A Critical Perspective on Vitamin D and Calcium Supplementation
Vitamin D and calcium supplementation are two heavily touted and prescribed supplements with ample epidemiological evidence to back their efficacy in reducing bone fracture and cardiovascular disease (CVD) risk (1,2, 3,4,5). Furthermore, deficiencies in either calcium or vitamin D are associated with a host of pathological conditions including: osteoporosis, neoplastic colonic growth, rickets, and dental caries (6). In light of recent research implicating calcium supplementation in increased cardiovascular risk and recent work on the role of nutrient synergy and the interaction of vitamin D and vitamin K (7) by Chris Masterjohn, today we are going to talk about the dangers of high vitamin D and calcium supplementation in regards to CVD and soft tissue calcification.
In the last post we explored the calcium homeostasis system in regards to bone health. There are important concepts to review from that post.
- Calcium is critical in cell signaling, enzymatic functions and bone health
- The levels of calcium (Ca2+) in our blood are tightly regulated through a highly complex feedback system.
- Vitamin D plays a role in regulating calcium levels by increasing intestinal calcium absorption.
Before we move on, there is one important concept we need to cover. Blood calcium is tightly regulated for numerous reasons; however, one of the main reasons is that due to the pH level of human blood and with its other constituents, calcium is on the verge of precipitation. Slight elevations in blood calcium above normal will result in the precipitation of calcium, an extremely dangerous condition. Therefore, when calcium levels begin to rise, your body begins to place it wherever it can. Although this is a vast oversimplification, I believe it gets the major point across. Now we progress onto vitamin D and calcium supplementation.
Vitamin D supplementation is ubiquitous throughout North America, especially in the Pacific Northwest where sun exposure is minimal during many months of the year, and our diets are often insufficient in terms of vitamin D. In many cases vitamin D supplementation is warranted, as low levels of vitamin D are in fact precursors of many health issues (there are too many to list). This is well-known, and a scientific fact I am not in contention with. I do believe low vitamin D levels are an issue in specific populations and are troublesome for our health. What I am discussing today is high doses of vitamin D along side high doses of calcium, a supplemental regimen a large population of people subscribe to.
Vitamin D: Too Much of a Good Thing?
For much of the last decade, large (mega) doses of vitamin D were promoted to restore normal blood levels of vitamin D and were concluded to be safe. What was overlooked in these recommendations is the danger of high levels of vitamin D supplementation specifically when coupled with calcium supplementation. To understand these dangers we must look at the nutrient synergy between vitamin D and vitamin K (we will also address vitamin A) and understand the mechanism by which excess vitamin D promotes soft tissue calcification and is exacerbated by calcium supplementation.
Vitamin D and Vitamin K are fat-soluble vitamins that have versatile homeostatic capacities at the organ, tissue, and cellular levels (8). There are several forms of vitamin K, but we are primarily concerned with vitamin K2, therefore we will regard vitamin K in this post as vitamin K2. Additionally, these two vitamins work in concert with each other along side vitamin A to ensure homeostatic regulation of calcium and phosphorous as well as promote normal bone development and maintain soft-tissue integrity. Vitamin A is critical in this process but I suggest reading Dr. Masterjohn’s work on this as I wish to focus on vitamin D and vitamin K in the current post.
Vitamin D promotes the production of matrix Gla protein (MGP) (9). MGP is critical in maintain vascular integrity as appears to be no effective alternative mechanism for calcification inhibition in the vasculature. Furthermore, as eloquently stated by Dr. Masterjohn in his post on nutrient synergy, these proteins are Vitamin K dependent, they require Vitamin K for carboxylation in order to function properly (Figure 1). Therefore, large amounts of MGP produced due to high levels of vitamin D may result in depleted vitamin K. This would prove dangerous if vitamin D levels continue to remain high as the only known inhibitor of soft tissue calcification, MGP, would remain in its inactive form, therefore increasing soft-tissue calcification (Figure 2). This mechanism was hypothesized by Masterjohn in 2007(7), and confirmed in 2008 (10). This indicates that excess vitamin D diminishes the ability of vitamin K dependent proteins to inhibit soft tissue calcification.
