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Is it enough to just focus on one vitamin or mineral for optimal health, especially if you are planning on taking a supplement? As with many health-related topics, there is a complexity in how nutrients are absorbed, interact with one another, and are used by our bodies.

As I detailed in a previous post, vitamins and minerals have the potential to have a synergistic relationship or an antagonistic one—or both, with the dosage potentially influencing the interaction.

For the most part, these interactions do not pose a significant consideration at levels found in food, although there may be some minor interactions, especially for those that work synergistically. Moderate levels in multivitamin and multimineral supplements may also not be enough to create a negative interaction in a manner that poses an issue. For most people, the greatest concern comes if they plan to supplement at very high doses, but it is best to discuss your situation with your doctor or another healthcare practitioner.

That being said, it remains important to be aware of the interactions of a said nutrient, such as vitamin D, with other nutrients, especially those that support them and those that may impact your health plan.

Vitamin D Supplementation 

Vitamin D is unique to most of the vitamins and minerals discussed as it acts similarly to a hormone and can be synthesized in sufficient quantities by the body—as long as there is sufficient exposure to the sun and there are no impediments in the steps to the alteration of vitamin D into its active form. This activation takes place in three steps, first in the skin, then the liver, and finally the kidneys.

However, due to its key role in health and the reduced synthesis due to living in higher latitudes and/or spending more time indoors, more and more individuals are taking it in supplemental form rather than solely relying on endogenous synthesis. Doctors and other healthcare practitioners more frequently recommend vitamin D supplementation for a variety of reasons, often at very high doses.

According to a 2019 ConsumerLab survey, the most common supplements people take include Vitamin D, fish oil, magnesium, curcumin and turmeric, multivitamins, probiotics, vitamin C, B complexes, and calcium. According to statistics from the National Center for Health, the most commonly used supplements are multivitamin-mineral supplements, vitamin D, and omega-3 fatty acid supplements.

Thus, with vitamin D continually ranking as one of the most common supplements, it may be a good idea to better understand some of the relationships it has with certain essential vitamins and minerals, especially:

• Calcium
• Magnesium
• Vitamin A
• Vitamin E
• Vitamin K

Vitamin D’s Role in Calcium Homeostasis—With Some Help from Vitamin K

One of the long-recognized roles of vitamin D in the body is calcium homeostasis and thus bone health. As such, it is becoming more and more well-known to include vitamin D with any calcium supplementation, but where does this relationship come from?

To answer, let’s start with a quick overview of the role vitamin D plays in calcium homeostasis. Vitamin D and parathyroid hormone (PTH) interact to maintain calcium and phosphate homeostasis. PTH stimulates the synthesis of vitamin D in the kidney, and vitamin D has a negative feedback on PTH secretion as well as increasing absorption of calcium in the intestines. PTH regulates serum calcium levels by acting on bone, kidneys, and the gut for storage, excretion, reabsorption, and absorption. Basically, when serum calcium levels are low, PTH increases serum calcium by releasing it from the bone and increasing absorption in the intestines and reabsorption in the kidneys. PTH also has a reciprocal effect on the metabolism of phosphate.

As such, there will be interactions between vitamin D and calcium, not only at the level of interaction in the body but also when supplementing, and vitamin D may play a larger role in increasing calcium levels than calcium supplementation alone.

For example, in one study on pregnant women, vitamin D had a significant impact on PTH levels, while calcium intake did not. However, these women did have sufficient intake levels of calcium, so calcium supplementation in those who are insufficient may react differently.

The benefits of co-supplementing with vitamin D and calcium go beyond bone health. In one study on women with gestational diabetes, co-supplementing with 100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D supplement per day improved high-sensitivity C-reactive protein and antioxidant status. A meta-analysis also found potential benefits to insulin resistance and glycemic status with high-dose and short-term combined vitamin D and calcium supplementation but recommended further studies.

Vitamin K may be an additional component that enhances this synergistic relationship between calcium and vitamin D. Vitamin K and vitamin D have a synergistic relationship in that they both play key roles in calcium homeostasis, vascular calcification, and bone health. As such, decreased levels of both vitamin K and vitamin D independently and synergistically have also been shown to increase the risk of hip fractures in the elderly, cardiovascular disease, and all-cause mortality.

The benefits of vitamin K also go beyond bone health. One study found benefits in taking 500 mg calcium, 200 IU vitamin D, and 90 ug vitamin K twice daily for 8 weeks compared to a placebo in women with polycystic ovarian syndrome (PCOS). Those taking the supplements had improved markers in their serum triglycerides, VLDL cholesterol, and insulin metabolism. Another study on women with PCOS also found similar benefits as well as improvements in hormonal markers. And another study on diabetic patients found that co-supplementing with vitamin D, calcium, and vitamin K led to a reduction in carotid intima-media thickness as well as markers of metabolic status.

As you can start to see, some of the benefits of vitamin D supplementation may just be enhanced with some additional support, such as that from vitamin K and calcium. But is that the end of the story?

Magnesium and Vitamin D

Calcium is not the only mineral that interacts with vitamin D. For one, adequate vitamin D status increases the absorption of important minerals such as calcium, magnesium, zinc, copper, and iron.

