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‘D’ Is For Defense: Vitamin D, Bone Healing And COVID-19

By Jason R. Miller, DPM, FACFAS and Tymoteusz Siwy, DPM

Vitamin D plays an important role in bone healing and activating the immune response. This has obvious benefits in foot and ankle surgery as well as the recent COVID-19 pandemic. Through direct and indirect effects, lower serum vitamin D levels are associated with an increased risk of fractures and stress fractures. One can counteract this through vitamin D supplementation. Prior studies associate hypovitaminosis D with an increased risk of respiratory tract infections.1-3 Researchers recently showed this to be true of SARS-CoV-2 infections as well. Lower vitamin D levels are associated with increased rates of infection and worse outcomes.1-3

There is definitely some debate regarding an appropriate blood concentration of vitamin D. The Endocrine Society recommendations are some of the most frequently used guidelines when it comes to diagnosing hypovitaminosis. Concentrations of less than 20 ng/mL are deficient and 21 to 29 ng/mL is insufficient whereas concentrations of 30 to 100 ng/mL are deemed sufficient.4,5 The Vitamin D Council recommends concentrations of at least 40 ng/mL.4,5 Until 1998, the threshold for vitamin D deficiency was 10 ng/mL based on correlation with the development of rickets.5 Experts established the 30 ng/mL parameter based on plateauing concentrations of serum parathyroid hormone (PTH).5 The National Institutes of Health (NIH) recommends vitamin D levels of 40 to 50 ng/mL as a minimum in active adults and children.

The incidence of hypovitaminosis D around the world varies, particularly depending on latitude and sun exposure. In the United States, 34 to 37 percent of adults are deficient (less than 20 ng/mL) whereas that number in Germany increases to 57 percent and 78 percent in Scotland.6 Insufficient vitamin D levels exist in 59 percent of Canadians and 73 percent of Australians (less than 30 ng/mL).6 The attitude toward sun exposure and the risk of skin cancer should be a consideration, and may be the reason behind more Australians than Canadians being deficient.

Clear correlations exist between vitamin D insufficiency and stress fractures or fractures. In a retrospective study of 124 patients with stress fractures, 52.83 percent of patients had vitamin D levels less than 30 ng/mL and 83.02 percent had Vitamin D levels less than 40 ng/mL.4 The authors of the study suggest considering the Vitamin D Council recommendations for a higher threshold of vitamin D deficiency.4 In a double-blind, placebo-controlled study looking at the impact of calcium and vitamin D supplementation, researchers noted a 21 percent lower incidence of fractures and 20 percent lower incidence of stress fractures in a cohort of 5,201 female Navy recruits.7 Both differences were significant. The supplemented group received 800 IU of vitamin D daily and 2,000 mg of calcium over the course of eight weeks of basic training. 

In a 2019 study involving 308 patients with foot and ankle fractures or stress fractures in the United Kingdom, Ribbans and colleagues found that only 19 percent of patients had adequate vitamin D levels (greater than 25 ng/mL).8 Accordingly, 58 percent were deficient or grossly deficient (less than 20 ng/mL).8 In a prospective, case control study, Smith and coworkers compared patients with low energy foot and ankle fracture to patients with an ankle sprain.9 There was a significantly greater prevalence of vitamin D deficiency or insufficiency in the fracture group in comparison to the ankle sprain group (47 versus 29 percent). Otherwise, the study authors noted patient characteristics and comorbidities were comparable between the two groups with no significant differences in smoking status, body mass index (BMI), age, ethnicity, or sex. 

In a meta-analysis of observational studies analyzing fracture preventive measures, an increase of vitamin D concentration of 10 ng/mL resulted in a seven percent reduction of any fracture and 20 percent reduction in hip fractures.10 Interestingly, randomized controlled trials (RCTs) of vitamin D supplementation alone (400 to 30,000 IU) showed no significant reduction in fracture risk. The combination of vitamin D (400 to 800 IU) and calcium (1,000 to 1,200 mg) supplements, however, reduced the risk of fractures by six percent and hip fractures by 16 percent.10 Considering the prevalence of vitamin D deficiency, recommending vitamin D and calcium supplements is likely of benefit to all patients, especially those at increased risk for stress fractures and fractures.

