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 Table of Contents  
Year : 2022  |  Volume : 36  |  Issue : 2  |  Page : 84-89

A prospective study to determine the effect of Vitamin D levels on musculoskeletal pain, anxiety, and depressions in patients with type II diabetes

1 Department of Physical Medicine and Rehabilitation (PMR), AIIMS, Raipur, Chhattisgarh, India
2 Department of Physical Medicine, VMMC and SJH, New Delhi, India
3 Department of Medicine, VMMC and SJH, New Delhi, India

Date of Submission06-Jan-2022
Date of Decision30-Apr-2022
Date of Acceptance03-May-2022
Date of Web Publication25-Aug-2022

Correspondence Address:
Dr. Raunak Kumar
Department of Physical Medicine and Rehabilitation (PMR), AIIMS, Raipur, Chhattisgarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpn.ijpn_1_22

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Objectives: The primary objective was to investigate the correlation of musculoskeletal pain (MSP) intensity with Vitamin D status and glycemic control in patients of type II diabetes mellitus. The secondary objective was to monitor the anxiety and depression levels with Vitamin D supplementation. Methods: A prospective observational cohort study was conducted over a period of 18 months where 100 patients of type II diabetes mellitus with MSP were screened for Vitamin D status and glycemic levels in terms of HbA1c, anxiety, and depression. MSP was assessed by Visual Analog Scale (VAS) score. The patients who were found with Vitamin D levels (<30 ug/dL) were supplemented with Vitamin D and followed at 3 monthly intervals for 6 months for determining the change in MSP, anxiety, and depression scores. Results: After adjusting for the duration of diabetes, HbA1c, and statin therapy, there was no significant correlation between VAS score and Vitamin D (r = −0.133, P = 0.195). After 6 months of Vitamin D supplementation, all cases attained optimal Vitamin D levels of mean (standard deviation [SD]) of 32.5 (4.1) ng/ml as compared to mean (SD) of 23.4 (2.5) ng/ml at baseline (P < 0.0001). Concurrently, there was a significant reduction in the median (range) VAS scores from 6 (2–10) to 4 (0–8), anxiety levels from 11 (7.75–18) to 10 (7–17), and depression levels from 10 (7–15) to 9 (6–14) (P < 0.0001), respectively. Conclusion: There was no significant independent correlation of MSP intensity with Vitamin D levels or glycemic control. However, the supplementation of Vitamin D significantly alleviated MSP in patients with diabetes, with a significant reduction in anxiety and depression among them.

Keywords: Diabetes mellitus, musculoskeletal pain, Vitamin D

How to cite this article:
Kumar R, Laisram N, Jain N. A prospective study to determine the effect of Vitamin D levels on musculoskeletal pain, anxiety, and depressions in patients with type II diabetes. Indian J Pain 2022;36:84-9

How to cite this URL:
Kumar R, Laisram N, Jain N. A prospective study to determine the effect of Vitamin D levels on musculoskeletal pain, anxiety, and depressions in patients with type II diabetes. Indian J Pain [serial online] 2022 [cited 2022 Nov 29];36:84-9. Available from: https://www.indianjpain.org/text.asp?2022/36/2/84/354715

  Introduction Top

Musculoskeletal pain (MSP) is prevalent in diabetics, and it can restrict the activities of daily living of a patient causing increased depression and anxiety.[1] The multifactorial causation includes increased body mass index (BMI) and body weight which stresses the knee and lower extremities;[2] diabetic neuropathy where the nerve involvement leads to muscle pain and weakness;[3] and use of statins which aids in lipid lowering and the deficiency in Vitamin D.[4]

The significance of Vitamin D has been explored beyond the maintenance of calcium–phosphate balance and bone health to its extraskeletal roles such as in lung disorders (chronic obstructive pulmonary disease),[5] neurological disorders (anxiety and depression), and metabolic disorders (diabetes).[5],[6],[7] The primary role of Vitamin D is to mineralize the bone and stabilize the phosphate levels of the muscles, and the extracellular milieu, if found defective in any chronic disease, prones the patient to muscle and bone pain.[6] Further, its deficiency has also been associated with disturbed mental health of an individual.[7]

The deficiency in Vitamin D is a global issue. India, a country with both tropical and temperate climates, has witnessed a rising prevalence of Vitamin D deficiency due to changing indoor work lifestyles, urbanization, pollution, and dietary habits.[8] The prevalence of Vitamin D deficiency in India varies from 50% to 94% (community-based studies), 37%–99% (hospital studies), and 34%–81% in school surveys on children.[8]

