Vitamin D deficiency among outpatients and hospitalized patients with diabetic foot ulcers: A systematic review and meta-analysis

Abstract

BACKGROUND

The definition of diabetic foot syndrome (DFS) varies depending on the location and resources. Few classifications are available according to the indication. DF ulcers and vitamin D deficiency are common diseases among patients with diabetes. Previous literature has shown an association between DF ulcer (DFU) and vitamin D deficiency. However, the available meta-0analysis was limited by substantial bias.

AIM

To investigate the association between DFUs and vitamin D levels.

METHODS

We searched PubMed, MEDLINE, and Cochrane Library, EBSCO, and Google Scholar for studies comparing vitamin D levels and DF. The keywords DFU, DFS, diabetic septic foot, vitamin D level, 25-hydroxy vitamin D, vitamin D status, and vitamin D deficiency were used. The search engine was set for articles published during the period from inception to October 2022. A predetermined table was used to collect the study information.

RESULTS

Vitamin D level was lower among patients with DFU compared to their counterparts [odds ratio (OR): -5.77; 95% confidence interval (CI): -7.87 to -3.66; χ² was 84.62, mean difference, 9; I² for heterogeneity, 89%; P < 0.001 and P for overall effect < 0.001]. The results remained robust for hospitalized patients (OR: -6.32 95%CI: -11.66 to -0.97; χ² was 19.39; mean difference, 2; I² for heterogeneity, 90%; P = 0.02).

CONCLUSION

Vitamin D was lower among outpatients and hospitalized patients with DFUs. Further larger randomized controlled trials are needed.

Key Words: Vitamin D deficiency; Diabetic foot ulcer; Outpatient; Hospitalized patients; Diabetic foot syndrome

Core Tip: This is the first study to assess the relationship between diabetic foot ulcer and vitamin D deficiency, avoiding the bias of the two published meta-analyses.

INTRODUCTION

Diabetes mellitus (DM) is an epidemic globally. DM is a morbid disease with many complications including microvascular and microvascular disease. Diabetic foot syndrome (DFS) is defined as peripheral neuropathy, limited joint mobility, peripheral arterial disease, immunopathy, ulceration, and Charcot arthropathy[1]. The combination of FS elements provides an environment for unrecognized injury, foot infection, and possible amputation[2]. DFS is characterized by peripheral arterial disease, but the symptoms are masked by the accompanying peripheral neuropathy. The pathology varies from pre-ulcerative callouses, ulceration, and necrosis developing at the site of high pressure (deformities of the toes and feet). Patient education and feet inspection are mandatory because repetitive trauma might pass unnoticed due to the loss of pain sensation[3]. DFS is a common complication of diabetes with a great economic burden; DTS substantially affects the patient's quality of life and leads to premature death. In addition, patients with DFS are prone to psychiatric disease[4].

There are nearly 40 classifications for DFS, with wide variation depending on the availability of resources and geographical variations. It is recommended to use classification in light of specific indications. Few classifications have been validated for use; the site, ischemia, neuropathy, bacterial infection, area, and depth (SINBAD) is six questions with yes or no answers with a maximum of six points. SINBAD score is better for communication between clinicians[5]. While, the Infectious Diseases Society of America/International Working Group on Diabetic Foot, and wound depth, ischemia, and foot infection scoring are better for infection and perfusion respectively[6,7]. The spectrum of DFS varies from minor erythema to tissue necrosis and lower limb deformity and amputation [8]. The mortality of DFS is comparable to breast and lung cancer. Five-year mortality for minor and major amputations, Charcot, and DF ulcer (DFU) were 56.6%, 46.2%, 30.5%, 29%, respectively. The pooled mortality from breast, all cancer, and lung cancer were 9%, 30%, and 80% respectively[9].

