© Borgis - Postępy Nauk Medycznych 10/2016, s. 781-786
*Michał Stuss1, 2, Ewa Sewerynek1, 2
Vitamin K2 and osteoporosis – facts and myths
Witamina K2 i osteoporoza – fakty i mity
1Chair of Endocrinology, Department of Endocrine Disorders and Bone Metabolism, Medical University of Łódź
Head of Department: Professor Ewa Sewerynek, MD, PhD
2Outpatient Clinic of Osteoporosis, Military Medical Academy University Teaching Hospital – Central Veterans’ Hospital in Łódz
Head of Clinic: Professor Ewa Sewerynek, MD, PhD
W ciągu ostatnich lat algorytmy diagnostyczno-lecznicze dotyczące osteoporozy uległy istotnym zmianom, pojawiło się na rynku również wiele leków, do których część pacjentów i lekarzy podchodzi z dużą ostrożnością. W związku z łatwym dostępem do wiedzy medycznej pacjenci częściej świadomie dokonują wyboru leków i bardziej wnikliwie czytają ulotki dołączone do zakupionych w aptece preparatów. Istnieje także pewna grupa chorych, świadomie rezygnująca z zaproponowanego, skutecznego w obliczu twardych dowodów naukowych leczenia na rzecz naturalnych metod postępowania, w tym również suplementów diety. Na rynku dostępne są liczne preparaty, stanowiące połączenia witamin, mikroelementów oraz substancji pochodzenia naturalnego, których skład najczęściej został specjalnie dobrany, aby wspomagać leczenie konkretnej jednostki chorobowej. Zgodnie z prawem farmaceutycznym wypuszczenie na rynek w/w produktów nie wymaga osobnych badań, a ich właściwości lecznicze, o których zapewnia producent, nie są wystarczająco poparte dowodami naukowymi, jednakże nie stanowi to reguły. Niniejszy tekst stanowi próbę odpowiedzi na pytanie, czy suplementacja witaminy K, w tym K2, istotnie wpływa na układ kostny i chroni przed osteoporozą.
The diagnostic-therapeutic algorithms, regarding osteoporosis, have over recent years demonstrated significant changes, as well as a number of medicinal products have been launched onto the market. It should be noted that a part of patients and their doctors take a cautious approach to these new developments. Taking the advantage of the fairly easy access to medical knowledge, patients are more and more aware of drug selection, while also reading with growing attention the leaflets, attached to medical products, sold at pharmacies and chemist’s shops. There is also a certain group of patients, consciously giving up the proposed lines of therapy, the efficacy of which is confirmed by relevant scientific evidence. These patients replace doctor’s therapy by natural methods, including diet supplementation. The market offers numerous agents which combine vitamins, microelements and various substances of the natural origin the composition of which is most often selected to support therapy of specific medical condition. Following the Pharmaceutical Law, the launching of the above-mentioned products onto the market does not require any separate studies and the medical properties of these products, assured in advertisements by their manufacturers, are not sufficiently supported by scientific evidence, however, it is not a rule in itself. This text has been set out to answer the question whether supplementation with vitamin K, including K2, significantly influences the bone tissue, providing protection against osteoporosis.
The term “Vitamin K” is referred to a group of compounds soluble in fats, called naphthoquinones. In its natural form, there are two types of vitamin K: K1 (phylloquinone) and K2 (menaquinone-n or MK-n). The particular forms of MK consist of 2-methyl-1,4-naphthoquinone, connected with a phytyl group (phylloquinone) and with a prenyl group of varying length (1).
Vitamin K1 is of plant origin and is a dominating form of vitamin K in daily diet. Green vegetables and some fruits, e.g., kiwi fruit, green grapes and avocado. Vitamin K2, i.e., n-menaquinone, is, in fact, a group of compounds, marked with numbers, corresponding to the length of the lateral chain (difarnesyl group and other isoprene groups). Compounds from the vitamin K2 group can, in the majority of cases, be synthesised by bacteria. Menatetrenone (MK-4) is an exception here. The type of menaquinone depends on the bacteria, participating in its synthesis. Vitamin K2-containing foodstuffs include: liver, eggs, butter, milk, cheeses and some vegetables. Natto is among the richest sources of vitamin K2 (mainly menaquinone-7). It is a product from fermented soybeans, which contains 1100 μg of vit. K/100g (2). Other compounds from the vitamin K2 group, such as, for example, MK-10 and MK-13, are produced by intestinal bacteria but their biological activity and digestibility are much lower. The supplements, available on the market, contain mainly phylloquinone, MK-4 or MK-7.
The reference dietary intake (RDI) is 65 μg/day for men and 55 μg/day for women (also pregnant and breast-feeding) (3). The above-mentioned RDI values are maintained within the range from 5 up to 65 μg/day, depending on gender and age and they apply only to phylloquinone (vitamin K1). American recommendations propose a slightly higher supplementation of phylloquinone (4), i.e., 120 μg/day for men and 90 μg/day for women. Now, there are no data in the literature, concerning the maximal, safe doses of vitamin K and of RDI for vitamin K2. In the majority of interventional studies, the applied daily supplementation considerably exceeded RDI (10 mg/day with vitamin K1 and 45 mg/day with vitamin K2-MK-4) and no serious adverse effects were noted. Therefore, it seems that the doses, used in the majority of available supplements, are safe (5-7).