Can Vitamin D Supplementation Have An Impact On Healing Existing Fractures?

Few studies focus on the effects of vitamin D supplementation in patients with an existing fracture beyond the efficacy of supplements on serum concentration of vitamin D. In a 2015 meta-analysis of research regarding vitamin D supplementation in fracture healing, Sprague and coworkers suggested that daily lower dose (1,000 to 4,000 IU) supplementation of vitamin D is as effective as starting with large initial loading doses followed by daily doses.11 Sprague ad colleagues noted increased serum concentration and increased bone mineral density.11 In a 2014 meeting abstract, Haines and colleagues noted promising preliminary results when looking at the effects of single dose 100,000 IU of oral vitamin D in comparison to placebo with a reduction of nonunion rates in the treatment group (2.3 versus 6.7 percent).12 They did concede that this difference was not statistically significant.12 A 2017 follow-up study reported equal rates of union between the two groups, each with 50 participants.13 

In their 2017 involving 643 fractures in 617 patients, Gorter and team prescribed 1,200 IU of vitamin D orally once a day for four months in deficient patients (less than 20 ng/mL) and no supplementation to patients without a deficiency.14 Following supplementation, only 21 percent of patients remained deficient. Patients who remained deficient despite supplementation had a delayed union rate of 9.7 percent while patients who were not initially deficient had a delayed union rate of 0.3 percent and patients who responded to vitamin D supplementation had a delayed union rate of 1.7 percent.

What You Should Know About Vitamin D Toxicity

Vitamin D toxicity is extremely uncommon but one should be aware of this. Due to a manufacturer error with supplements, Araki and colleagues reported two cases of vitamin D toxicity.15 The first case involved a patient ingesting nearly two million IU daily for two months. He presented with severe hypercalcemia, fatigue, polyuria, polydipsia and a serum vitamin D level of 1,220 ng/mL. The patient became asymptomatic after vitamin D levels decreased to under 400 ng/mL but his vitamin D did not normalize for 13 months.15 The second patient ingested nearly one million IU daily for one month. He presented with hypercalcemia, nausea, vomiting, polyuria, polydipsia and a vitamin D concentration of 645 ng/mL. His vitamin D levels did not return to normal for approximately one year.15 

On a personal note, due to patient misunderstanding and pharmacist error, the senior author treated a patient who took 50,000 IU daily instead of weekly for nearly three months. Ironically, the patient’s serum level was only 59 ng/mL after this high dosing, which elevated from 13 ng/mL just prior to supplementation. 

What Role Does Vitamin D Play In COVID-19?

Vitamin D has effects far beyond bone and mineral homeostasis. It plays a considerable role in stimulating an innate immune response. Macrophages and dendritic cells synthesize activated vitamin D from circulating 25-hydroxyvitamin D. Activated vitamin D then binds to a protein called vitamin D receptor (VDR) intracellularly and promotes the expression of cathelicidin and β-defensin. Both are lysosomal protein components, act as chemokines and stimulate production of antiviral chemokines and proinflammatory cytokines.  Vitamin D also upregulates production of toll-like receptors (TLRs) that recognize foreign proteins on bacteria or viruses. Finally, vitamin D upregulates the production of nitric oxide intracellularly, which promotes cell autophagy.16-18 

Activated vitamin D also regulates the adaptive immune response. It inhibits the maturation of dendritic cells and chronic inflammatory response by inhibiting the proliferation of type-1 and -17 T-helper cells.16-18 This indirectly downregulates proinflammatory cytokines. It also directly inhibits the NFκB pathway of B cells, further inhibiting the production of proinflammatory cytokines. T-cells are instead differentiated into type-2 helper cells and regulatory T cells with anti-inflammatory effects. This is the proposed mechanism by which vitamin D reduces COVID-19’s morbidity and mortality secondary to a cytokine storm and the resulting breakdown of alveolar epithelium and alveolar edema.16-18