Research on Vitamin D deficiency (in relation to MSP) holds importance since its supplementation has shown pain relief for diabetic neuropathy in few European studies.[7] We hypothesize that this can be true for the Indian subcontinent, and thus, the present study was conducted to investigate the correlation of the deficiency in Vitamin D with MSP and glycemic control in patients of T2DM. We also assessed their anxiety scores and depression scores in association with the deficiency in Vitamin D. Further follow-up of the study participants was done after Vitamin D supplementation (in cases with deficiency/insufficiency of Vitamin D) to determine the improvements in the intensity of the pain, anxiety, and depression scores.

  Methods Top

A prospective observational cohort study was conducted over a period of 18 months from November 2014 to May 2016, where all the cases of T2DM were screened for the presence of specific or nonspecific MSP. The study protocol was approved by the institutional ethical committee (IEC/VMMC/SJH/Thesis/Oct 2014/387).

The sample size calculation was based on the study of Molsted S et al.,[1] who observed a prevalence of MSP as 52% for pain in shoulder or neck, 60% for lower back pain, and 71% for pain in hands and knees. Considering this value for reference, with a 10% margin for error and 5% alpha error, the minimum sample size required was 96 patients. Considering loss to follow-up, the total sample size taken was 100.

The formula used was:

n ≥ (p[1 − p])/(ME/zα)2

where Zα is the value of Z at two-sided alpha error of 5%,

ME is the margin of error,

p is the proportion of patients with pain.

Out of 212 known cases of T2DM who visited the department of physical medicine and rehabilitation during the study period, 115 cases had MSP. Any patient with pain due to trauma, malignancy, referred visceral pain, infective disorders, pain due to rheumatoid arthritis, or connective tissue disorder was excluded since these may confound the results. Besides, pregnant patients, patients taking Vitamin D supplementation in the last 3 months, patients having chronic renal or hepatic disorder, patients on medication for diabetic neuropathic pain, or those who took analgesic medication in the last 7 days were also excluded since it may affect the Vitamin D levels, pain sensation, and Visual Analog Scale (VAS) scores.

Of all the patients screened, 100 patients satisfied the eligibility criteria who were explained about the study to obtain written informed consent. The participant flow diagram is shown in [Figure 1].
Figure 1: Participant flow diagram

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The general information of the patient (age and gender), smoking status, BMI (kg/m2), and duration of diabetes was obtained. Five milliliters of venous blood sample was collected in the red plain vial, ethylenediaminetetraacetic acid lavender vial, and gray vial to measure 25-hydroxyvitamin D, glycated hemoglobin (HbA1c), and fasting blood sugar (FBS) levels. The samples were sent to the laboratory. The gray and plain vials were centrifuged at 2000 rpm for 10 min to separate serum for estimation of the parameters. Vitamin D was measured by electrochemiluminescence immunoassay with Cobas e analyzer. It was interpreted as deficient (<20 ng/ml), insufficient (20–29 ng/ml), and optimum (30–100 ng/ml).[9],[10]

HbA1c cutoff of 7 g% was used to label the patients as good and bad control.

Assessment of MSP included the site of pain and the pain intensity by Visual Analog Scale (VAS score, 1–10).[11]

Assessment of anxiety and depression was done using the Hospital Anxiety and Depression Scale questionnaire.[12]

The patients who were found with Vitamin D levels <30 were prescribed Vitamin D capsules once weekly for 12 weeks with calcium, following which Vitamin D levels were measured again. The patients whose Vitamin D levels reached optimum levels were discontinued, whereas the rest of the patients were given another course of supplementation. During this interim, patients were advised to maintain their sugar levels with regular intake of medications which they were taking and regular exercises. No additional exercise regime was advised to them.

The final follow-up of the patients was done at 6 months, during which the outcome measures included change in Vitamin D levels, MSP intensity, anxiety, and depression scores. Of 100 patients, 22 had normal Vitamin D levels who were not given any Vitamin D supplementation. Ten patients were lost to follow-up, and the final data could be recorded for only 90 patients, among which 78 undertook Vitamin D supplementation for low Vitamin D and 12 patients had normal Vitamin D at baseline [Figure 1].

Statistical analysis

The data were entered into the Microsoft Excel spreadsheet and analyzed using SPSS version 21.0. The data presentation was done as median (interquartile range: 25%–75%) and number (%).

The association of quantitative variables (age, duration of diabetes, and FBS) with Vitamin D status was done using the Kruskal–Wallis test. Qualitative variables such as gender, HbA1c, anxiety score, depression score, and statin therapy were associated with Vitamin D status using the Chi-square test. BMI and smoking status were associated using Fisher's exact test as one of the cells had an expected value of <5.

Wilcoxon signed-ranks test was used to compare VAS score between the first visit and after 6 months. Spearman rank correlation coefficient was used to correlate VAS score with Vitamin D and HbA1c with VAS score and Vitamin D. Partial correlation coefficient was used to correlate VAS score and Vitamin D after adjusting for duration of diabetes, HbA1c, and statin therapy. P < 0.05 was considered statistically significant.

  Results Top

Out of 100 patients of MSP in T2DM, 28% had periarthritis shoulder, 20% had low backache, 18% had carpal tunnel syndrome, 10% had plantar fasciitis, 10% had trigger finger, 8% had nonspecific generalized body ache, and 6% were found to have osteoarthritis knee.

The median age of the study patients was 52 years, with a gender distribution of 1.38:1 (F:M). The median duration of diabetes mellitus was 5 years, over which 28% had controlled glycated Hb levels. More than half of the patients were on statin therapy. The pain intensity was mild in 14%, moderate in 68%, and severe in 18% of cases. Among the studied patients, 51% had anxiety and 41% had depression [Table 1].
Table 1: Distribution of patient characteristics

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Vitamin D levels were normal in 22% of cases, insufficient in 24% of cases, and deficient in 54% of cases. The mean (SD) Vitamin D levels were 23.4 (2.5) ng/ml. Hence, based on the Vitamin D levels, 78 patients were given Vitamin D supplementation and followed up after 6 months of supplementation.

There was a significant association of fasting blood glucose (FBG) with Vitamin D levels. FBG was 160 mg/dL in patients with optimum Vitamin D levels, which was significantly higher as compared to insufficient (133.5 mg/dL) and deficient Vitamin D (133 mg/dL). Other parameters such as depression, anxiety, and pain, though higher in patients with Vitamin D insufficiency, statistically showed no significant association (P > 0.05), as shown in [Table 2].
Table 2: Association of variable with Vitamin D status

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There was a significant negative correlation between MSP intensity (VAS score) and Vitamin D levels (r = −0.231, P = 0.021) [Figure 2]. After adjusting for the duration of diabetes, HbA1c, smoking, and statin therapy, there was no significant correlation between VAS score and Vitamin D levels (r = −0.133, P = 0.195).
Figure 2: Correlation of pain intensity (VAS score) and Vitamin D levels at baseline. VAS: Visual Analog Scale

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With HbA1c, VAS score showed a nonsignificant positive correlation (r = 0.15, P = 0.136). Compared to the first visit, where 24 (30.77%) had controlled HbA1c (<7 g%), after 6 months of follow-up, 31 (39.74%) had controlled HbA1c (P = 0.241).

After 6 months, all patients had optimal Vitamin D levels of mean (SD) of 32.5 (4.1) ng/ml, and there was a significant reduction in the median (range) VAS scores from 6 (2–10) to 4 (0–8) with P < 0.0001 [Figure 3]. Among the Vitamin D-deficient patients (n = 54), pain intensity reduced from severe to moderate in 8/12 patients, from moderate to mild in 29/38 patients, and from mild to no pain in 2/4 patients. Among the Vitamin D insufficient patients (n = 24), pain intensity reduced from severe to moderate in 1/2 patient, from moderate to mild in 12/18 patients, and from mild to no pain in 2/4 patients. The patients who had sufficient Vitamin D levels at the baseline showed no change in the pain intensity or decrease in the Vitamin D levels at 6 months of follow-up.
Figure 3: Comparison of pain intensity (VAS score) between the first visit and after 6 months with/without Vitamin D supplementation (n = 90). VAS: Visual Analog Scale

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There was also a significant fall in the median anxiety levels from 11 (7.75–18) to 10 (7–17) and depression levels from 10 (7–15) to 9 (6–14) (P < 0.0001).

  Discussion Top

The primary goal of the index study was to determine if MSP in diabetics is associated with Vitamin D levels.

