Interactions of Vitamin D, Magnesium, Zinc, K2, Boron, and Vitamin C in Human Health: A Comprehensive Review

Abstract

Human health depends on an integrated network of biochemical and cellular interactions regulated by micronutrients. Vitamins and minerals act as cofactors, coenzymes, and signaling mediators that sustain metabolic homeostasis, immune competence, and tissue integrity. Increasing evidence emphasizes the synergistic and interdependent nature of micronutrient metabolism rather than isolated effects.

Among these, vitamin D, magnesium, zinc, vitamin K₂, boron, and vitamin C form a functional cluster influencing calcium regulation, immune function, redox balance, and hormonal modulation. Deficiency or imbalance in one can diminish the bioefficacy of others, producing systemic dysregulation.

This review explores the individual and interactive roles of these six micronutrients in bone metabolism, immune response, cardiovascular integrity, and antioxidant defense. Vitamin D facilitates calcium absorption; magnesium enables its enzymatic activation; zinc supports immune signaling and gene stability; vitamin K₂ directs calcium to bone while limiting vascular calcification; boron modulates steroid hormones and vitamin D bioavailability; and vitamin C provides antioxidant protection and collagen support.

Collectively, they operate as a metabolic network in which magnesium and boron enhance vitamin D activity and vitamin K₂ complements it in calcium homeostasis. Integrating mechanistic and clinical evidence, this review advocates a systems-based approach to micronutrition, highlighting the need for combined supplementation strategies, preventive applications in chronic disease, and future randomized trials to evaluate their synergistic potential. 

Keywords: vitamin D, magnesium, zinc, vitamin K₂, boron, vitamin C, micronutrient synergy, calcium homeostasis, immune modulation, chronic disease prevention.

Abstract | Introduction | Micronutrients |Synergistic Micronutrients | Synergistic Interactions | Implications |

Introduction

The paradigm of nutrition science has evolved from viewing micronutrients in isolation to appreciating their synergistic interactions, where the combined effects exceed the sum of individual contributions [2]. This growing recognition stems from epidemiological and mechanistic studies demonstrating that deficiencies or imbalances in one nutrient can impair the efficacy of others, leading to suboptimal health outcomes [1]. For example, nutrient synergies influence bone health, immune function, and cardiovascular integrity, areas where isolated supplementation often yields inconsistent results without considering interactions [3].

Vitamin D (also referred to as calciferol), a fat-soluble, plays a vitamin pivotal role in calcium and phosphorus homeostasis, immune modulation, and cellular differentiation [4]. It is also produced endogenously when ultraviolet (UV) rays from sunlight strike the skin and trigger vitamin D synthesis.

Magnesium, an essential mineral, is a cofactor in over 300 enzymatic reactions, regulating muscle and nerve function, blood pressure, and energy production [16].

Zinc, a trace element, is integral to immune response, protein synthesis, and wound healing [8]. Vitamin K2 (menaquinone), distinct from K1, activates proteins involved in calcium binding, supporting bone density and vascular health [7]. Boron, though not officially essential, influences steroid hormone metabolism, bone formation, and cognitive function [11]. Vitamin C, a water-soluble antioxidant, is crucial for collagen biosynthesis, immune defense, and iron absorption [10].

The aim of this review is to synthesize current evidence on the individual functions of these micronutrients and, more importantly, their intricate interdependencies in various physiological processes, including bone metabolism, immune function, and oxidative stress management. By integrating findings from clinical trials, observational studies, and mechanistic research, this article underscores the need for a holistic approach to micronutrient optimization.

Individual Functions of the Micronutrients

Vitamin D

Vitamin D functions as a steroid hormone that influences over 2,000 genes related to calcium metabolism, immune regulation, and cell differentiation. It exists in two primary forms—D₂ (ergocalciferol) and D₃ (cholecalciferol)—which are converted in the liver to 25-hydroxyvitamin D [25(OH)D], and subsequently in the kidneys to the biologically active form 1,25-dihydroxyvitamin D [1,25(OH)₂D].