The lifetime of developing FUs among patients with diabetes varies between 19% and 34% with nearly two-thirds of recurrence in 5 years, and 1 in 5 patients with moderate to severe FUs resulting in amputation. The majority of lower extremities amputations are preceded by FUs and three amputations occur every minute due to diabetes. Patients with FUs had a 2.5 times mortality rate compared to their counterparts[10,11].

25-hydroxyvitamin D (25(OH)D) is present in almost all immune cells and is a major immunomodulatory hormone. In addition, the vitamin is a potent endothelial membrane stabilizer[12]. Due to its anti-inflammatory effects, the active form of vitamin D plays an important role in inflammatory diseases including rheumatic disorders, and a growing piece of evidence is present regarding its effects on infectious diseases[13]. Vitamin D deficiency is common; larger studies suggest that in Europe, 40% and 13% of the population are vitamin D-deficient and severely deficient, respectively[14]. Vitamin D deficiency is associated with vascular diseases including DM, hypertension, and dyslipidemias[15].

The small number of included studies, including studies published by the same authors and including poster presentations[16,17], limits the previous meta-analysis on vitamin D deficiency and diabetic septic foot. Therefore, this meta-analysis investigated vitamin D levels among patients with the diabetic septic foot.

MATERIALS AND METHODS

Eligibility criteria

The studies were eligible if they compared the level of vitamin D among patients with DFU and their counterparts without DFUs and they are randomized controlled trials or case-control studies, prospective and retrospective cohorts, and cross-sectional studies. Case reports, case series, and animal and experimental studies were excluded.

Outcomes measures

The primary outcome was the level of vitamin D among patients with DFUs.

Vitamin D assessment methods

Vitamin D measurement varied between the included studies. References 18, 19, 21, and 23 used the enzyme-linked immunosorbent assay; references 20, 22, and 25 used radioimmunoassays; references 24, 26, and 28 used the electrochemiluminescence immunoassay; reference 27 used liquid chromatography-tandem mass spectrometry; and reference 29 used the chemiluminescence assay.

Setting and DFU definition

All of the studies used outpatients except 18, 24, 28, and 29, in which hospitalized patients were included.

Information sources and search

The researcher searched PubMed, MEDLINE, and Cochrane Library, EBSCO, and Google Scholar using the keywords DFU, DFS, diabetic septic foot, vitamin D level, 25-hydroxy vitamin D, vitamin D status, and vitamin D deficiency. The search engine was set for articles published during the period from inception to October 2022. A predetermined table was used to collect study information including author name, year of publication, country, age, sex, patient’s number in the control and interventional groups, duration of diabetes, hemoglobin A1c (HbA1c) in the intervention and control groups, vitamin D level among patients with FUs and control groups (Figure 1 and Tables 1-3).

Figure 1 Vitamin D levels among diabetic patients with and without diabetic foot ulcer.

Table 1 Basic characteristics of patients with and without diabetic foot ulcers.

Ref.	Study type	Country	Duration	Diabetes	Control	Results
Afarideh et al[18], 2016	Cross-sectional, 30, and 30	Iran	-	41.93 ± 45.48	39.94 ± 26.07	Non-significant, 0.487
Çağlar et al[19], 2018	Prospective, 58 interventions and 47 controls	Turkey	12 mo	7.9 ± 6.3	11.6 ± 6.5	Lower among diabetes, < 0.001
Dai et al[20], 2020	Prospective, 21, and 30	China	9 mo	11.21 ± 5.20	17.73 ± 3.20	Lower among diabetes, < 0.001
Danny Darlington et al[21], 2019	Cross-sectional, 67, and 66	India	-	19.38 ± 5.32	21.91 ± 5.16	No significant difference, 0.306
Feldkamp et al[22], 2018	Cross-sectional, 104, and 103	Germany	-	11.8 ± 11.3	19 ± 14.4	Lower among diabetes, < 0.001
Gupta et al[23], 2016	Retrospective, 50, and 50	India	-	14.25 ± 8.46	21.28 ± 10.98	Lower among diabetes, < 0.001
Tang et al[24], 2021	Prospective, 547, and 1174	China	8 yr	35.8 ± 10.98	45.48 ± 12.91	Lower among diabetes, < 0.001
Tiwari et al[25], 2014	Cross-sectional, 112 cases, 107 controls	India	-	40.2 ± 3.7	49.4 ± 3.2	Lower among diabetes, 0.06
Todorova et al[26], 2020	Cross-sectional, 73, and 169	Bulgaria	-	11.6	13.5	Lower among diabetes, 0.001
Tsitsou et al[27], 2021	Cross-sectional, 33, and 35	Greece	-	17.9 ± 6.7	19.8 ± 8.7	Non-significant, 0.329
Wang et al[28], 2022	Retrospective, 242, 187	China	34 mo	26.89	35.64	Lower among diabetes, < 0.001
Xiao et al[29], 2020	Cross-sectional, 245, and 4039	China	-	36.96 ± 18.03	40.97 ± 17.82	Lower among diabetes, 0.001

