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 Table of Contents  
Year : 2022  |  Volume : 14  |  Issue : 2  |  Page : 149-153

Correlation of Vitamin D levels with markers of bone metabolism in COVID-19 patients

1 Department of Orthopaedics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
2 Department of Pulmonary Medicine, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
3 Department of Biochemistry, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India

Date of Submission27-Nov-2022
Date of Acceptance29-Nov-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Dr. Ankit Kumar Garg
D Block, Department of Orthopaedics, All India Institute of Medical Sciences, Tatibandh, Raipur - 492 099, Chhattisgarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jotr.jotr_115_22

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Introduction: Low serum Vitamin D levels are common in orthopedic patients in India. Low serum Vitamin D levels are implicated in COVID-19 worsening the illness. With this background, we assessed serum Vitamin D levels in COVID-19 patients presenting to us and correlated them with other markers of bone metabolism and systemic immune response. Materials and Methods: A cross-sectional analytical study was done on 107 COVID-19 patients. The sample was taken for serum calcium, serum Vitamin D, serum phosphate, bone-specific alkaline phosphatase (ALP), serum parathyroid hormone, creatine phosphokinase (CPK), CPK myocardial band (MB), serum protein, C-reactive protein, erythrocyte sedimentation rate, and hemoglobin in these patients. The levels were correlated with each other to assess their relations in COVID-19 patients. Results: One hundred out of 107 patients had low serum Vitamin D levels. In these patients, serum lactate dehydrogenase and serum ALP levels were high, and creatine kinase MB levels were low. The illness was found more in diabetic/hypertensive and rheumatoid arthritis patients. The values and findings correlate with increased disease activity and osteopenia with no obvious muscular injury. Conclusion: Managing Vitamin D deficiency (VDD) has been taken up as a major step in COVID-19 affection. The markers of bone metabolism and their correlation with serum Vitamin D were equivocal in COVID-19-affected and not affected Indian populations. The risk of infection has been more in diabetic, hypertensive, and rheumatoid arthritis patients, all of whom were also suffering from VDD.

Keywords: Coronavirus disease-19 pandemic, hypovitaminosis D, markers of bone metabolism, serum Vitamin D

How to cite this article:
Agrawal AC, Behera AK, Mohapatra E, Sakale HS, Shah S, Kar BK, Ojha MM, Nayak B, Garg AK. Correlation of Vitamin D levels with markers of bone metabolism in COVID-19 patients. J Orthop Traumatol Rehabil 2022;14:149-53

How to cite this URL:
Agrawal AC, Behera AK, Mohapatra E, Sakale HS, Shah S, Kar BK, Ojha MM, Nayak B, Garg AK. Correlation of Vitamin D levels with markers of bone metabolism in COVID-19 patients. J Orthop Traumatol Rehabil [serial online] 2022 [cited 2023 Apr 1];14:149-53. Available from: https://www.jotr.in/text.asp?2022/14/2/149/365823

  Introduction Top

Vitamin D is an endogenously synthesized steroid hormone that can be taken from food and dietary supplements. Vitamin D deficiency (VDD) leads to several problems affecting all age groups globally.[1] Vitamin D helps in immunomodulation by increasing the secretion of antiviral peptides, leading to improved mucosal defenses and increased innate immunity.[2],[3] Several studies have demonstrated a critical link between VDD and other systemic diseases, including acute respiratory tract infections and the influenza epidemic in the past.[4],[5],[6],[7],[8] COVID-19 is caused by a novel coronavirus (SARS-CoV-2; formerly called 2019-nCov) and was first identified amidst an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. It was initially reported to the WHO on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency and declared it a global pandemic on March 11, 2020. The disease is new and has very high mortality in its severe form. Garg et al.[9] reported Vitamin D as a factor for determining the severity of COVID-19 infection. Normal serum Vitamin D level is supposed to prevent the cytokine storm and subsequent acute respiratory distress syndrome (ARDS), which is the common cause of mortality in infection by virus-like COVID-19. The COVID-19 pandemic has affected millions of people across the globe both in terms of health and finances.

Nevertheless, our understanding of the pathophysiology and clinical implications of the virus is less and requires much research into it. Several data demonstrate that elderly subjects and those with preexisting medical issues, including chronic respiratory disease, diabetes, cardiovascular diseases, and cancer, are more prone to manifest severe illness with SARS-CoV-2 infection.[10] In a multicenter study done on 150 orthopedic outpatient department patients, the incidence of hypovitaminosis D (serum level <30 ng/dl) was 88.3%, and severe hypovitaminosis D (serum level ≤9 ng/dl) was 29%. With this background, we planned to do this study to determine serum Vitamin D levels in COVID-19 patients and its correlation with markers of bone metabolism and inflammation to assess its severity.