Vitamin D influences the production and release of several neurotransmitters, including dopamine, serotonin, and acetylcholine. Its receptors are present in neurons and glial cells, suggesting direct modulation of synaptic activity. Adequate vitamin D status supports mood regulation, cognitive function, and neuroprotection against oxidative stress.

Vitamin D, primarily obtained through sunlight exposure and dietary sources, is hydroxylated in the liver and kidneys to its active form, calcitriol (1,25-dihydroxyvitamin D) [4]. It enhances intestinal calcium and phosphorus absorption, promotes bone mineralization, and modulates immune responses by regulating T-cell differentiation and cytokine production [4]. Deficiency is linked to rickets in children, osteomalacia in adults, and increased risk of autoimmune diseases, infections, and cancers [10]. Beyond skeletal health, vitamin D supports muscle function, cardiovascular integrity, and neurological processes [6].

Magnesium

Magnesium is involved in ATP-dependent reactions, DNA/RNA synthesis, and neuromuscular transmission [16]. Magnesium is a central mineral required for over 300 enzymatic reactions, including those involved in energy metabolism, nucleic acid synthesis, and neuroendocrine signaling.
It maintains cardiac rhythm, regulates blood glucose, and supports bone density by influencing parathyroid hormone secretion [16]. Low magnesium levels are associated with hypertension, diabetes, osteoporosis, and migraines [16]. Dietary sources include nuts, seeds, and leafy greens, with absorption modulated by gut health and other minerals [16].

Zinc

Zinc acts as a catalytic component in enzymes like superoxide dismutase and DNA polymerases, facilitating immune cell proliferation, wound healing, and sensory functions (taste and smell) [8]. Zinc is integral to DNA transcription, cell proliferation, and immune defense. It stabilizes cell membranes and influences over 300 enzymes, including those involved in antioxidant defense and hormone receptor binding. It is vital during growth periods, with deficiency causing growth retardation, diarrhea, and impaired immunity [9]. Zinc also modulates inflammation and oxidative stress, reducing risks of chronic diseases like atherosclerosis and neurodegeneration [10].

Vitamin K2

Vitamin K2 (menaquinone) directs calcium to where it is needed—bones and teeth—and prevents its deposition in arteries and soft tissues. Vitamin K2 activates osteocalcin and matrix Gla protein, directing calcium to bones and inhibiting arterial calcification [7]. It supports cardiovascular health by preventing vascular stiffness and reduces fracture risk in osteoporosis [2]. Sources include fermented foods like natto (fermented soy), with menaquinone-7 (MK-7) being highly bioavailable [2]. Emerging evidence links K2 to anti-inflammatory effects and cancer prevention [7]. Gut microbiomes are key to creating vitamin K2. 

Boron

Though often overlooked, boron influences multiple biochemical pathways involving vitamin D, magnesium, and steroid hormones. Boron enhances vitamin D and estrogen metabolism, promoting bone growth and reducing inflammation in conditions like arthritis [11]. It modulates enzyme activity in steroid hormone pathways and supports cognitive function by influencing neurotransmitter levels [12]. While not essential, boron deficiency impairs reproduction and wound healing, with benefits observed in low-dose supplementation [14].

Vitamin C

Though often overlooked, boron influences multiple biochemical pathways involving vitamin D, magnesium, and steroid hormones. As an electron donor, vitamin C neutralizes free radicals, regenerates other antioxidants like vitamin E, and is essential for collagen hydroxylation [8]. It boosts immune function by enhancing phagocyte activity and lymphocyte proliferation, while deficiency leads to scurvy [9]. Vitamin C also aids iron absorption and may lower risks of cardiovascular disease and certain cancers [10].

Synergistic Interactions and Physiological Processes

The interdependencies among these micronutrients amplify their effects in key physiological domains.