Table 2 Age, sex, duration of diabetes, and hemoglobin of patients with and without diabetic foot ulcers.

Ref.	Study type	Country	Age	Sex	DM duration	HbA1c
Afarideh et al[18], 2016	Cross-sectional, 30, and 30	Iran	Matched	Matched	Matched	Matched
Çağlar et al[19], 2018	Prospective, 58 interventions and 47 controls	Turkey	Controls younger	Matched	Controls newly diagnosed	Matched
Dai et al[20], 2020	Prospective, 21, and 30	China	Matched	Matched	Matched	Matched
Danny Darlington et al[21], 2019	Cross-sectional, 67, and 66	India	Matched	Matched	Matched	Poor glycemic among foot ulcer
Feldkamp et al[22], 2018	Cross-sectional, 104, and 103	Germany	Matched	Matched	Matched	Matched
Gupta et al[23], 2016	Retrospective, 50, and 50	India	Control was younger	Males high among DM	Lon among diabetes	Poor glycemic among foot ulcer
Tang et al[24], 2021	Prospective, 547, and 1174	China	Control was younger	Higher females in control	Lon among diabetes	Matched
Tiwari et al[25], 2014	Cross-sectional, 112 cases, 107 controls	India	Matched	Matched	Matched	Matched
Todorova et al[26], 2020	Cross-sectional, 73, and 169	Bulgaria	Control was younger	Matched	Matched	NA
Tsitsou et al[27], 2021	Cross-sectional, 33, and 35	Greece	Matched	Matched	Matched	Matched
Wang et al[28], 2022	Retrospective, 242, 187	China	Control was younger	Males higher among DM	Lon among diabetes	NA
Xiao et al[29], 2020	Cross-sectional, 245, and 4039	China	Matched	Females more	Matched	Poor glycemic among foot ulcer

DM: Diabetes mellitus; HbA1c: Hemoglobin A1c; NA: Not available.

Table 3 Newcastle Ottawa scale risk of bias of the included studies.

Ref.	Country	Selection bias	Comparability bias	Outcome	Total score
Afarideh et al[18], 2016	Iran	4	2	2	8
Çağlar et al[19], 2018	Turkey	4	2	2	8
Dai et al[20], 2020	China	4	2	2	8
Danny Darlington et al[21], 2019		4	1	2	7
Feldkamp et al[22], 2018	India	4	2	2	8
Gupta et al[23], 2016	Germany	4	2	2	8
Tang et al[24], 2021	India	4	2	2	8
Tiwari et al[25], 2014	China	4	1	2	7
Todorova et al[26], 2020	India	4	2	2	8
Tsitsou et al[27], 2021	Bulgaria	4	1	2	7
Wang et al[28], 2022	Greece	4	2	2	8
Xiao et al[29], 2020	China	4	1	2	7

Data analysis

The RevMan (version 5.4) system for meta-analysis was used, and the data were all continuous. We pooled data from 12 studies to compare vitamin D levels among patients with and without diabetic septic foot; a subanalysis was done to compare vitamin D among hospitalized patients. Random effect was used because significant heterogeneity was observed. Funnel plots were used to assess lateralization. P < 0.05 was considered statistically significant.

