The Nutritional Dynamic Duo: Vitamins D and K

by Sara Gottfried, MD and Nilima Desai MPH, RD

Dynamic duos exist throughout culture: Batman and Robin. Thelma and Louise. They also exist in lifestyle medicine, because nutrients don’t fly solo. They interact often interdependently, act as cofactors in metabolic pathways, and compete for receptors. One example is how vitamin C helps you absorb more iron, like you find in red pepper hummus. Other examples are zinc and copper, vitamin B₁₂ and folate, or even the combination of berberine and milk thistle, which may increase the efficacy of berberine. One nutritional bioactive may be more important than the other for a specific biochemical scenario, or more proven in the scientific literature, but when combined, there’s synergy. The sum is greater than the parts.

The nutritional duo increasingly under consideration is vitamin D and K and how the synergy between them may improve patient outcomes. We all know that vitamin D deficiency and insufficiency are common, as described in detail in this foundational article on vitamin D deficiency and why the problem persists. Additionally, nutrient gaps for vitamin K are common. In this article, we will cover the role of vitamin D versus K, the data favoring vitamin D₃ over D₂ for supplementation, and the role of vitamin K₁ versus K₂. We will conclude with the clinical takeaways for how to manage the pairing of vitamin D and K in your clinical practice.

Introduction

Vitamins D and K are both essential fat-soluble vitamins that are pleiotropic nutrients and have important clinical significance for the skeletal and cardiovascular systems and beyond—meaning they have benefits outside of just bone strength and metabolism.¹

Vitamin D (ergocalciferol-D₂ and cholecalciferol-D₃) acts as a steroid hormone and plays a central role in many components of our skeletal and extraskeletal health, including calcium homeostasis, bone mineralization, and promoting immune and cardiovascular function.²

Vitamin K (phylloquinone-K₁ and menaquinones-K₂) is another group of essential fat-soluble vitamins and cofactors that are required for the production of several important proteins that are involved in calcium and blood coagulation homeostasis.³ Vitamin K also plays a central role in decreasing calcium accumulation in the smooth muscles of vascular walls.³

Vitamin D₂ vs. D₃

The biochemical steps required for the activation of both D₂ and D₃ result in the same active metabolite, calcitriol (1,25[OH]₂D), but research has shown differences between the two forms in raising the serum 25(OH)D levels, the best indicator of vitamin D status.⁷

A meta-analysis of 7 intervention studies (conducted in the US, Canada, UK, Australia, Denmark, and Italy) that included 1,016 participants aged 18-97 years with varying vitamin D doses (1,000-300,000 IU), treatment time periods (28d-24wk), and methods of administration (oral vs. intramuscular injections), demonstrated that vitamin D₃ supplementation is more efficacious at raising serum D levels, producing a significant increase in serum 25(OH)D levels from baseline compared to vitamin D₂.⁷

Another study involving 107 subjects tested the effects of supplementing with 2,000 IU/d of vitamin D₂, D₃, or placebo during an 8-week period on the serum concentrations of 25(OH)D, 25(OH)D₂, and 25(OH)D₃.⁸ In the vitamin D₃ supplementation arm, the concentrations of 25(OH)D₃ increased significantly from 16.6 ng/mL at baseline to 35.3 ng/mL after 8 weeks, whereas in the placebo group, 25(OH)D₃ levels decreased from 15.8 ng/mL at baseline to 12.5 ng/mL after 8 weeks.⁸ In the group receiving vitamin D₂, the 25(OH)D₂ levels increased significantly, but the 25(OH)D₃ levels decreased from 14.6 ng/mL at baseline to 6.7 ng/mL after 8 weeks.⁸ One of the possible explanations for this occurrence can be attributed to the possibility that D₂ impairs hydroxylation of D₃ in circulation.⁸ Therefore, based on these results, it can be concluded that vitamin D₃ increased 25(OH)D more effectively than vitamin D₂.⁸

The research investigation continues to fully elucidate the mechanisms underlying the relative potency of vitamin D₃ vs. D₂ supplements on 25(OH)D levels. In fact, dosing schedule (daily vs. bolus dosing) and gender may play mediating effects on the differences, in addition to difference in metabolism (e.g., speed of hydroxylation) and catabolism of D₂ vs. D₃.⁹

Vitamin K₁ vs. K₂

Vitamin K₁: Transported principally to the liver and regulates cofactors that aid in coagulation of the blood.³