Figure 2. Excess Vitamin D produces large amounts of inactive MGP, reduces the “pool” of vital K, thereby reducing the body’s ability to produce active MGP and allows for soft tissue calcification.
Increasing vitamin D intake through dietary or supplemental sources increases intestinal absorption of calcium. Likewise, increasing calcium intake through supplementation or dietary sources also increases calcium absorption. Notice how I purposely mentioned absorption and not blood levels. As previously stated, calcium is highly regulated; whatever excess calcium is absorbed must either be excreted or placed somewhere “safe”. This can be observed in a 2003 study by Bischoff et al. (11). In this study the experiment groups received either 1,200 mg calcium or 1,200 mg calcium and 800 IU per day over a 12-week period. At the end of the 12 weeks, neither group observed a change in their blood calcium levels, thus, indicating the calcium was going somewhere.
Increasing the calcium load on our system is not entirely problematic in and of itself if we have a balance between vitamin D and vitamin K. However, as previously mentioned, in the presence of excess vitamin D we deplete the capacity of our vitamin K to properly “activate” MGP to inhibit soft tissue calcification (Figure 3). Now if we have increased calcium absorption through calcium supplementation, along with increased calcium absorption from vitamin D supplementation, with the concomitant “vitamin K” deficiency, we promote an environment in which excess calcium will be deposited into our vascular tissue (Figure 4). Vascular calcification is a major contributor to atherosclerosis and increases the likelihood of vascular plaque “rupture”, myocardial infarction, and valve stenosis (12).
Figure 3. Low levels of blood calcium in the presence of Vitamin K deficiency and normal Vitamin K status. In vitamin K deficiency, active MGP (aMGP) is unable to inhibit the migration of calcification into the vascular tissue. At low levels, the calcification process occurs but at a slow rate.
Figure 4. High levels of blood calcium in the presence of Vitamin K deficiency and normal Vitamin K status. In vitamin K deficiency, active MGP (aMGP) is unable to inhibit the migration of calcification into the vascular tissue. At high levels, the calcification process occurs at a much higher rate. Additionally, as vitamin D increases calcium absorption, high vitamin D not only reduces the “pool” of vitamin K, it also can promote hypercalcemia.
The molecular mechanisms support my hypothesis as to why vitamin D and calcium supplementation ought to be carefully considered and reevaluated. The next step is to examine the evidence of the research. There are quite a few epidemiological studies surrounding this issue but I want to examine a few particular ones that highlight the vitamin D and vitamin K relationship to vascular calcification.
Perhaps one of the most interesting series of studies examining the effect of lack of sufficient vitamin K are those involving Warfarin. Warfarin, also known as Coumadin, is a drug that inhibits clotting by inhibiting the recycling of oxidized vitamin K2 (Figure 5). Although a different mechanism than vitamin D toxicity, this mimics the same physiological condition as Warfarin essentially reduces the pool of vitamin K that is able to carboxylate proteins such as MGP. As previously mentioned, reducing the amount of vitamin K capable of carboxylating proteins decreases the ability to activate MGP and inhibit soft tissue calcification.
Figure 5. From “Vitamins D and K as Pleiotropic Nutrients: Clinical Importance to the Skeletal and Cardiovascular Systems and Preliminary Evidence for Synergy”
In 2005 Koos et al. examined the effect of vitamin K antagonist oral anticoagulants. In a retrospective study, Koos et al. compared the calcification in the aortic valve and coronary arteries amonst patients with long-term vitamin K antagonist anticoagulant drug therapy against those without drug therapy. Briefly, they were exploring if the mechanism explained above increased the calcification of heart valves and arteries. Here are the results from the study.
“Patients on oral anticoagulant therapy had increased coronary calcium (coronary Agatston score 1,561 ± 1,141 vs 738 ± 978, respectively; p = 0.024) and valvular calcium (valvular Agatston score 2,410 ± 1,759 vs 1,070 ± 1,085, respectively; p = 0.002) compared with patients without anticoagulation treatment. The results of our study have demonstrated that oral anticoagulation may be associated with increased valvular and coronary calcium in patients with aortic valve disease, presumably due to decreased activation of the matrix Gla protein.” (13)
Koos et al. (2005) effectively demonstrated that inhibiting vitamin K recycling creates a state in which MGP is inactivated, leading to soft tissue calcification, which in this study was vascular tissue. This study is important in that we can observe the detrimental effects on soft tissue due to inadequate vitamin K.
While the work by Koos et al. (2005) was retrospective, it was based upon a prospective study conducted in rats. In a series of rat model studies in 2000, Price et al found that Warfarin (the vitamin K antagonist) did indeed induce artery calcification in rats. Furthermore, they found that arterial calcification was accelerated when given high doses of vitamin D (14). The soft tissue calcification was not benign either, the survival of the rats injected with both vitamin D and Warfarin rapidly plummeted (Figure 6). We will discuss the gravity of the implications in the conclusion.
Figure 6. Vitamin D and Warafarin on survival rates in Price et al. study. Image from Price, PA, Faus SA, Williamson MK. Warfarin-Induced Artery Calcification Is Accelerated by Growth and Vitamin D. Arterioscler Thromb Vasc Biol. 2000;20:317-327
To prove that excess vitamin D results in depletion of vitamin K and subsequently our bodies ability to inhibit soft tissue calcification I direct you to the same paper Masterjohn covers in this article. The study by Fu et al demonstrated that when vitamin A is administered with vitamin D, we observe a decrease in ectopic calcium deposition in soft tissue, renal tissue in this study, due to modulating vitamin D’s ability to increase MGP production, thereby altering vitamin K’s ability to modulate those proteins (15). Essentially, Fu et al demonstrated that reducing vitamin K dependent proteins by modifying vitamin D’s ability to produce them, we spare vitamin K and therefore reduce soft tissue calcification.
We now have evidence that when vitamin K is unable to carboxylate MGP we observe soft tissue calcification (13). There is also a sound hypothesis and evidence indicating that excess vitamin D can result in soft tissue calcification by “depleting the vitamin K pool” (7, 15). The depletion of vitamin K is problematic in regards to soft tissue health, and diets sufficient in vitamin K appear to have beneficial effects on heart disease through the aforementioned mechanisms (16)
How is this relevant?
To contextualize the importance of this concept, let us examine a case study. A woman in her late 40’s is diagnosed with a heart condition known as atrial fibrillation. A standard course of treatment for this condition is to prescribe an anticoagulant, typically Coumadin (Warfarin) (17). The anticoagulant therapy is appropriate and by itself is not problematic; however, the woman visits her family medicine doctor and is informed that she has low vitamin D and ought to think about taking a vitamin D supplement. The woman reads about vitamin D and finds out she can take up to 10,000 IU per day in order to increase her vitamin D levels to normal levels. Additionally, she begins taking a calcium supplement as she does not not consume dairy and “knows” that middle-aged women ought to take calcium supplements to prevent osteoporosis. This woman now has a vitamin K antagonist, over production of vitamin K dependent proteins due to excess vitamin D supplementation, and is increasing her calcium intake to above normal levels. The end result is extensive arterial and valvular calcification over the course of a few years and a atrial valve replacement. Unfortunately, this story is not uncommon and occurs far more often than one would think.
Taken together, the above hypotheses, mechanisms, and evidence suggest that high doses of vitamin D supplementation alongside high doses of calcium supplementation increase the risk of soft tissue calcification and CVD. Additionally, low levels of vitamin D and calcium also have known health risks, and like every thing else in life, we must strike a balance. Therefore, one must take a critical assessment of their vitamin D, vitamin K, and calcium status before beginning a supplementation regimen. Additionally, the consumption of a well-balanced evolutionary based diet can provide adequate nutrients on both a macronutrient and micronutrient level.