Bone Health and Mineral Metabolism

Vitamin D and magnesium interact closely, with magnesium serving as a cofactor for vitamin D hydroxylation enzymes, enhancing its bioavailability [1]. Supplementation of magnesium in vitamin D-deficient individuals improves serum 25-hydroxyvitamin D levels [1]. Vitamin D and K2 synergize to optimize calcium utilization: vitamin D promotes absorption, while K2 ensures deposition in bones rather than arteries, reducing calcification risks [2]. Boron extends vitamin D’s half-life, augmenting bone mineralization [13]. Zinc and vitamin K2 enhance bone components, with zinc potentiating K2’s effects on osteocalcin [1]. Magnesium and boron interact to improve calcium retention and bone density [11]. Vitamin C supports collagen matrix formation, complementing these minerals in skeletal integrity [3].

Immune Function and Oxidative Stress

Zinc and vitamin D collaborate in immune modulation, with zinc facilitating vitamin D receptor expression and both enhancing antiviral responses [10]. Vitamin C and zinc reduce cold duration via antioxidant synergy, decreasing rhinorrhea and inflammation [8]. Magnesium and vitamin C alleviate oxidative stress, with combined effects on synovitis and joint health [16]. Boron and zinc show antagonistic effects on nutrient uptake but synergistic benefits in longevity and immune support [12]. Vitamin K2’s anti-inflammatory role is amplified by vitamin C’s redox modulation [7].

Cardiovascular and Metabolic Processes

Vitamin D, K2, and magnesium maintain vascular health by balancing calcium homeostasis and reducing hypertension risks [6]. Zinc and magnesium supplementation lowers C-reactive protein, mitigating metabolic syndrome [15]. Boron influences magnesium absorption, indirectly supporting cardiovascular function [11]. Vitamin C enhances endothelial function, synergizing with these nutrients to prevent oxidative damage [9].

Synergistic Interactions of the Individual Micronutrients

1. Vitamin D: The Central Hormonal Regulator

Vitamin D functions as a steroid hormone that influences over 2,000 genes related to calcium metabolism, immune regulation, and cell differentiation. It exists in two primary forms—D₂ (ergocalciferol) and D₃ (cholecalciferol)—which are converted in the liver to 25-hydroxyvitamin D [25(OH)D], and subsequently in the kidneys to the biologically active form 1,25-dihydroxyvitamin D [1,25(OH)₂D].

1.1 Activation and Magnesium Dependence

Magnesium acts as a cofactor in all enzymatic steps of vitamin D metabolism, including its synthesis, transport, and activation. Low magnesium levels impede the conversion of 25(OH)D to 1,25(OH)₂D, leading to apparent vitamin D resistance despite supplementation.

1.2 Vitamin D and Immune Regulation

Vitamin D enhances innate immunity by stimulating antimicrobial peptides such as cathelicidin and defensin, while modulating adaptive immunity by shifting T-cell responses toward regulatory phenotypes. Its interplay with zinc and vitamin C reinforces mucosal and epithelial defense mechanisms.

2. Magnesium: The Cofactor of Life

Magnesium is a central mineral required for over 300 enzymatic reactions, including those involved in energy metabolism, nucleic acid synthesis, and neuroendocrine signaling.

2.1 Magnesium and Vitamin D Interactions

As a cofactor for vitamin D-binding protein, 25-hydroxylase, and 1α-hydroxylase, magnesium ensures vitamin D’s proper transport and activation. Studies indicate that magnesium supplementation enhances vitamin D status more effectively than vitamin D intake alone.

2.2 Cardiovascular and Neurological Roles

Magnesium regulates vascular tone, cardiac rhythm, and synaptic transmission. It also mitigates the pro-calcific effects of excess calcium and vitamin D when unbalanced by K2 and boron.

3. Zinc: The Modulator of Immune and Endocrine Function

Zinc is integral to DNA transcription, cell proliferation, and immune defense. It stabilizes cell membranes and influences over 300 enzymes, including those involved in antioxidant defense and hormone receptor binding.

3.1 Zinc and Vitamin D Synergy

Vitamin D enhances intestinal zinc absorption and regulates zinc transporter proteins (ZnT and ZIP families). In turn, zinc modulates the vitamin D receptor (VDR) and affects its DNA-binding efficiency, forming a feedback loop essential for immune homeostasis.