Vitamin K₂ (MK-4, MK-7): Transported to extrahepatic tissues, such as bone and the vascular wall. It is a cofactor for carboxylase activity and facilitates the ɣ-carboxylation of bone-specific proteins such as osteocalcin (OC) and matrix Gla (MGP).³ OC takes calcium from the blood and binds it to the bone matrix, which in turn helps increase bone formation.¹⁰ MGP inhibits calcium precipitation in the matrix of the cartilage, vessel wall, and soft tissue, thus helping to prevent vascular and soft tissue calcification.³

Studies have compared the effects of vitamin K₁ vs. K₂ on blood coagulation factor and serum half-life of vitamin K and have found the impact of K₂ to be greater than K₁ for both.¹¹ 

Proposed synergy between vitamins D and K: bone and cardiovascular health

• Animal and human studies have demonstrated that vitamin D helps stimulate the production of vitamin K-dependent proteins OC and MGP, which support bone mineralization and decrease vascular calcification.¹²
• Long-term supplementation of vitamin D can lead to increased production of vitamin K-dependent proteins. If the increased demand is not adequately supported through diet or supplementation, the proteins can remain uncarboxylated, which can lead to increased vascular calcification and lower BMD.¹²
• Excess supplemental calcium intake without the support of vitamin D and K can lead to increased calcium deposits in the vascular tissue instead of the bones.¹²
• Vitamin K₂, when combined with vitamin D₃, decreases bone resorption by inhibiting osteoclastic activity.¹³
• In clinical settings, both vitamins D and K have been found to downregulate proinflammatory cytokines (IL-6, TNF-α) and reduce oxidative stress.¹ Inflammation and oxidative stress have been linked to osteoporosis and cardiovascular disease.¹

Image adapted from: van Ballegooijen AJ et al. Int J Endocrinol. 2017;2017:7454376.

Research

Bone mineral density

Study 1

A randomized controlled trial (RCT) involving 92 osteoporotic, postmenopausal women, aged 55-81 years, was conducted to assess the effect of the combined administration of vitamin D₃ (as 1α-hydroxyvitamin D₃) and K₂ on bone mineral density (BMD) of the lumbar spine over a 2-year period.⁴ BMD was measured at baseline, 1 year, and 2 years. The participants were divided into 4 different groups:⁴

C Group: calcium lactate, 2 g/day

D Group: 1α-hydroxyvitamin D₃, 0.75 mcg/day

K Group: vitamin K₂, 45 mg/day

DK Group: 1α-hydroxyvitamin D₃ + K₂

This study demonstrated that BMD of the lumbar spine in osteoporotic women increased significantly with either the D₃ (D group) or K₂ (K group) administration (p<0.05 and p<0.001), whereas calcium (C group) administration resulted in BMD losses. Furthermore, the combined administration of D₃ and K₂ (DK group) produced even a higher increase in the BMD of the lumbar spine, compared to vitamin D₃ and K₂ interventions alone.

The mechanism for the beneficial impact of the combined administration of vitamins D₃ and K₂ remains unclear, and further studies are needed to understand this.

 Study 2

Another RCT involving 126 postmenopausal women with osteopenia and osteoporosis was conducted to assess the effect of combined use of vitamins D₃ (as 1α-hydroxyvitamin D₃) and K₂ on the vertebral BMD over a 2-year period.⁵ The participants were divided into the following 4 groups:⁵

Group 1: 1α-hydroxyvitamin D₃ 1mcg/day

Group 2: vitamin K₂, 45 mg/day

Group 3: 1α-hydroxyvitamin D₃ + K₂

Group 4: control- dietary therapy alone

At the end of the study period, vertebral BMD decreased 4% in the control group, whereas it increased significantly in the group receiving combination therapy (D₃ + K₂) 4.92% ± 7.89%, p<0.01. Vertebral BMD increased 0.135% in the K₂ group compared to control; the BMD result in the D₃ group was significantly different from control but not from the K₂ group.

Based on these data, it can be concluded that combination therapy may have a synergistic effect on improving vertebral BMD compared to D₃ or K₂ alone.

Study 3

An RCT involving 78 postmenopausal women aged 60+ was conducted to assess the effects of vitamins D and K on BMD and undercarboxylated OC (UcOC), a hip fracture indicator, over a 6-month period; 45 women completed the study and were included in the per protocol analysis.⁶

Vitamin D+K Group:  15 mg K₂ 3x/d, 400 IU D₃ 1x/d, 315 mg CaCO₃* 2x/d

Control Group: 400 IU D₃ 1x/d, 315 mg CaCO₃ 2x/d

*CaCO₃ = calcium carbonate

There was a statistically significant (p=0.049) increase in lumbar spine (L3) BMD in the vitamin D+K group compared to the control group. In addition, compared to baseline, the vitamin D+K group significantly decreased UcOC concentration (p≤0.01). UcOC also nonsignificantly increased in the vitamin D+K group.

Some observational and animal studies also support these findings.¹² There were limitations to the study, including the small number of participants, high dropout rate, and lack of a separate comparator group that did not receive any supplementation.

 Additional health benefits

Researchers are also studying the impact of joint supplementation of vitamins D and K on glucose metabolism and inflammation. These studies have demonstrated beneficial effects on markers of oxidative stress, upregulation of insulin receptor genes, and enhancement of β cell proliferation.¹²

Conclusion

Vitamins D and K represent common, significant nutrient gaps for the majority of Americans.¹⁴ Due to the synergy and overlap of these two nutrients in the regulation of calcium levels as well as the interplay in bone and cardiovascular health, the combination of D + K contributes to lower morbidity and mortality related to these conditions.¹

Clinical takeaway: When you prescribe vitamin D to your patients for vitamin D deficiency or insufficiency, it is prudent to consider vitamin K, another common fat-soluble nutrient gap. Furthermore, the evidence to date for bone and cardiovascular health supports recommending vitamin D₃ together with vitamin K₂.

Citations

1. Kidd PM. Vitamins D and K as pleiotropic nutrients: clinical importance to the skeletal and cardiovascular systems and preliminary evidence for synergy. Altern Med Rev. 2010;15(3):199-222.
2. Kulie T et al. Vitamin D: An evidence-based review. J Am Board Fam Med. 2009;22(6):698-706.
3. Schwalfenberg GK. Vitamins K₁ and K₂: The emerging group of vitamins required for human health. J Nutr Metab. 2017:6254836.
4. Iwamoto J et al. Effect of combined administration of vitamin D₃ and vitamin K₂ on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci. 2000;5:546-551.
5. Ushiroyama T et al. Effect of continuous combined therapy with vitamin K₂ and vitamin D₃ on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas. 2002:211-221.
6. Je SH et al. Vitamin K supplement along with vitamin D and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty years old. J Korean Med Sci. 2011;26(8):1093-1098.
7. Tripkovic L et al. Comparison of vitamin D₂ and vitamin D₃ supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012;95(6):1357-1364.
8. Lehmann U et al. Bioavailability of vitamin D₂ and D₃ in healthy volunteers, a randomized placebo-controlled trial. J Clin Endocrinol Metab. 2013;98:4339-4345.
9. Hammami MM et al. Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial. BMC Endocr Disord. 2017;17(1):12.
10. Maresz K. Proper calcium use: Vitamin K₂ as a promoter of bone and cardiovascular health. Integr Med. 2015;14(1):34-39.
11. Sato T et al. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. J Nutr. 2012;11:93.
12. van Ballegooijen AJ et al. The synergistic interplay between vitamins D and K for bone and cardiovascular health: A narrative review. Int J Endocrinol. 2017;2017:7454376.
13. Plaza SM et al. Vitamin K₂ in bone metabolism and osteoporosis. Altern Med Rev. 2005;10(1):24-35.
14. Fulgoni VL 3^rd et al. Foods, fortificants, and supplements: Where do Americans get their nutrients? J Nutr. 2011;141(10):1847-1854.

Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.

Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.

Nilima Desai, MPH, RD is Sr. Manager of Medical Marketing and Metagenics Institute. Nilima is a Registered Dietitian (RD) who received her undergraduate degree from California State University Long Beach in Nutrition and Dietetics and her Master’s in Public Health Nutrition from Loma Linda University. She has over 14 years of experience delivering medical nutrition therapy in the areas of diabetes, renal disease, weight management, and vegetarian nutrition. She also served on the board of the Renal Practice Group of the Academy of Nutrition and Dietetics from 2012-2016 as the Membership Chair. In her free time she runs half marathons and shuttles her two kids to their activities.