RESULTS

The current meta-analysis included 12 studies including 7619 patients. The included studies were seven cross-sectional, three prospective, and two retrospective studies; nine were published in Asia and three were from Europe[18-29]. The included studies were of good quality as assessed by the Newcastle Ottawa Scale[30]. Vitamin D was lower among patients with DFUs [odds ratio (OR): -5.77, 95% confidence interval (CI): -7.87 to -3.66; χ² was 84.62; mean difference, 9; I² for heterogeneity, 89%; P < 0.001, and P for overall effect < 0.001] (Figure 2). Vitamin D level was low when a subanalysis was conducted including only hospitalized patients with diabetes septic foot (OR: -6.32; 95%CI: -11.66 to -0.97; χ² was 19.39; mean difference, 2; I² for heterogeneity, 90%; P = 0.02) (Figure 3). Vitamin D level was lower among patients with DFUs after including studies that controlled for age, sex, duration of diabetes, and HbA1c (OR: -6.32; 95%CI: -923 to -3.42; χ² was 18.72; mean difference, 4; I² for heterogeneity, 79%; P < 0.001) (Figure 4).

Figure 2 Vitamin D level among diabetic patients with and without septic foot.

Figure 3 Vitamin D level among diabetic patients with and without septic foot (hepatized).

Figure 4 Vitamin D level among diabetic patients with and without septic foot (controlling for age, sex, duration of diabetes, and hemoglobin).

DISCUSSION

In the present meta-analysis, vitamin D levels were lower among patients with DFUs compared to their counterparts without FUs (OR: -5.77; 95%CI: -7.87 to -3.66). There were no differences between hospitalized patients and outpatients. The results remained robust when including studies that controlled for age, sex, duration of diabetes, and HbA1c. The quality of the included studies was good[30]. The current findings were in line with a narrative review including three studies[31]. The present findings were similar to the first meta-analysis published by Dai and colleagues in 2019. Dai et al[16] found an association between vitamin D levels and DFUs. However, Kota et al[32] included studies published by the same authors and some were poster presentations. Yammine et al[33] found similar results. Importantly, Yammine and colleagues included poster presentations, studies published by the same authors, and studies that assessed Charcot’s joints[34]. In addition, the previous meta-analysis included Zubair et al[35] study in which vitamin D median was reported and not the mean ± standard deviation. A recently published meta-analysis reported similar findings to our results. However, the substantial heterogeneity including posters, research by the same authors, and different primary outcomes limited their results[17]. The main strength of this meta-analysis is the subanalysis on vitamin D among hospitalized patients. Although a single measurement is not enough during stress, the results remain robust even among admitted patients[36].

Vitamin D has been considered a magic bullet and cures many chronic disorders. However, the results were obtained from observational studies. The findings of lower FUs among patients with higher vitamin D may not prove causality. Other confounders might explain the lower vitamin D levels among patients with DFUs including a healthier diet, good exposure to sunlight, and physical activity[37,38]. In addition, vitamin D improves glycemic control among patients with diabetes[39,40]. Thus, high vitamin D may indirectly protect against DFUs by improving glycemic control.

Osteoblasts (bone formation) and osteoclasts (bone resorption) orchestrate bone remodeling. Osteoclasts genesis activation is through receptor activator of tumor necrosis factor (RANK-osteoprotegerin), ultimately leading to osteolysis and destruction of bone tissue. This pathway is of great therapeutic and clinical implications. Medications that influence different levels of RANK-osteoprotegerin are bisphosphonates, calcitonin, and denosumab. Denosumab is encouraging for the treatment of Charcot diabetic foot. However, bisphosphonates have been evaluated recently due to the adverse events. Calcitonin efficacy is limited[41,42].

