Most people know that adequate calcium intake is essential for healthy bone formation. Since calcium is the primary mineral found in bones, it has been added to many foods in order to ensure our population does not have a deficiency. For decades marketing campaigns by dairy farmers and family doctors have been advocating high levels of calcium in order to build bones and prevent osteoporosis. In 2011, the benefits of calcium were called into question when a research study found that calcium supplementation was linked to a higher risk of heart attacks and strokes.1 This news sent shock-waves through the medical and scientific communities as they searched to make sense of this evidence. Could the mineral that was thought to be so vital in preventing weak bones be contributing to cardiovascular disease?
The answer is no. Calcium and progressive resistance training are still the most important factor in bone health. However, to make sense of this new connection with heart health we need to look beyond just calcium and explore two other key factors in the regulation of calcium levels. Starting with the basics, calcium is the primary mineral that is part of the “mineral-protein matrix” that makes up bones. Vitamin D and vitamin K are the biological signals that direct calcium from the digestive tract where it is absorbed and then directed into the bones.2 With insufficient (or deficient) levels of these vitamins, calcium is poorly absorbed and can be inappropriately stored in areas such as blood vessels. One theory behind the calcium and heart disease connection suggests since calcium was just supplemented by itself in the study, without considering vitamin D and K, excess amounts of calcium where stored in the wrong areas (i.e. the blood vessels). This can lead to the hardening of arteries (calcification) and possibly increase the risk of heart attacks and strokes. So what is it about vitamin D and K that optimizes calcium usage by the body?
Vitamin D and Bone health
The 2 ways the body obtains vitamin D, is either through a conversion process in the skin or absorption through the digestive system. However, once produced or absorbed, it still must undergo further conversion by the liver and kidneys before it reaches the fully activated form, 1 alpha, 25-dihydroxyvitamin D3. 2 The effect of vitamin D was first connected to calcium regulation and bone formation and the active form is referred to as calcitrol, but we now know that vitamin D has multiple actions through out the body, including the control of genes.2 In regards to bone health, adequate vitamin D levels are required to absorb calcium from the intestinal tract. When calcium levels are deficient (below 80nmol/L or 32ng/mL) then absorption can fall from 30-40% to 10-15%.3 This means that even though a person is supplementing with the recommended 1000mg/day of calcium then they may only be getting 100mg that is actually absorbed. There is strong evidence supporting the supplementation of vitamin D and calcium together to reduce the risk of fractures.2,4 The synergist action is most likely responsible for this observed benefit. However it is important to reiterate that even though vitamin D is given together with calcium in these studies, the key end point must be that vitamin D levels reached levels greater than 80nmol/L since this is the level that has been shown to optimally absorb calcium.3 This underscores the importance of measuring a person’s plasma levels in order to determine what dose is required to replete their vitamin D level. The more deficient a person is, the greater the dose that will be required to bring their levels back up. The other benefit of vitamin D is that it has been show to improve muscle pain, posture and balance which are all key in preventing falls which can lead to a fracture.3,5
Vitamin K and Bone Health
While the connection between vitamin D and calcium levels for bone health is well known, the relationship of vitamin K and calcium is relatively new. Vitamin K is most well known for its effect on the blood coagulation system. It is a key factor in making the blood more “sticky” in order to prevent excess bleeding. It most well known as the target for the blood thinning drug called Coumadin (Warfarin®). Vitamin K is actually a family of molecules with a number of unique forms. Vitamin K1 (phylloquinone) is found in plants while vitamin K2 (menaquinone) is formed by bacteria after fermentation. Vitamin K2 is further divided into MK-4 and MK-7 forms.2,6 The majority of vitamin K in the human diet comes from dark green leafy plants, which is in the K1 form. Human gut bacteria can also produce the K2 form but these amounts are poorly absorbed.2 Other sources of K2 include animal products, cheeses and fermented foods such as natto (a Japanese food made from fermented soy beans).2,6
One of the main biological roles of vitamin K is that it is responsible for a process called carboxylation. This process is essential for proteins to become activated. In relation to bone health, vitamin K regulates osteocalcin, a protein important for bone mineralization.7,8 Osteocalcin is the 2nd most abundant protein in bone, after collagen. Its role is to bind calcium in the bone structure or “lattice.” 7,8 A simple way of looking at osteocalcin is that it acts in a similar way to a sticky glue so that calcium can attached to the mineral-protein matrix. When a person has insufficient levels of carboxylation, which is governed by vitamin K, then the calcium binding capacity of osteocalcin is greatly reduced.8 Studies have also shown that vitamin K supplementation can also improve osteoporosis and reduce fracture rates.10 A two-year long Japanese study found that vitamin K2 supplements reduced spine fractures by 52% compared to those that did not get the treatment of 45mg of MK-4 per day.9 Although this dose is relatively high, lower dosages have also been proven to provide substantial benefits by also up regulating carboxylation.
