Review Open Heart: first published as 10.1136/openhrt-2015-000300 on 6 October 2015. Downloaded from The health benefits of vitamin K James J DiNicolantonio,1 Jaikrit Bhutani,2 James H O’Keefe1 To cite: DiNicolantonio JJ, ABSTRACT percentage of undercarboxylated osteocalcin ’ Bhutani J, O Keefe JH. The Vitamin K has important functions within the body, indicates poor vitamin K status, this value health benefits of vitamin K. some of which are still being discovered. Research has Open Heart 2015;2:e000300. can also vary based on recent vitamin K shown that vitamin K is an anticalcification, anticancer, 214 doi:10.1136/openhrt-2015- intake and supplementation and may not bone-forming and insulin-sensitising molecule. Recent 000300 indicate chronic vitamin K status. Moreover, data indicate that subclinical vitamin K deficiency is not a normal carboxylated MGP protein in the uncommon. Additionally, vitamin K antagonists such as warfarin may cause detrimental side effects, which serum may not necessarily indicate a normal Received 1 June 2015 may partly be blunted through vitamin K vitamin K status, as carboxylated MGP in the Revised 27 August 2015 serum could be normal, but suboptimal in Accepted 18 September 2015 supplementation. the arteries (where vitamin K2 is needed to prevent vascular calcification.) INTRODUCTION Vitamin K is a fat-soluble vitamin, important VITAMIN K AND BONE HEALTH for the function of numerous proteins within Osteoporosis is a leading contributor of frac- the body, such as the coagulation factors (II, tures worldwide, causing more than 8.9 VII, IX, X and protein C and protein S), million fractures annually.15 Moreover, osteocalcin (a bone-forming protein) and Osteoporosis affects an estimated 200 million matrix-Gla protein (MGP) (an anticalcifica- women worldwide (approximately 1/10th of – tion protein), to name a few.1 3 Vitamin K women aged 60, 1/5th of women aged 70, exists naturally as vitamin K1 (phylloquin- 2/5ths of women aged 80, and 2/3rds of 15 one) and vitamin K2 (menaquinone, MK-4 women aged 90). One in 3 women and 1 2–5 through MK-10). Vitamin K1 is mainly in 5 men over 50 will experience an osteo- porotic fracture.15 Additionally, 61% of all found in green leafy vegetables as well as http://openheart.bmj.com/ olive oil and soyabean oil, whereas vitamin osteoporotic fractures occur in women.15 It K2 (menaquinone) is found in small has been predicted that the incidence of hip amounts in chicken, butter, egg yolks, cheese fracture is expected to increase by 310% in and fermented soyabeans (better known as men and 240% in women by 2050; thus, the – natto).269 economic toll of osteoporosis is expected to fi 15 Vitamin K1 and vitamin K2 are required for signi cantly increase. Indeed, it has been the γ-glutamyl carboxylation of all vitamin estimated that there is a 40% lifetime risk for K-dependent proteins.2 Despite the fact that fractures affecting the hip, forearm and ver- mammalian bacterial intestinal flora are able tebrae (similar to the risk for cardiovascular on September 30, 2021 by guest. Protected copyright. 15 to produce vitamin K2, the amount produced disease), with nearly 75% of these types of is thought to be negligible.2 The adequate fractures occurring in patients aged 65 years intake (AI) for vitamin K has been proposed age and above.15 16 Osteoporosis has been to be 90 µg/day for women and 120 µg/day shown to account for more days spent in the for men.210However, it has been speculated hospital than diabetes, heart attacks or breast that the AI for vitamin K (90–120 µg/day) is cancer.15 It is also a major cause of disability, not sufficient to induce complete carboxyl- which has been shown to be greater than ation of all vitamin K-dependent that caused by cancer (except lung cancer) 1 Mid America Heart Institute proteins.21112 and comparable to or greater than disability at Saint Luke’s Hospital, Kansas City, Missouri, USA from rheumatoid arthritis, asthma and high 15 2Pt. BD Sharma Post blood pressure related heart disease. The Graduate Institute of Medical VITAMIN K DEFICIENCY overall mortality within the first 12 months Sciences, Rohtak, Haryana, The measurement and treatment of vitamin after a hip fracture is approximately 20%, India Kdeficiency based on blood tests is not being higher in men than women.15 – Correspondence to perfect. Plasma phylloquinone concentra- Moreover, men make up 20 25% of all hip 15 Dr James J DiNicolantonio; tions fluctuate based on recent dietary fractures, and have an estimated 30% life- [email protected] intakes.213Despite the fact that a high time risk of experiencing an osteoporotic DiNicolantonio JJ, Bhutani J, O’Keefe JH. Open Heart 2015;2:e000300. doi:10.1136/openhrt-2015-000300 1 Open Heart Open Heart: first published as 10.1136/openhrt-2015-000300 on 6 