  Materials and Methods Top

Study design and subjects

The current study was undertaken as a cross-sectional analytical study after taking due approval from the institutional ethics committee (AIIMSRPR/RC (P)/2020/181). Informed written consent was obtained either from the participants themselves or their first-degree relatives. All participants were COVID-19 patients of any age group who were admitted to the tertiary COVID-19 care center during the study.

Sample size

A nonprobability convenience-based sampling technique was done. A total of 107 were enrolled in the study.

Intervention and evaluation

All the study participants were asked in a questionnaire asking about the musculoskeletal problems they face before and after COVID-19 infection in a yes or no format. The questions included back pain, neck pain, knee pain, heel pain, wrist pain, elbow pain, shoulder pain, calf pain, forefoot pain, and hand pain. A morning fasting blood sample was collected for the subsequent investigation – serum calcium, serum Vitamin D, serum phosphate, bone-specific alkaline phosphatase (ALP), serum parathyroid hormone, creatine phosphokinase (CPK), CPK myocardial band (MB), serum protein, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and hemoglobin. Based on multiple guidelines, a serum 25 (OH) D level of <20 ng/mL has been defined as VDD. Serum 25 (OH) D concentrations were estimated by automated immunoassays. All investigations were carried out following relevant guidelines and regulations.

Statistical analysis

Statistical analysis was carried out using statistical packages for SPSS 24.0 (SPSS Inc., Chicago, IL, USA). Continuous and categorical variables were expressed as mean ± standard deviation and percentages, respectively. Pearson's correlation was applied to see the association between serum Vitamin D levels and bone markers. One-way ANOVA was used to compare the mean value of markers in different Vitamin D levels. Two-sided P values will be considered statistically significant at P < 0.05.

  Results Top

A total of 130 COVID-19 patients were enrolled in our study, out of which 23 were excluded and data from 107 patients are included in the final analysis. The mean age of the study population was 42.23 ± 17.52 years. Out of 107, there were 76 males (71%) and 29 females (31%) [Figure 1].
Figure 1: Gender distribution of the population

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Vitamin D in COVID-19 patients

The mean concentration (in ng/mL) of 25 (OH) D was 17.35 ranging from 4.2 being the lowest and 80.5 being the highest. On categorization of the patients based on Vitamin D levels, out of the 107 participants, only 7 (6.5%) had sufficient Vitamin D, 22 (20.5%) of them were deficient, and 78 (72.8%) were insufficient [Figure 2]. Most of the patients (93.4%) were highly deficient in Vitamin D.
Figure 2: Pie chart showing the distribution of Vitamin D levels

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Bone metabolism markers in COVID-19

The analysis of serum levels of inflammatory markers revealed that the mean values of creatine kinase MB (CKMB) (IU/ml) and lactate dehydrogenase (LDH) (U/L) were found to be 1.64 (0.18–8.23) and 522.04 (276–1433). CKMB values were much lower than the general population, and LDH values were higher than the general population [Table 1].
Table 1: Bone metabolism markers in COVID-19

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Correlation of serum Vitamin D with markers of bone metabolism

On analysis of serum Vitamin D with markers of bone metabolism, we found a significant negative correlation between serum Vitamin D levels and ALP. As Vitamin D increases, ALP decreases and vice versa [Figure 3]. We also found a significant difference in mean CKMB values, those having less serum Vitamin D had lesser CKMB values [Table 2].
Figure 3: Negative correlation between serum Vitamin D levels and ALP. ALP: Alkaline phosphatase

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Table 2: Mean values of bone metabolism markers in Vitamin D deficient, insufficient, and sufficient patients

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Musculoskeletal pain and COVID-19

In the questionnaire circulated among the patients, most patients complained about back pain and neck pain. While 22 patients complained of back pain before COVID-19, 66 complained after COVID-19. The subsequent most common complaint following back pain was neck pain, 22 and 56 before and after COVID-19, respectively [Figure 4].
Figure 4: Association of musculoskeletal pain in COVID-19 patients

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Comorbidities associated with COVID-19 patients

Most of our participants suffered from hypertension followed by diabetes mellitus. The third in the sequence is rheumatoid arthritis with seven cases [Figure 5].
Figure 5: Comorbidities associated with COVID-19 patients

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  Discussion Top

The role of Vitamin D is not only limited to the maintenance of a normal healthy bone and calcium homeostasis but it has a proven role in enhancing immune defense mechanisms. Its interaction with the majority of immune cells such as neutrophils, B- and T-lymphocytes, macrophages, and dendritic cells helps in immunomodulation.[11] It enhances the production of anti-inflammatory cytokines and inhibits the pro-inflammatory cytokines, thus providing an overall anti-inflammatory response. It is also known to promote the innate immune system.[12],[13] In our study, we found that patients who were having COVID-19 infection had a severe deficiency of Vitamin D levels. In these patients with VDD, the chemical markers of inflammation were found to be at higher levels.