The other essential role of vitamin K in relation to calcium balance is that it can prevent soft tissue calcification. Vitamin K controls a protein called Matrix GLA.7 This protein is responsible for protecting soft tissues like blood vessel walls and preventing excess calcium from becoming deposited. It acts as a calcium mop in areas of the body that should not be hardened or calcified. The ability of vitamin K to not only increase calcium usage in bone formation but also prevent the calcification of arteries clearly highlights its importance in both bone and cardiovascular health. In light of the study mentioned at the beginning of this article linking calcium usage to cardiovascular health, vitamin K seems to be the neglected factor in protecting the hardening of arteries, which can lead to an increased risk of heart attacks and strokes.
A note about forms and dosage of vitamin K
Recently there has been some confusion about whether the MK-4 or MK-7 forms of vitamin K2 are most effective at lower doses. MK-4 is considered the “active” form of vitamin K2 and is converted from MK-7 slowly. The vast majority of the studies showing vitamin K2 reducing fracture risk have only used the MK-4 form at 25-90mg daily.10 The advantage of MK-7 is that it may be more bioavailable at lower doses found in Canadian vitamin K supplements (100mcg is the highest level allowed by health Canada) since it lasts longer in the bloodstream. Finally, a comparison study showed that amounts of MK-4 lower than 420 mcg did not result in detectable levels in the bloodstream at 0, 2 and 4 hours and beyond, while amounts of MK-7 as low as 60 mcg resulted in measurable levels in the blood, peaking at 6 hours. 11 However, no measurements were taken within the first two hours. Other studies have shown that doses of MK-4 of at least 500-1500 mcg are required for the carboxylation of osteocalcin, while doses of 45-90 mcg of MK-7 accomplish this task.8,11 It is also thought that MK-4 has other specific functions that are not related to just to osteolcalcin formation and carboxylation, such as reducing inflammation and protecting the liver.8 In light of this most recent research and the balance of the existing evidence, a combination of both MK-4 and MK-7 may be the most effective approach in order to harness the benefits of both forms at low doses.
In summary, the uncertainty and conflicting research surrounding calcium supplementation leading to artery hardening may be explained by a lack of vitamins D and K, which are essential for normal calcium usage in the bone and blood vessels. A promising area further supporting the concurrent use of vitamin D and K is the emerging evidence suggesting they are synergistic and complementary when used together, especially in osteoporosis.12 As part of a bone building program, vitamin D and K supplementation should always accompany calcium use in order increase bone formation, maximize absorption, and prevent the deposition of calcium in soft tissues.
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1) Bolland et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691
2) 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 Sep;15(3):199-222.
3) Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep. 2008 Apr;10(2):110-7.
4) Abrahamsen et al. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010 Jan 12;340:b5463.
5) Dhesi et al. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing. 2004 Nov;33(6):589-95.
6) Booth SL Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009;29:89-110.
7) Oldenburg et al. The vitamin K cycle. Vitam Horm. 2008;78:35-62.
8) Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm. 2008;78:131-56.
9) Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. 2000 Mar;15(3):515-21
10) Iwamoto J, Sato Y, Takeda T, Matsumoto H. High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature. Nutr Res. 2009 Apr;29(4):221-8.
11) Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. 2012 Nov 12;11:93.
12) Je 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 Aug;26(8):1093-8.