3.2 Zinc in Immune and Bone Health

Zinc deficiency impairs T-cell function, cytokine signaling, and osteoblast activity, leading to increased susceptibility to infections and osteoporosis. Adequate zinc supports vitamin D-mediated bone mineralization.

4. Vitamin K2: The Calcium Traffic Controller

Vitamin K2 (menaquinone) directs calcium to where it is needed—bones and teeth—and prevents its deposition in arteries and soft tissues.

4.1 Vitamin D–K2 Axis

Vitamin D enhances calcium absorption, but without sufficient K2, the absorbed calcium may accumulate in vessels rather than bones. K2 activates osteocalcin and matrix Gla protein (MGP), both of which are dependent on K2-mediated carboxylation.

4.2 Cardiovascular Implications

Clinical studies demonstrate that combined supplementation of vitamin D and K2 reduces vascular calcification and improves arterial flexibility, highlighting their complementary physiological balance.

5. Boron: The Silent Enhancer of Micronutrient Metabolism

Though often overlooked, boron influences multiple biochemical pathways involving vitamin D, magnesium, and steroid hormones.

5.1 Boron and Vitamin D Activation

Boron enhances the half-life and bioavailability of 25(OH)D, supporting vitamin D’s endocrine and immune functions. It may also regulate magnesium retention and calcium utilization.

5.2 Hormonal and Cognitive Roles

Boron supports estrogen and testosterone balance, cognitive performance, and bone strength, acting as a trace element integrator that fine-tunes nutrient metabolism.

6. Vitamin C: The Redox Guardian and Collagen Architect

Vitamin C (ascorbic acid) serves as an antioxidant, enzyme cofactor, and collagen stabilizer. It participates in hydroxylation reactions essential for connective tissue integrity.

6.1 Vitamin C and Zinc–Vitamin D Interactions

Together with zinc and vitamin D, vitamin C enhances epithelial barrier function and antiviral defense, particularly in respiratory health. Vitamin C’s redox activity protects vitamin D receptors and zinc enzymes from oxidative damage.

6.2 Bone and Vascular Health

Vitamin C stimulates osteoblast differentiation and collagen matrix formation, complementing the calcium–vitamin D–K2 triad in skeletal maintenance. It also supports endothelial nitric oxide availability, countering calcific stress.

Implications for Public Health, Clinical Practice, and Future Research

Public health strategies should emphasize balanced intake through diet and targeted supplementation, particularly in at-risk populations like the elderly or those with malabsorption issues [3]. Clinically, combined therapies (e.g., vitamin D with magnesium and K2) could improve outcomes in osteoporosis and cardiovascular disease management [5]. Future research should prioritize large-scale RCTs examining multi-nutrient interventions, dose-response relationships, and long-term effects on chronic diseases, while accounting for genetic and environmental factors [1]. Addressing knowledge gaps in boron and K2 interactions will further refine personalized nutrition approaches [14].

This article is for informational purposes only and does not constitute medical advice. Excessive intake or deficiency of vitamins and minerals can be harmful. Always consult a healthcare professional before supplementation. Individual requirements may vary based on age, health status, and existing medical conditions. 

Conclusion

The interplay of vitamin D, magnesium, zinc, vitamin K2, boron, and vitamin C represents a fundamental model of micronutrient interdependence in human physiology. Each nutrient supports and regulates the bioavailability and efficacy of others through shared pathways in enzyme activation, gene expression, mineral transport, and redox homeostasis. Recognizing these synergistic dynamics can revolutionize nutritional therapy, shifting the paradigm from isolated supplementation toward holistic micronutrient harmonization for optimal health, longevity, and disease prevention.

