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Essential vitamins and minerals work together systemically at the cellular level, and micronutrient imbalances may lead to a cascade of health issues. Clinical assessments and personalized treatment strategies that discover and address nutrient deficiencies and insufficiencies help move patients of all life stages to better health and well-being. Vitamin D, considered both a nutrient and a hormone, is one vital component for multisystem health, from bone to brain.¹ Ensuring its adequate levels through baseline testing, nutritional and/or supplement treatments appropriate for an individual, and subsequent nutrient monitoring are clinical approaches and tools for chronic disease treatment and prevention.

A recent study published in the New England Journal of Medicine (NEJM) investigated vitamin D supplementation and its effect on the prevention of fractures.²

• The VITAL randomized controlled trial (RCT) included 25,871 generally healthy mid-life and older adults who were divided into the treatment group (daily intake of 2,000 IU of supplemental vitamin D₃ and 1g omega 3 fatty acids) or the placebo group.
• Baseline 25-hydroxyvitamin D levels were available for 16,757 participants, and follow-up blood samples were available for approximately 6,000 participants.
• The authors noted that most participants may have had replete levels of vitamin D (i.e., mean baseline 25-hydroxyvitamin D level of 30.7±10.0 ng/mL) at the start of the study.
• The authors noted that the VITAL RCT was not designed to assess effectiveness of supplementation in vitamin D–deficient populations, or those with low bone mass or osteoporosis.
• With these stipulations, the authors reported that supplemental vitamin D₃ without co-administered calcium did not result in a lower risk of fracture compared to placebo.

Concurrent to the VITAL study, a NEJM editorial was published and broadly expanded the study results into a sweeping vitamin D testing recommendation.³ The Cummings et al editorial declared that based upon the recent and other VITAL study results, testing the 25-hydroxyvitamin D levels of patients within the general population and implementing vitamin D supplementation treatments to attain specific serum levels or in the prevention of disease are not justified practices. This declaration is not supported by the totality of the evidence.

While the VITAL study adds to the vitamin D conversation regarding benefits, dosage, and populations, and may help inform direction of future vitamin D–related research, the study results are not a foundation for broad recommendations to suspend vitamin D testing, especially in the age of personalized medicine, undiagnosed micronutrient deficiencies, and the expanding prevalence of chronic disease.

A Crucial Component: Vitamin D Deficiency and Supplementation

Vitamin D is commonly known for its crucial function in calcium homeostasis and bone metabolism. In fact, among the universal recommendations in the 2022 Osteoporosis International clinician’s guide for the prevention and treatment of osteoporosis, both monitoring serum 25-hydroxyvitamin D levels and maintaining serum vitamin D sufficiency (? 30 ng/mL but below ? 50 ng/mL) through supplemental vitamin D as needed is included.⁴ Beyond bone, vitamin D influences the expression of hundreds of genes and is an important component in an array of physiological roles such as reduction of inflammation and modulation of cell growth, immune function, and glucose metabolism.⁵

Even with its confirmed health importance, deficiency of vitamin D has been reported in the US population. Per National Health and Nutrition Examination Survey (NHANES) data, prevalence of vitamin D deficiency (<20ng/mL) has been estimated at 28.9% in the US.⁶ And severe vitamin D deficiency (<12ng/mL) has reportedly impacted an estimated 5.9% of the population.⁷ Increasing this micronutrient malnutrition concern, the risk of low vitamin D levels extends beyond the numbers, with certain populations at greater risk of deficiency, such as people with dark skin tones; adults who are obese, current smokers, or physically inactive; and populations that are less educated or are low-income.⁶

To address this nutrient shortfall, vitamin D supplementation may be one part of personalized treatment plans. Yet mixed evidence has been presented in vitamin D–related intervention and observational studies.^8-10 Some studies have shown little to no benefit of vitamin D supplementation on the prevention or treatment of chronic conditions such as cancer, cardiovascular disease, type 2 diabetes, and depression;⁵ however, other studies continue to show that deficiency or insufficiency of vitamin D are associated with increased risk of multiple diseases or chronic conditions while replete levels are associated with improved outcomes.^11-15 In this paradox, personalized medicine may be better equipped to determine the individual for whom supplementation is most valuable.

Vitamin D Testing and Multimodal Treatments

While vitamin D–related research continues to evolve, testing for vitamin D deficiency or insufficiency due to observed symptoms, known risk factors or imbalances, potential root causes of disease, or any other clinically relevant determination establishes a patient’s baseline vitamin D level to inform their most appropriate and beneficial therapeutic plan. This may include vitamin D supplementation.

Specific to bone health, practitioners who personalize care agree that vitamin D supplementation is not a standalone therapy. Rather, a bone health regimen would include a multimodal approach appropriate for a patient that may incorporate lifestyle-based interventions, from nutrition and supplement support to exercise and movement programs. And recent research indicates that vitamin D supplementation at moderate daily doses has very low risk of harm.¹⁶ Large vitamin D supplementation clinical trials (n= ~30,000 participants) between 2017 and 2020 reported no significant adverse effects, including no changes in kidney function.¹⁶

In addition to level of sunlight exposure, dietary habits, medication interactions, and any alterations in vitamin D absorption and bioavailability, potential genetic variants in vitamin D metabolism further emphasize the importance of testing as part of an individual patient’s clinical assessment and treatment. Recent studies suggest that genetic variants, including those on VDR, CYP2R1, CYP27B1, and GC, may not only impact the benefit of vitamin D supplementation for a patient but may also help to explain some of the inconsistency among vitamin D–related clinical trials.^17-19

Conclusion

In conclusion, it may be useful to consider vitamin D supplementation in the context of any other hormone replacement therapy. A practitioner would never initiate levothyroxine treatment before doing a full individualized assessment and measuring baseline thyroid hormone status. Similarly, establishing a patient’s baseline vitamin D level is essential before implementing treatment and while monitoring treatment progress.

The broad recommendations of the Cummings et al editorial in NEJM does not account for a personalized health perspective, or for the necessity of establishing baseline vitamin D levels for tracking the benefit of an intervention. Further, the recommendation was primarily based off of the recent VITAL study, which was not designed to evaluate the effect of supplementation in vitamin D–deficient populations. Rather than eliminating the evaluation of vitamin D levels, additional research is needed within those specific populations. Baseline levels must also be measured in all future study candidates, excluding those who are replete or in excess, in order to compare with follow-up testing results and to fully elucidate the benefit of vitamin D supplementation on bone health as well as for system-wide health.

References

1. Bivona G, Gambino CM, Iacolino G, Ciaccio M. Vitamin D and the nervous system. Neurol Res. 2019;41(9):827-835. doi:1080/01616412.2019.1622872
2. LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-309. doi:1056/NEJMoa2202106
3. Cummings SR, Rosen C. VITAL findings – a decisive verdict on vitamin D supplementation. N Engl J Med. 2022;387(4):368-370. doi:1056/NEJMe2205993
4. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician’s guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. Published online July 28, 2022]. Osteoporos Int. Published online April 28, 2022. doi:1007/s00198-021-05900-y
5. National Institutes of Health. Vitamin D. Updated August 12, 2022. Accessed August 19, 2022. https://ods.od.nih.gov/factsheets/vitamind-healthprofessional/
6. Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr. 2018;119(8):928-936. doi:1017/S0007114518000491
7. Schleicher RL, Sternberg MR, Looker AC, et al. National estimates of serum total 25-hydroxyvitamin D and metabolite concentrations measured by liquid chromatography-tandem mass spectrometry in the US population during 2007-2010. J Nutr. 2016;146(5):1051-1061. doi:3945/jn.115.227728
8. Pittas AG, Dawson-Hughes B, Sheehan P, et al. Vitamin D supplementation and prevention of type 2 diabetes. N Engl J Med. 2019;381(6):520-530. doi:1056/NEJMoa1900906
9. Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med. 2017;282(5):452-460. doi:1111/joim.12651
10.  Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;2014(4):CD000227. doi:1002/14651858.CD000227.pub4
11.  Dror AA, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022;17(2):e0263069. doi:1371/journal.pone.0263069
12.  Guzman-Prado Y, Samson O, Segal JP, Limdi JK, Hayee B. Vitamin D therapy in adults with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2020;26(12):1819-1830. doi:1093/ibd/izaa087
13.  Ghorbani Z, Togha M, Rafiee P, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci. 2019;40(12):2459-2477. doi:1007/s10072-019-04021-z
14.  Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol. 2019;19(1):284. doi:1186/s12883-019-1500-6
15.  Linsalata M, Riezzo G, Orlando A, et al. The relationship between low serum vitamin D levels and altered intestinal barrier function in patients with IBS diarrhoea undergoing a long-term low-FODMAP diet: novel observations from a clinical trial. Nutrients. 2021;13(3):1011. doi:3390/nu13031011
16.  Bouillon R, Manousaki D, Rosen C, Trajanoska K, Rivadeneira F, Richards JB. The health effects of vitamin D supplementation: evidence from human studies. Nat Rev Endocrinol. 2022;18(2):96-110. doi:1038/s41574-021-00593-z
17.  Yao P, Sun L, Lu L, et al. Effects of genetic and nongenetic factors on total and bioavailable 25(OH)D responses to vitamin D supplementation. J Clin Endocrinol Metab. 2017;102(1):100-110. doi:1210/jc.2016-2930
18.  Barry EL, Peacock JL, Rees JR, et al. Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: a randomized clinical trial. JAMA Oncol. 2017;3(5):628-635. doi:1001/jamaoncol.2016.5917
19.  Shirvani A, Kalajian TA, Song A, et al. Variable genomic and metabolomic responses to varying doses of vitamin D supplementation. Anticancer Res. 2020;40(1):535-543. doi:21873/anticanres.13982