Research has observed conflicting conclusions in regard to the association of Vitamin D with MSP in patients with diabetes.[13],[14],[15] Ahmadieh et al.[16] observed a significant association of low Vitamin D levels (<20 ng/ml) with increased macrovascular complications of diabetes such as retinopathy and neuropathy, which indirectly accounted for higher nerve pain. The study holds strength as they adjusted for the confounders such as age, smoking, BMI, and duration of diabetes. However, Alkhatatbeh et al.[14] found no association of pain intensity with the Vitamin D status of the patients; however, their study was limited by a cross-sectional study design where the confounders were not adjusted.

The results of the present study identified a significant correlation of pain intensity with lower Vitamin D levels; however, this correlation became nonsignificant after adjusting for confounding variables such as duration of diabetes, smoking, HbA1c levels, and use of statins.

The association of duration of diabetes and HbA1c levels remains self-explained as they are linked with the severity of diabetes.[14],[15],[16],[17] Smoking status remains an important confounder as it significantly holds higher odds for Vitamin D deficiency and its associated psychological disturbances.[18]

Apart from the duration, smoking, and HbA1c levels, we adjusted for statins as they have been seen to cause MSP in 5%–18% of cases.[17] It is a common drug being used in patients with diabetes and metabolic syndrome for controlling lipid levels, and its increasing use has been evidenced to be linked with increasing MSP in such patients known as “statin myopathy.”[17] The exact mechanism remains undeciphered, but research has linked it with impairment of ubiquitin–proteasome pathway in the muscles or a genetic predisposition.[17]

Although Vitamin D failed to show an independent association with MSP, the study holds strength in witnessing a marked improvement in the pain scores with Vitamin D supplementation over a period of 6 months. During this period of follow-up, seven patients developed controlled glycosylated Hb levels, which could not be adjusted. This holds importance as HbA1c showed a mild nonsignificant positive correlation with VAS scores, and this can be responsible for partially controlling the pain in such patients. Still, one cannot ignore the effect of Vitamin D supplementation in causing the fall in pain after 6 months. This has been consistently seen in the previous studies because of which the opinion of Vitamin D monitoring and supplementation for curbing MSP among diabetics has been upheld.[19]

However, the research still continues, and there has been criticism on this aspect as there is no such evidence from randomized controlled trials (RCTs). From our point of view, randomization and achieving a control population with matched confounders (age, BMI, statin use, comorbidities, gender, intake of any medications, etc.) is near to impossible. Even RCT may fail to reach the highest level of quality in terms of matching the confounders for the study on patients with diabetes.

Diabetes is a disease that has been categorized as a mood disorder itself leading to anxiety and depression on account of disturbance in the stress balance and inflammatory response. There has been an increasing prevalence of these mood disorders in diabetes (40%–60%) which has curtailed the quality of life of the patients.[20]

Further, anxiety and depression are mental expressions that seem to be perturbed in pain and are also governed by Vitamin D levels.[21],[22] However, the study results failed to observe any significant association between anxiety, depression, and Vitamin D deficiency. Findings were in line with Alkhatatbeh et al.,[14] suggesting that Vitamin D might not be an independent factor causing anxiety and depression among diabetics. However, the follow-up of the patients showed a significant improvement in the anxiety and depression scores after normalization of Vitamin D levels which was concurrent with the decrease in the pain scores. This improvement in mental health might be because of the mitigation in pain, allowing the patients to better perform the daily chores.

Limitations of the study

The study holds strength in being one of the first prospective Indian studies to determine the effects of Vitamin D supplementation on MSP in diabetics. Nonetheless, the study had certain limitations. Muscle enzymes such as creatinine kinase and myoglobin were not assessed at presentation or at the follow-up. These enzymes are released into the blood following muscle destruction, and thus, their values might be better indicators of MSP rather than the self-reporting questionnaire that was used for the assessment. Second, ours was not a randomized case–control study, a design that holds one of the prime significance while witnessing the effects of a blood parameter. However, to minimize the bias, we adjusted the confounders while assessing the correlation of Vitamin D levels with MSP. Finally, genes such as CoQ10 and SLCO1B1 were not studied. Some of the genes have been linked with muscle degeneration and insulin resistance.

  Conclusion Top

We observed no significant independent correlation of MSP with Vitamin D levels or glycemic control. However, the supplementation of Vitamin D significantly alleviated MSP associated with diabetes with a significant reduction in anxiety and depression among such patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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