Magnesium acts as a cofactor for vitamin D in several key stages, including the creation, transportation, and activation of the vitamin hormone. Thus, adequate magnesium may be necessary to fully optimize vitamin D levels. With vitamin D and magnesium’s separate relationship with calcium, it is important to consider a person’s status and intake of all three vitamins and how they interact.

Magnesium also interacts with calcium, as it is important to have the right ratio of calcium to magnesium. It is common for the ratios to be imbalanced, due to an increase in calcium intake without a similar intake in magnesium, despite intakes of both minerals rising in the past few decades. Furthermore, modern diets are low in magnesium, especially those high in processed foods.

How does this interaction play out with co-supplementation? Well, in one study on pregnant women with gestational diabetes, taking a supplement with calcium, vitamin D, magnesium, and zinc for six weeks led to a significant reduction in biomarkers for oxidative stress and inflammation. A similar benefit was found in women with PCOS, with co-supplementation with magnesium, zinc, calcium, and vitamin D leading to improvement in hormonal markers as well as those of inflammation and oxidative stress.

Thus, it may be important to look to magnesium when considering supplementing with vitamin D, especially as many are already at risk of low levels of this key mineral.

Vitamin A and Vitamin D: Key Antagonists?

So far, we have talked about the vitamins and minerals that act as a team with vitamin D for overall health. Conversely, the relationship between vitamin D and A often falls under the antagonistic category, but in reality, like many nutrient interactions, it’s more complex.

Higher vitamin A or retinol intake in those with lower vitamin D status may slightly increase the risk of total fractures, at least in postmenopausal women. The reason for this? Well, animal and mechanistic studies have pointed to the idea that very high levels of vitamin A, specifically the active form retinoic acid, interferes with vitamin D, which could then impact calcium homeostasis and bone health. Vitamin A and D may compete for the same receptor, which could account for some cases of antagonistic actions.

Vitamin A, as well as zinc and magnesium, play roles in the activation and function of vitamin D, including interacting with gene expression. The receptor for the activated vitamin D, calcitriol 1,25-(OH)2D3 to RXR, needs to be activated by retinoic acid. This then can activate genes involved in the inflammatory and autoimmune responses, including inhibiting NF-kB. Thus, the anti-inflammatory actions of vitamin D require vitamin A.

When looking at human studies, in one study, taking vitamin A antagonized the normal serum calcium response to taking a vitamin D3 supplement (a 2.3% increase in those who took just the vitamin D and 1.4% in those who took both), but the researchers did not see any effect on bone resorption nor on vitamin absorption. The subjects took 15 mg of retinyl palmitate, 2 mcg of 1,25(OH)2D3, both supplements, or a placebo. The researchers postulated that the antagonistic relationship was likely due to an interruption on intestinal calcium absorption but that further studies were necessary.

One cohort study looking at the associations of supplementing with vitamin A and D during pregnancy and infancy and the risk of developing childhood asthma did not find any associations from high doses of both vitamins, which could mean the antagonist relationship does not exist for every circumstance. For this study, the highest quintile of vitamin A intake was at or above 2,031 RAEs/day, or 2.5 times the recommended allowance for pregnant women. The cutoff for vitamin D was at or above 13.6 ug/day.

Another study found high intake of vitamin A from supplements attenuated the inverse association between serum 25(OH)D levels and overall mortality. This was likely due to how vitamin A interacted with vitamin D receptors. However, to remain a beneficial association between higher levels of 25(OH)D and lower risk of mortality, participants had to take less than or equal to 5,000 IU of preformed vitamin A.

So, to recap, taking excessively high levels of vitamin A, especially the pre-formed version found in supplements, may interfere with vitamin D.

Interactions at the Absorption Level: Fat-Soluble Vitamins

The last important potential interactions with vitamin D to discuss is at the absorption levels. Oral intake of vitamin D, whether from food or supplementation, must be absorbed in the intestines. Vitamin D falls under the category of fat-soluble vitamins and can fight for absorption and transportation with some of the other fat-soluble vitamins, namely vitamin A and vitamin E.

Based on one study, high levels of vitamin A can decrease vitamin D uptake by 30%, and medium and high levels of vitamin E lead to a reduction of vitamin D uptake by 15% and 17%, respectively. Vitamin K and vitamin D can also compete for absorption in the intestines.

Conclusion

With the importance vitamin D plays in overall health and well-being, and the relationships between the minerals and vitamins listed above and vitamin D as well as additional essential nutrients, it just demonstrates the interwoven connections of the various nutrients, with some having a much closer relationship than others.

While it may be tempting to just give up and pop a multi-vitamin/mineral to make sure you have all you need, there may be benefits at times to focusing your supplementation for your unique circumstances.

It is always best to talk with your doctor, nutritional professional, or another healthcare practitioner about your situation to see what you should do. If you do choose to supplement with vitamin D, it may be a good idea to review your status of these other nutrients and whether it is necessary to supplement with them—or take them at a different time than your vitamin D—to get the most out of your actions.