In this review, some of the included studies were not matched for age, duration of diabetes, duration of diabetes, or HbA1c. The young age of control subjects, their good glycemic control, and the short duration of diabetes might increase their risk of DFUs.

Vitamin D supplementation and diabetic septic foot

Although, the association between low vitamin D levels and diabetic septic foot was documented. However, the effect of vitamin D therapy on DFUs is unclear. In addition, it is not clear if the relationship is correlated or causal[43]. A double-blinded randomized controlled trial showed that high-dose vitamin D supplementation (170 μg/d) was superior to low doses (20 μg/d) on diabetic ulcer healing[44]. A recent review showed that vitamin D improved diabetic septic foot healing, an effect mediated by the remodeling and proliferation of cells involved. In addition, vitamin D suppresses proinflammatory responses, enhances antimicrobial peptides, and enhances anti-inflammatory effects[45]. The review by Papaioannou and colleagues, which included 34 studies[46], supported the above findings. A randomized controlled trial published in Asia showed that vitamin D supplementation reduced ulcer length, width, and depth[47]. A recent review of the literature concluded that vitamin D supplementation might slow the progression of neural damage. In addition to the adjuvant role in neuropathic pain and cardiovascular autonomic neuropathy among patients with type 2 diabetes[48].

The current meta-analysis strength is that we included observational studies excluding poster presentations, studies published by the same authors, and studies that used the median of vitamin D. The limitation of this study was the substantial heterogeneity.

CONCLUSION

Vitamin D levels were lower among patients with DFUs compared to their counterparts without ulcers. A low level was observed among hospitalized patients. Randomized control trials investigating the association of vitamin D and DFs and assessing the role of vitamin D supplementation are needed.

ARTICLE HIGHLIGHTS

Research background

Vitamin D deficiency is associated with various disorders ranging from glycemic control to cancer and suicide. Diabetic foot syndrome (DFS) is a common disorder with high morbidity and mortality. The association of DF ulcers (DFUs) with vitamin D deficiency was documented. However, the available meta-analyses were limited by bias and few included studies.

Research motivation

Diabetes mellitus (DM) is approaching an epidemic, the disease is associated with vascular and neuropathic complications. Most people with diabetes are not approaching the recommended targets for cardiovascular risk factors with increasing FUs. DFUs are a preventable disease and vitamin D deficiency is promising. Despite the association of vitamin D deficiency and DM and its complications. However, a cause and effect were not confirmed. In addition, vitamin D supplementation is not without complications and vitamin D is readily synthesized by sun exposure. We included vitamin D supplementation to address this issue.

Research objectives

To assess vitamin D levels among patients with diabetic septic foot and the role of vitamin D supplementation in the treatment of DFS.

Research methods

We searched four databases and included studies other than case reports, perspectives, opinions, and editorials. The studies were included if they assessed the relationship between diabetic foot ulcers and vitamin D levels. The most recent RevMan system was used for data analysis.

Research results

Evidence from observational studies confirmed the association between vitamin D deficiency and diabetic foot ulcers, both among outpatients and hospitalized patients, the associations remained robot after controlling for demographic factors, the duration since the diagnosis of type 2 diabetes, and glycated hemoglobin (odds ratio: -6.32, 95% confidence interval: -923 to -3.42).

Research conclusions

Vitamin D deficiency was associated with DFUs, and vitamin D supplementation was effective in slowing the progress. Various therapies along the RANK-osteoprotegerin pathway are promising.

Research perspectives

The question of vitamin D and the optimal effective dose is elucidated. In addition, future therapies along the RANK-osteoprotegerin might address this dangerous diabetes complication.

ACKNOWLEDGEMENTS

The author would like to acknowledge the Saudi Digital Library for the free access of the databases.