October 2015. Downloaded from fracture when over 50, similar to the lifetime risk of fracture, as there is a lack of evidence. The USPSTF also developing prostate cancer.15 Fragility fractures are the states that “Daily supplementation with ≤400 IU of primary cause of hospitalisation and/or death for US vitamin D3 and ≤1000 mg of calcium has no net benefit adults ≥age 65 and above.15 Furthermore, 44% of for the primary prevention of fractures” and that nursing home admissions are due to fractures.15 It is “Evidence is lacking regarding the benefit of daily sup- obvious that osteoporosis is extremely common and this plementation with >400 IU of vitamin D3 and >1000 mg condition leads to disability, costs and even death. Thus, of calcium for the primary prevention of fractures in preventing and treating this disease is of utmost import- postmenopausal women, and the balance of benefits ance. However, the recently updated USA Preventive and harms cannot be determined.”17 Thus, what else Services Task Force (USPSTF) has recently stated that can a clinician prescribe to help to prevent osteoporosis there is insufficient evidence that calcium and vitamin D and its consequences? A broad amount of data seems to prevent a fracture in premenopausal women or in men indicate substantial potential for supplementary vitamin who have not experienced a fracture and now recom- K. However, currently few guidelines recommend mends against daily supplementation with 400 IU or less vitamin K therapy for prevention or treatment of of vitamin D3 and 1000 mg or less of calcium for the osteoporosis. primary prevention of fractures in non-institutionalised Vitamin K1 (5 mg daily) given to 440 postmenopausal postmenopausal women. Thus, unless you are an institu- women with osteopenia for 2 years in a randomised, tionalised postmenopausal woman or you have already placebo-controlled, double-blind trial caused a greater experienced a fracture, the USPSTF does not recom- than 50% reduction in clinical fractures (9 vs 20, mend calcium and vitamin D for preventing a first-time p=0.04) versus placebo, despite the fact that there was no improvement in bone mineral density.18 Moreover, there was a 75% reduction in cancer incidence with fi vitamin K1 (3 vs 12, p=0.02). The bene t of vitamin K Box 1 The health benefits of vitamin K (box 1) on bone is thought to be unrelated to increasing BMD 19 Bone health but rather increasing bone strength. A recent May help to prevent fractures due to osteopenia and osteopor- meta-analysis has shown that vitamin K2 (45 mg/day) sig- osis18–20 nificantly reduces hip (77% reduction), vertebral (60% Trial evidence reduction) and all non-vertebral fractures (81% reduc- 20 Vitamin K1 (5 mg daily) given to 440 postmenopausal women tion). Whether the results of vitamin K2 at a dose of with osteopenia for 2 years in a randomised, placebo-controlled, 45 mg can be translated to over the counter doses of double-blind trial caused a greater than 50% reduction in clinical – vitamin K1 (such as 1 5 mg) is still a matter of debate, fractures (9 vs 20, p=0.04) versus placebo. but vitamin K on its own has already been shown to 1 http://openheart.bmj.com/ A recent meta-analysis has shown that vitamin K2 (45 mg/day) reduce fractures and cancer in a clinical trial, although significantly reduces hip (77% reduction), vertebral (60% reduc- more data are needed to confirm these benefits. tion) and all non-vertebral fractures (81% reduction).20 Cancer (especially liver cancer) May help to prevent liver cancer and death in patients with liver cirrhosis and hepatocellular carcinoma (HCC)54–61 VITAMIN K AND VASCULAR CALCIFICATIONS Trial evidence Coronary artery calcium (CAC) has been shown to have 3 Five randomised controlled trials tested vitamin K2 (45 or 90 mg/ increasing prevalence as kidney function declines. day) in patients with HCC. Vitamin K2 significantly improved Indeed, CAC prevalence has been reported in 13% of 74 1-year overall survival, (RR=1.03, 95% CI 1.00 to 1.05, p=0.03) ‘healthy’ patients without renal disease,21 40% of on September 30, 2021 by guest. Protected copyright. Vascular calcifications patients with chronic kidney disease patients not on dia- May help to prevent vascular calcifications (especially in patients 21 22 52675 lysis, 57% of patients starting dialysis and 83% of on warfarin) 23 Trial evidence patients on long-term dialysis. Diets lacking vitamin K can precipitate the development of vitamin K deficiency Significantly delayed the development of coronary artery calcium in as little as 7 days.24 Additionally, subclinical vitamin K in a 3-year, double-blind, randomised controlled trial of 452 fi patients. de ciency is not uncommon, especially in patients 25 In a 3-year, double-blind, placebo-controlled trial, vitamin K1 receiving warfarin.