of vitamin D in the brain electrical dynamics and the electrocardiographic changes. After 4 days of treatment with vitamin D at a dose of 25,000 IU/kg, the serum calcium levels found were increased in comparison with the control group. The electrocorticogram analysis found a reduction in wave activity in the delta, theta, alpha and beta frequency bands. For ECG was observed changes with shortened QT follow-up, which could be related to serum calcium concentration. This study presented important evidence about the cerebral and cardiac alterations caused by high doses of vitamin D, indicating valuable parameters in the screening and decision-making process for diagnosing patients with symptoms suggestive of intoxication.

Low serum 1,25-dihydroxyvitamin D (1,25(OH)₂D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)₂D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)₂D₃ and 24,25(OH)₂D₃) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)₂D₃ levels were low at baseline (normal range: 60–120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)₂D₃. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0–47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5–143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)₂D₃ and 24,25(OH)₂D₃ increased from 48.3 pmol/L (IQR: 35.9–57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3–6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1–130.6 pmol/L) and 12.3 nmol/L (IQR: 9–16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)₂D₃ in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)₂D₃ deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.

High vitamin D deficiency rates, with rickets and osteomalacia, have been common in South Asians (SAs) arriving in Britain since the 1950s with preventable infant deaths from hypocalcaemic status-epilepticus and cardiomyopathy. Vitamin D deficiency increases common SA disorders (type 2 diabetes and cardiovascular disease), recent trials and non-linear Mendelian randomisation studies having shown deficiency to be causal for both disorders. Ethnic minority, obesity, diabetes and social deprivation are recognised COVID-19 risk factors, but vitamin D deficiency is not, despite convincing mechanistic evidence of it. Adjusting analyses for obesity/ethnicity abolishes vitamin D deficiency in COVID-19 risk prediction, but both factors lower serum 25(OH)D specifically. Social deprivation inadequately explains increased ethnic minority COVID-19 risks. SA vitamin D deficiency remains uncorrected after 70 years, official bodies using ‘education’, ‘assimilation’ and ‘diet’ as ‘proxies’ for ethnic differences and increasing pressures to assimilate. Meanwhile, English rickets was abolished from ~1940 by free ‘welfare foods’ (meat, milk, eggs, cod liver oil), for all pregnant/nursing mothers and young children (<5 years old). Cod liver oil was withdrawn from antenatal clinics in 1994 (for excessive vitamin A teratogenicity), without alternative provision. The take-up of the 2006 ‘Healthy-Start’ scheme of food-vouchers for low-income families with young children (<3 years old) has been poor, being inaccessible and poorly publicised. COVID-19 pandemic advice for UK adults in ‘lockdown’ was ‘400 IU vitamin D/day’, inadequate for correcting the deficiency seen winter/summer at 17.5%/5.9% in White, 38.5%/30% in Black and 57.2%/50.8% in SA people in representative UK Biobank subjects when recruited ~14 years ago and remaining similar in 2018. Vitamin D inadequacy worsens many non-skeletal health risks. Not providing vitamin D for preventing SA rickets and osteomalacia continues to be unacceptable, as deficiency-related health risks increase ethnic health disparities, while abolishing vitamin D deficiency would be easier and more cost-effective than correcting any other factor worsening ethnic minority health in Britain.