The deficit of vitamin K is, as a rule, defined as bleeding, induced by the lack of activation of blood coagulation proteins, what is often assessed by undercarboxylated prothrombin concentration which increases proportionally to vitamin K deficit. The symptomatic deficit of vitamin K is rare and mostly associated with severe liver and pancreas disease, digestion and/or absorption disorders, alcoholism, cystic fibrosis or with chronic malnutrition (8). One should also remember about the drugs which may affect vitamin K absorption and metabolism, including phenytoin, cephalosporins, cholestyramine and high doses of vitamin E (9).
The subclinical deficit of vitamin K is more often observed in clinical practice than its clinically overt form and is most often biochemically defined as a low result of serum vitamin K concentration assay (the standard acc. to various sources: 0.5-2.5 nM; 0.2-3.2 ng/mL) or a high level of undercarboxylated osteocalcin) (≥ 4.0 ng/mL) (10-12).
Vitamin K effects on the osseous system
Vitamin K plays the role of a co-factor for the gamma-glutamyl carboxylase (GGK) enzyme, localised at the endoplasmic reticulum. The proteins, which undergo vitamin K-dependent carboxylation, are called Gla proteins, demonstrate abilities to bind calcium ions and are present in the extracellular fluid, as well as in systemic fluids (13).
Vitamin K deficits result in reducing fraction of carboxylated Gla proteins, what translates into lower activity of the processes for which they are responsible; it may increase the risk of osteoporosis or enhance its course. It has been proven that vitamin K affects carboxylation of the following proteins present in the osseous tissue and in the cartilage: osteocalcin, matrix Gla protein (MGP) Gla-rich protein (GRP), S protein and gas 6 (11, 14). Osteocalcin is produced by osteoblasts in the course of bone mineralisation, being a local inhibitor for the process, thus protecting the tissue against excessive calcification. It has high affinity to hydroxyapatite calcium and its presence is thus most often confirmed in the extracellular matrix of the osseous tissue, while its much lower concentrations are found in blood serum (15). Osteocalcin concentration assays are used to evaluate the bone formation process intensity (as bone formation marker) but a hormonal role is also assigned to the above-mentioned protein (16-19). Therefore, vitamin K plays a significant role in the process of bone formation, especially in bone tissue mineralisation. Moreover, vitamin K2 may also act via other, GGK-unrelated mechanisms (10). There is also some evidence that vitamin K2-menaquinone (MK-7) may inhibit bone resorption, as well as osteoclastogenesis, while stimulating the bone formation process in result of induced osteoblastogenesis. It has also been demonstrated that menaquinone may play the role of a regulator in the transcription processes of genes responsible for bone metabolism (mainly bone formation), via the receptors for steroids and xenobiotics (20). It appears from other studies that OC may play some role also in the interactions between osteoclasts and osteoblasts and thus control the process of bone resorption (21, 22).
The presence of MGP is found in many systemic tissues and, similarly as in case of OC, its higher activity is observed in bones. MGP is responsible for calcium mobilisation in the osseous system. It also prevents precipitation of calcium ions in blood vessels, as well as exerts prophylactic effects against calcification of soft tissues (23). The role of the other mentioned Gla proteins has not yet been enough understood.
Does vitamin K protect against osteoporosis?
As it has already been mentioned, there is a strong evidence for the beneficial role of vitamin K in bone metabolism control, what may also be associated with the prophylactics of osteoporosis. At present, the synergistic effects of many vitamins and minerals are analysed, many of which may improve the motor system, including, among others, magnesium, calcium, vitamin K and vitamin D (24-26). It has been demonstrated that a combined supplementation of vitamin K and vitamin D brings better therapeutic effects than a separate use of each of them, while their combination may stimulate the bone formation process.
Vitamin K and bone mineral density
In clinical studies, evaluating bone mineral density (BMD), the beneficial therapeutic effects of the supplementation with vitamin K has often been demonstrated. However, data from observational studies are not entirely in line with one another, regarding the issue of the above-mentioned correlations (27-30). In two studies on the Japanese population, there was a significant relationship between the high intake of Natto, rich in vitamin K1 and MK-7, and high BMD values (31, 32). In another study on an analogous population, the authors demonstrated a positive correlation between low concentrations of vitamin K1 and K2 in serum and low BMD (33).
In one of the metanalyses (5), based in their majority on randomised clinical studies, carried out on the population of healthy subjects and the population of patients with osteoporosis, the authors demonstrated a significant correlation between a high intake of vitamin K and BMD increase within the lumbar spine. In that case, the relationship between the administered therapy and hip BMD was insignificant. It should also be mentioned that, out of the 17 clinical studies, analysed by the above-mentioned group, vitamin K2 was used in 10, while MK-7 only in 2. Moreover, in a group, receiving vitamin K1 only, the described beneficial therapeutic effect was not found (5). In one of randomised, double-blinded clinical studies, carried out with participation of 244 Danish post-menopausal women (34), after 3 years of supplementation with 180 μg of MK-7, a statistically significant increase of BMD was observed in the femoral neck (34).
In the Postmenopausal Health Study II (PHSII), healthy female patients after menopause were enrolled to a one-year observation. All of them consumed milk and yoghurts, enriched with calcium, vitamin D and vitamin MK-7 (100 μg/day) and were educated in healthy life-style, what resulted in a significantly higher BMD increase in the lumbar spine vs. the control group (with no vitamin supplementation nor education) (35). In turn, in another study on the Norwegian population, the expected BMD increase within the proximal femur or in the lumbar spine was not demonstrated despite a relatively big dose of MK-7 supplement (360 μg/day), however, that observation had been carried out for merely 12 months (36).
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