Researchers have explored the protective effects of vitamin D in viral infections even prior to the SARS-CoV-2 global pandemic outbreak. A meta-analysis of RCTs identified a significant effect of vitamin D supplementation on risks of contracting an acute upper or lower respiratory tract infection.18 Assessing individual participant data obtained from individual study investigators, the study authors found that patients treated with one or more boluses of 30,000 IU or greater had significant protective effects if their baseline concentration was greater than 10 ng/mL in comparison to the placebo group. Daily supplementation or weekly doses resulted in a reduction in respiratory tract infections in patients with levels both less than and greater than 10 ng/mL with a significant reduction in infection risk in comparison to the patients treated with one or more boluses. These protective effects fell below the threshold of statistical significance in patients with concentrations greater than 30 ng/mL.18 

Evidence points to a correlation between vitamin D insufficiency and COVID-19 incidence and mortality. Increasing latitude is associated with lower exposure to sunlight and, by proxy, a higher incidence of vitamin D deficiency. COVID-19 mortality rises at increasing distances from the equator, including differences within countries such as the U.S. and Italy.2,16,19 There are flaws with such correlations since no individuals are tested and the data relies on many generalizations. More direct studies have found significantly increased rates of COVID-19 positivity in patients who are vitamin D deficient (21.6 percent versus 12.2 percent in sufficient patients). Patients treated for the deficiency with supplements show comparable positivity rates to patients who have sufficient vitamin D levels.3 

There is research on the effect of vitamin D supplementation but no published double blind RCTs exist as of the writing of this blog. In a 2020 quasi-experimental study, Whittemore evaluated 77 elderly hospitalized patients.19 Treatment groups consisted of patients who had regular monthly or every two to three months large boluses of vitamin D; patients who received a single 80,000 IU bolus shortly following COVID-19 diagnosis; and patients who refused supplementation. Patients on a regular supplementation regimen had significantly lower 14-day mortality (hazard ratio of 0.19) in comparison to the single bolus group and the group that did not receive supplements.19 They also had a lower incidence of severe disease (odds ratio of 0.08 in comparison to 0.46 in the group that did not receive supplements).19 

A small RCT by Rastogi and coworkers supplemented pre-symptomatic and asymptomatic COVID-19 positive patients with either 60,000 IU orally daily for seven days or placebo (distilled water).20 The study included 40 patients with vitamin D levels less than 20 ng/mL. At day 14, the mean vitamin D level in the treatment group was 51.7 ng/mL, which is significantly higher than the 15.2 ng/mL achieved in the placebo group.20 The study authors reported that 62.5 percent of treated patients were negative at 14 days in comparison to 20.8 percent. The study authors found no significant differences in D-dimer, procalcitonin, c-reactive protein (CRP) and ferritin, but noted that calcium was marginally greater in the treatment group.20 

Vitamin D deficiency is also associated with an increase in stain-associated muscle symptoms (SAMS), which is one of the leading causes of patient discontinuation of cholesterol-lowering statin drug use.21

In Conclusion

Vitamin D is a crucially important vitamin with hormonal functions and a wide range of effects on our body. It is best known for its role in calcium and phosphate homeostasis and, by extension, regulation of bone turnover. There is no clear consensus regarding the exact concentration that is physiologically sufficient for optimal functioning. However, it appears to be, at the very least, greater than 30 ng/mL. 

In his practice, the senior author strives to reach concordance with the NIH criteria and therefore do not accept 30 ng/mL as acceptable. Lower vitamin D concentrations carry an increased risk of fractures, stress fractures and impaired osseous healing. It also has a role in managing immune response to bacterial and viral challenges, particularly respiratory tract infections. 

This has caused vitamin D to become a popular target for research in 2020 and beyond due to the COVID-19 pandemic. While this area of research is still in its infancy, trends are emerging suggesting a correlation between vitamin D deficiency and SARS-CoV-2 susceptibility, prognosis, and mortality. The foot and ankle surgeon should be vigilant in testing patients with planned reconstructive osseous procedures and stress fractures to prevent possible delayed/non-unions and infections. Go get your D on!