Unlike in the Western world, the prevalence of hypovitaminosis D does not correlate well to the lower socioeconomic strata probably due to higher sunlight exposure in the population group.[14] However, an epidemiological comparison of the mortality from COVID-19 between the two counties largely correlates with the VDD. In a study by Laird et al.,[15] they found that optimization of Vitamin D benefits patients with COVID-19.

In the current study, we found a high level of LDH in patients with COVID-19 (mean 522.04), which correlated to the disease severity. Henry et al.[16] and Zhou et al.[17] in similar studies found that there is a 6- and 16-fold increase in odds of developing severe disease and mortality, respectively, in patients with COVID-19. Yuan et al.[18] in their study concluded that the COVID-19 mRNA clearance ratio positively correlated with LDH levels. Such findings can be explained by the SARS-CoV-2-mediated activation of the inflammasomes causing cellular pyroptosis and aggravated symptoms.[19] This may also explain the association of LDH levels with ARDS in patients with COVID-19.

Many studies have described the association between calcium in viral fusion for different enveloped viruses such as SARS-CoV, MERS-CoV, and Ebola virus. Calcium directly interacted with these viruses' fusion peptides, promoting their replication.[20],[21],[22] Hypocalcemia is a common laboratory finding in patients with SARS-CoV and Ebola virus and an independent risk factor for predicting hospitalization. Similarly, in tumor lysis syndrome, a strong association was found between hypocalcemia and high LDH and CRP levels.[23] Such findings reveal the possibility of identifying severe patients using ionized calcium as an independent marker at the initial hospital evaluation. CKMB and LDH, both markers of cardiac injury, showed a change in their levels across all three categories of Vitamin D deficient cases. However, CKMB was found to be lower as the half-life of CKMB is 48–72 h, which implies that probably CKMB returned to a normal level at the time of investigation, although LDH remained elevated due to its longer half-life. The initial rise in CKMB and LDH can be attributed to coexistent cardiac injury by SARS-CoV-2 or due to associated viral myalgia causing nonspecific elevation of CKMB, which returned to normal level after 48–72 h.

SARS-CoV-2 has a strong affinity for the β-cell of the pancreas. It may lead to sustained hyperglycemia and newly onset diabetes mellitus which can further worsen the patient outcome. In addition, acute metabolic complications such as diabetes ketoacidosis or hyperosmolar hyperglycemic syndrome can be precipitated due to cytokine storm, counter-regulatory hormonal response, and impairment of the functions of pancreatic β-cells in patients with preexisting diabetes, leading to poor outcome and complications.[24]

The most common comorbidity in patients with COVID-19 is hypertension. It has been postulated that SARS-CoV-2, binds to angiotensin-converting enzyme-2 (ACE2) receptors commonly present in the heart, lung, kidney, liver, brain, and ileum to enter target cells. The use of ACE inhibitors can decrease the severity of infection.[25] The acute phase reactants such as CRP and ESR can act as sensitive markers to indicate inflammation and tissue damage.[26] Wu et al.[27] and Piva et al.[28] in their study found that the mean level of CRP and ESR, respectively, was higher in patients with severe disease as compared to patients in the nonsevere group. The possible explanation for such findings indicates higher inflammation in patients with severe disease. Furthermore, older patients in the severe group can have a higher level of ESR due to their age.[28]

  Conclusion Top

Managing VDD has been taken up as a major step in COVID-19 affection. The markers of bone metabolism and their correlation with serum Vitamin D were equivocal in COVID-19-affected and not affected Indian populations. The risk of infection has been more in diabetic, hypertensive, and rheumatoid arthritis patients, all of whom were also suffering from VDD.


We acknowledge the patients and their families for the consent.

Financial support and sponsorship

The study was financially supported by part of the Intramural Grant given by AIIMS Raipur.

Conflicts of interest

There are no conflicts of interest.