References

  1. Bleizgys, Andrius. “Zinc, Magnesium and Vitamin K Supplementation in Vitamin D Deficiency: Pathophysiological Background and Implications for Clinical Practice.” Nutrients, vol. 16, no. 6, 2024, p. 834. DOI: https://doi.org/10.3390/nu16060834.
  2. van Ballegooijen, Adriana J., et al. “The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review.” International Journal of Endocrinology, vol. 2017, 2017, art. 7454376. DOI: https://doi.org/10.1155/2017/7454376.
  3. Capozzi, Anna, et al. “Calcium, vitamin D, vitamin K2, and magnesium supplementation and skeletal health.” Maturitas, vol. 140, 2020, pp. 55-63. DOI: https://doi.org/10.1016/j.maturitas.2020.05.020.
  4. Laird, Eamon, et al. “Vitamin D and Bone Health; Potential Mechanisms.” Nutrients, vol. 2, no. 7, 2010, pp. 693-724. DOI: https://doi.org/10.3390/nu2070693.
  5. Hasific, Selma, et al. “Effects of Vitamins K2 and D3 Supplementation in Patients with Severe Coronary Artery Calcification: A Study Protocol for a Randomised Controlled Trial.” BMJ Open, vol. 13, no. 7, 2023, e073233. DOI: https://doi.org/10.1136/bmjopen-2023-073233.
  6. van Ballegooijen, Adriana J., et al. “Joint Association of Low Vitamin D and Vitamin K Status With Blood Pressure and Hypertension.” Hypertension, vol. 69, no. 6, 2017, pp. 1084-92. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.116.08869.
  7. Hariri, Elias, et al. “Vitamin K₂—a neglected player in cardiovascular health: a narrative review.” Open Heart, vol. 8, no. 2, 2021, e001715. DOI: https://doi.org/10.1136/openhrt-2021-001715.
  8. Wintergerst, Eva S., et al. “Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.” Annals of Nutrition and Metabolism, vol. 50, no. 2, 2006, pp. 85-94. DOI: https://doi.org/10.1159/000090495.
  9. Firouzi, Safieh, et al. “The effect of Vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients.” Clinical Nutrition Open Science, vol. 44, 2022, pp. 144–154. DOI: https://doi.org/10.1016/j.nutos.2022.06.006.
  10. Name, José João, et al. “Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity.” Frontiers in Nutrition, vol. 7, 2020, p. 606398. DOI: https://doi.org/10.3389/fnut.2020.606398.
  11. Pizzorno, Lara. “Nothing Boring About Boron.” Integrative Medicine: A Clinician’s Journal, vol. 14, no. 4, 2015, pp. 35-48.
  12. Rondanelli, Mariangela, et al. “Pivotal role of boron supplementation on bone health: A narrative review.” Journal of Trace Elements in Medicine and Biology, vol. 62, 2020, p. 126577. DOI: https://doi.org/10.1016/j.jtemb.2020.126577.
  13. Hunt, C. D., et al. “Dietary boron modifies the effects of vitamin D3 nutrition on indices of energy substrate utilization and mineral metabolism in the chick.” J Bone Miner Res, vol. 9, no. 2, 1994, pp. 171-82. DOI: https://doi.org/10.1002/jbmr.5650090206.
  14. Sojan, Jini Mary, et al. “Zebrafish as a Model to Unveil the Pro-Osteogenic Effects of Boron-Vitamin D3 Synergism.” Frontiers in Nutrition, vol. 9, 2022, p. 868805. DOI: https://doi.org/10.3389/fnut.2022.868805.
  15. Hamedifard, Zahra, et al. “The effects of combined magnesium and zinc supplementation on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease.” Lipids in Health and Disease, vol. 19, no. 112, 2020, pp. 1-12. DOI: https://doi.org/10.1186/s12944-020-01298-4.
  16. Fiorentini, Diana, et al. “Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency.” Nutrients, vol. 13, no. 4, 2021, p. 1136. DOI: https://doi.org/10.3390/nu13041136.

  17. Ray, Amit. "List of Important Neurotransmitters and their Functions." Compassionate AI, 3.7 (2022): 36-38. https://amitray.com/neurotransmitters/.
  18. Ray, Amit. "Interactions of Vitamin D, Magnesium, Zinc, K2, Boron, and Vitamin C in Human Health: A Comprehensive Review." Compassionate AI, 4.10 (2025): 48-50. https://amitray.com/vitamin-d-magnesium-zinc-k2-boron-vitamin-c-health-review/.
Tags: