Hard-to-heal Wounds associated with low vitamin D – review

Correlation between vitamin D levels and hard-to-heal wounds: a systematic review

J Wound Care. 2021 Jun 1;30(Sup6):S4-S10. doi: 10.12968/jowc.2021.30.Sup6.S4.

Karen Smith 1, Susan Hewlings 1

Wound healing often needs some combination of:
Vitamin D - (nanoemulsion works very well)
Vitamin D - non-daily
Resveratrol or something to improve the vitamin D receptor
Omega-3
Topical

This review appears to only consider daily oral Vitamin D mono-therapy

Objective: Hard-to-heal wounds are a major biological, psychological, social and financial burden on both individual patients and the broader health system. They are associated with a variety of comorbidities and have a complex aetiology, but are typically associated with nutritional deficiencies, such as low vitamin D levels. This systematic literature review evaluates the current research regarding the connection between inadequate vitamin D status and wound healing.

Method: PubMed and EBSCO databases were searched following PRISMA guidelines for primary research studies relating to pressure ulcers, diabetic ulcers or venous ulcers and vitamin D status.

Results: A total of 10 studies, involving 2359 participants, met the inclusion criteria. There was a strong correlation between low levels of 25-hydroxyvitamin D and the presence of all three types of hard-to-heal wounds.

Conclusion: Research suggests a correlation between low vitamin D levels and hard-to-heal wounds. However, it is not clear if the relationship is causal or only correlational. There is also emerging evidence on the use of vitamin D supplementation for the treatment of hard-to-heal wounds. More research is needed to understand the correlation between vitamin D and hard-to-heal wounds.

References

The dysvascular foot: a system for diagnosis and treatment -Sep 1, 1981·Foot & Ankle·F W Wagner
Prevalence and correlates of vitamin D deficiency in US adults -Feb 12, 2011·Nutrition Research·Kimberly Y Z Forrest, Wendy L Stuhldreher
Serum 25-hydroxyvitamin D is a reliable indicator of vitamin D status -Jul 22, 2011·The American Journal of Clinical Nutrition·Robert P Heaney
Management of diabetic foot ulcers.– Apr 25, 2012·Diabetes Therapy : Research, Treatment and Education of Diabetes and Related Disorders·Kleopatra Alexiadou, John Doupis
Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection– Jun 22, 2012·The British Journal of Nutrition·Shalbha TiwariSurya Kumar Singh
Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers -Nov 24, 2012·Revista do Colégio Brasileiro de Cirurgiões·Claudine Juliana Cristina Caznoch BurkiewiczGleim Dias De Souza
25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: is there any relationship? -Aug 21, 2013·Diabetes & Metabolic Syndrome·Mohammad ZubairJamal Ahmad
Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection -Oct 22, 2014·The British Journal of Nutrition·Shalbha TiwariSurya Kumar Singh
Vitamin D and calcium regulation of epidermal wound healing -Aug 19, 2015·The Journal of Steroid Biochemistry and Molecular Biology·Yuko OdaDaniel D Bikle
Vitamin D and the skin: Focus on a complex relationship: A review -Dec 9, 2015·Journal of Advanced Research·Wedad Z Mostafa, Rehab A Hegazy
Raised serum 25-hydroxyvitamin D levels in patients with active diabetic foot ulcers -May 7, 2016·The British Journal of Nutrition·Mohsen AfaridehAlireza Esteghamati
The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial =Jul 2, 2016·Journal of Diabetes and Its Complications·Reza RazzaghiZatollah Asemi
Revised National Pressure Ulcer Advisory Panel Pressure Injury Staging System: Revised Pressure Injury Staging System =Oct 18, 2016·Journal of Wound, Ostomy, and Continence Nursing : Official Publication of the Wound, Ostomy and Continence Nurses Society·Laura E EdsbergMary Sieggreen
The quality of life of people who have chronic wounds and who self-treat -May 12, 2017·Journal of Clinical Nursing·Suzanne KappNick Santamaria
Nutritional blood parameters and nutritional risk screening in patients with spinal cord injury and deep pressure ulcer-a retrospective chart analysis – Oct 24, 2017·Spinal Cord·Cristina LussiAnke Scheel-Sailer
An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds – Jan 7, 2018·Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research·Samuel R NussbaumDonna Cartwright
Pressure Ulcer and Nutrition – May 11, 2018·Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine·Seied Hadi SaghaleiniZohreh Ostadi
Severe Vitamin D3 Deficiency in the Majority of Patients with Diabetic Foot Ulcers – Jul 6, 2018·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·Joachim FeldkampMichael Roden
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Serum vitamin D levels and chronic refractory wounds: Unveiling of association and exploration of potential molecular mechanisms - Aug 2026

Clin Invest Med. 2026 Aug 7. doi: 10.3138/CIM-2025-0211PDF behind paywall

Guowei Zhou, Jia Fu, Qirui Xiong, Bing'e Ma, Chaoqun Ma

A large US population survey (NHANES, 5,415 adults) found that people in the top quarter of vitamin D levels had 37% fewer hard-to-heal wounds than those in the bottom quarter.

The benefit rose steadily with vitamin D level — no plateau, no threshold — and held in every subgroup tested.

But this is a snapshot in time, not a trial. A non-healing foot or leg ulcer keeps people indoors and off their feet, which by itself lowers vitamin D. The arrow may well point the other way.

The numbers


Participants	5,415 adults (NHANES)
Highest vs. lowest vitamin D quartile	37% lower odds of chronic refractory wound
Statistical significance	P = 0.04 (marginal)
Dose-response	Linear — P for nonlinearity = 0.328
Subgroups	Association consistent throughout
Proposed pathways	AGE-RAGE, IL-17, PI3K-Akt

What this study does NOT show

It does not show that vitamin D prevents or heals wounds. Cross-sectional data captures both at the same moment and cannot tell which came first.
Reverse causation is the leading alternative explanation. Chronic leg and foot ulcers cause pain and immobility → less time outdoors → less sun → lower vitamin D. This is at least as plausible as the reverse.
"Refractory" overstates what was measured. NHANES has no clinical wound examination. The wound variable is self-reported. Nothing establishes that these wounds failed standard treatment, which is what "refractory" means clinically.
No dose, target level, or threshold. The paper reports quartiles, not actionable numbers.
No healing outcomes. Nothing on closure rate, time to heal, recurrence, infection, or amputation.
Residual confounding is likely. Diabetes, obesity, peripheral artery disease, kidney disease, and smoking each independently lower vitamin D and impair healing. Statistical adjustment reduces but does not remove this.
The result is fragile. P = 0.04 on a single quartile contrast. The abstract does not report the number of wound cases or the confidence interval.

A note on the "molecular mechanisms" half of the paper

The second half is network pharmacology plus molecular dynamics simulation — entirely computational. No cells, no tissue, no animals, no measured protein.

These software pipelines return AGE-RAGE, IL-17, and PI3K-Akt for a very wide range of input compounds; they are among the most commonly returned pathways regardless of what is fed in. Treat this section as hypothesis-generating software output, not as mechanistic confirmation of the survey finding. It does not strengthen the association.

Why it is on this page anyway

It is the largest, most representative dataset yet applied to this question, and the linear dose-response with no threshold is a genuinely useful addition — it argues against the idea that only severe deficiency matters.

The stronger evidence for causation remains the intervention trials already listed on this page — Razzaghi 2016 (diabetic foot ulcer), Burkiewicz 2012 (leg ulcers), and the venous ulcer RCT — not this survey.