Dr. Miller is the Director of the Pennsylvania Intensive Lower Extremity Fellowship at Premier Orthopaedics in Malvern, Pa.

Dr. Siwy is a first-year podiatric medicine and surgery resident at Tower Health/Phoenixville Hospital in Phoenixville, Pa. 

References

1. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365-408.

2. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Network Open. 2020;3(9):e2019722.

3. Annweiler G, Corvaisier M, Gautier J, et al. Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: The GERIA-COVID quasi-experimental study. Nutrients. 2020;12(11): 3377-3388.

4. Miller JR, Dunn KW, Ciliberti LJ, Patel RD, Swanson BA. Association of vitamin D with stress fractures: a retrospective cohort study. J Foot Ankle Surg. 2016;55(1):117-120.

5. Holick MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017;18(2):153-165.

6. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144(Pt A):138-145.

7. Lappe J, Cullen D, Haynatzki G, Recker R, Ahlf R, Thompson K. Calcium and vitamin D supplementation decreases incidence of stress fractures in female navy recruits. J Bone Miner Res. 2008;23(5):741-749.

8. Ribbans WJ, Aujla RS, Ashour R, Allen PE, Wood EV. Vitamin D and foot and ankle trauma: an individual or societal problem. Foot (Edinb). 2019;39:100-105.

9. Smith JT, Halim K, Palms DA, Okike K, Bluman EM, Chiodo CP. Prevalence of vitamin D deficiency in patients with foot and ankle injuries. Foot Ankle Int. 2014;35(1):8-13.

10. Yao P, Bennett D, Mafham M, et al. Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Network Open. 2019;2(12):e1917789.

11. Sprague S, Petrisor B, Scott T, et al. What is the role of vitamin D supplementation in acute fracture patients? A systematic review and meta-analysis of the prevalence of hypovitaminosis d and supplementation efficacy. J Orthop Trauma. 2015;30(2):53-63.

12. Haines NM, Kempton L, Seymour R, et al. The effect of acute high-dose vitamin D supplementation on fracture union in patients with hypovitaminosis D: a pilot study. Abstract presented at Orthopaedic Trauma Association Annual Meeting 2014; October 18, 2014; Tampa, Fla.

13. Haines NM, Kempton L, Seymour RB, et al. The effect of a single early high-dose Vitamin D supplement on fracture union in patients with hypovitaminosis D: a prospective randomised trial. Bone Joint J. 2017;99-B(11):1520-1525.

14. Gorter EA, Krijnen P, Schipper IB. Vitamin D status and adult fracture healing. J Clin Orthop Trauma. 2017;8(1):34-37.

15. Araki T, Holick MF, Alfonso BD, et al. Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States. J Clin Endocrinol Metab. 2011;96(12):3603-3608.

16. Bilezikian JP, Bikle D, Hewison M, et al. Vitamin D and COVID-19. Eur J Endocrinol. 2020;183(5):R133-R147.

17. Mohan M, Cherian JJ, Sharma A. Exploring links between vitamin D deficiency and COVID-19. PLOS pathogens. 2020;16(9):e1008874.

18. 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.

19. Whittemore PB. COVID-19 fatalities, latitude, sunlight, and vitamin D. Am J Infect Control. 2020;48(9):1042-1044.

20. Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomized, placebo-controlled study (SHADE study). Postgrad Med J. 2020. Available at: https://pmj.bmj.com/content/early/2020/11/12/postgradmedj-2020-139065.info . Published November 12, 2020. Accessed January 12, 2021.

21. Pennisi M, Di Bartolo G, Malaguarnera G, et al. Vitamin D serum levels in patients with statin-induced musculoskeletal pain. Disease Markers. 2019. Available at: https://doi.org/10.1155/2019/3549402 . Published March 25, 2019. Accessed January 12, 2021.

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