  References Top

Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 2017;18:153-65.  Back to cited text no. 1
Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005;19:1067-77.  Back to cited text no. 2
Wang TT, Dabbas B, Laperriere D, Bitton AJ, Soualhine H, Tavera-Mendoza LE, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem 2010;285:2227-31.  Back to cited text no. 3
Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in autoimmunity: Molecular mechanisms and therapeutic potential. Front Immunol 2016;7:697.  Back to cited text no. 4
Infante M, Ricordi C, Sanchez J, Clare-Salzler MJ, Padilla N, Fuenmayor V, et al. Influence of vitamin D on islet autoimmunity and beta-cell function in type 1 diabetes. Nutrients 2019;11:2185.  Back to cited text no. 5
Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and extraskeletal actions of vitamin D: Current evidence and outstanding questions. Endocr Rev 2019;40:1109-51.  Back to cited text no. 6
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129-40.  Back to cited text no. 7
Cannell JJ, Vieth R, Willett W, Zasloff M, Hathcock JN, White JH, et al. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol 2008;117:864-70.  Back to cited text no. 8
Garg M, Al-Ani A, Mitchell H, Hendy P, Christensen B. Editorial: Low population mortality from COVID-19 in countries south of latitude 35 degrees North-supports vitamin D as a factor determining severity. Authors' reply. Aliment Pharmacol Ther 2020;51:1438-9.  Back to cited text no. 9
Allegra A, Pioggia G, Tonacci A, Musolino C, Gangemi S. Cancer and SARS-CoV-2 infection: Diagnostic and therapeutic challenges. Cancers (Basel) 2020;12:1581.  Back to cited text no. 10
Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients 2013;5:2502-21.  Back to cited text no. 11
Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583.  Back to cited text no. 12
Gombart AF, Pierre A, Maggini S. A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients 2020;12:236.  Back to cited text no. 13
Kamboj P, Dwivedi S, Toteja GS. Prevalence of hypovitaminosis D in India & way forward. Indian J Med Res 2018;148:548-56.  Back to cited text no. 14
[PUBMED]  [Full text]  
Laird E, Rhodes J, Kenny RA. Vitamin D and inflammation: Potential implications for severity of covid-19. Ir Med J 2020;113:81.  Back to cited text no. 15
Henry BM, Aggarwal G, Wong J, Benoit S, Vikse J, Plebani M, et al. Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis. Am J Emerg Med 2020;38:1722-6.  Back to cited text no. 16
Zhou Y, Ding N, Yang G, Peng W, Tang F, Guo C, et al. Serum lactate dehydrogenase level may predict acute respiratory distress syndrome of patients with fever infected by SARS-CoV-2. Ann Transl Med 2020;8:1118.  Back to cited text no. 17
Yuan J, Zou R, Zeng L, Kou S, Lan J, Li X, et al. The correlation between viral clearance and biochemical outcomes of 94 COVID-19 infected discharged patients. Inflamm Res 2020;69:599-606.  Back to cited text no. 18
Yap JK, Moriyama M, Iwasaki A. Inflammasomes and pyroptosis as therapeutic targets for COVID-19. J Immunol 2020;205:307-12.  Back to cited text no. 19
Millet JK, Whittaker GR. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology 2018;517:3-8.  Back to cited text no. 20
Straus MR, Tang T, Lai AL, Flegel A, Bidon M, Freed JH, et al. Ca (2+) ions promote fusion of middle East respiratory syndrome coronavirus with host cells and increase infectivity. J Virol 2020;94:e00426-20.  Back to cited text no. 21
Nathan L, Lai AL, Millet JK, Straus MR, Freed JH, Whittaker GR, et al. Calcium ions directly interact with the Ebola virus fusion peptide to promote structure-function changes that enhance infection. ACS Infect Dis 2020;6:250-60.  Back to cited text no. 22
Rahmani B, Patel S, Seyam O, Gandhi J, Reid I, Smith N, et al. Current understanding of tumor lysis syndrome. Hematol Oncol 2019;37:537-47.  Back to cited text no. 23
Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: Understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol 2020;8:782-92.  Back to cited text no. 24
Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Int J Infect Dis 2020;94:91-5.  Back to cited text no. 25
Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805-12.  Back to cited text no. 26
Wu S, Zhou Y, Hua HY, Zhang Y, Zhu WY, Wang ZQ, et al. Inflammation marker ESR is effective in predicting outcome of diffuse large B-cell lymphoma. BMC Cancer 2018;18:997.  Back to cited text no. 27
Piva E, Sanzari MC, Servidio G, Plebani M. Length of sedimentation reaction in undiluted blood (erythrocyte sedimentation rate): Variations with sex and age and reference limits. Clin Chem Lab Med 2001;39:451-4.  Back to cited text no. 28


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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