Menaquinone-4 (Vitamin K2)

Vitamin K? therapy for postmenopausal osteoporosis

Vitamin K may play an important role in the prevention of fractures in postmenopausal women with osteoporosis. Menatetrenone is the brand name of a synthetic vitamin K2 that is chemically identical to menaquinone-4. The present review study aimed to clarify the effect of menatetrenone on the skeleton in postmenopausal women with osteoporosis, by reviewing the results of randomized controlled trials (RCTs) in the literature. RCTs that investigated the effect of menatetrenone on bone mineral density (BMD), measured by dual-energy X-ray absorptiometry and fracture incidence in postmenopausal women with osteoporosis, were identified by a PubMed search for literature published in English. Eight studies met the criteria for RCTs. Small RCTs showed that menatetrenone monotherapy decreased serum undercarboxylated osteocalcin (ucOC) concentrations, modestly increased lumbar spine BMD, and reduced the incidence of fractures (mainly vertebral fracture), and that combined alendronate and menatetrenone therapy enhanced the decrease in serum ucOC concentrations and further increased femoral neck BMD. This review of the literature revealed positive evidence for the effects of menatetrenone monotherapy on fracture incidence in postmenopausal women with osteoporosis. Further studies are required to clarify the efficacy of menatetrenone in combination with bisphosphonates against fractures in postmenopausal women with osteoporosis.

Retracted Note: Effects of Vitamin K2 on Osteoporosis

The article entitled "Effects of Vitamin K2 on Osteoporosis, published in Curr Pharm Des 2004; 10(21): 2557-76, by Iwamoto J, Takeda T and Sato Y." has been retracted by the Editorial office of the journal Current Pharmaceutical Design, as the text, data and some figures used/referred in this review article are from sources which have been retracted or under investigation on the basis of data fabrication and falsification, authorship misconduct, duplicate publication, unethical research practices, text recycling/self-plagiarism, and unresolved concerns about data integrity and research conduct. The authors were informed of this complaint and were requested to give justification on the matter in their defense. However, no reply was received from their side in this regard. Some sources that have been retracted are as follows: 1. Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 2003; 44: 751-6. Available at: https://eymj.org/DOIx.php?id=10.3349/ymj.2019.60.1.115. 2. Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998; 23: 291-6. Available at: https://www.sciencedirect.com/science/article/pii/S8756328298001082. 3. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. Bone 2002; 31: 114-8. Available at: https://pubmed.ncbi.nlm.nih.gov/ 12110423/. Bentham Science apologizes to its readers for any inconvenience this may have caused. The Bentham Editorial Policy on Article Retraction can be found at https://benthamscience.com/editorial-policies-main.php. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

MK-7 and Its Effects on Bone Quality and Strength

Vitamin K acts as a cofactor and is required for post-translational γ-carboxylation of vitamin K-dependent proteins (VKDP). The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. In this review, we comprehensively discuss the various properties of MK-7.

Vitamin K

Vitamin K is naturally found in human milk. Maternal vitamin K supplementation is typically not needed to meet the 75 mcg per day recommended adequate dietary intake. However, maternal supplementation with 5 mg daily increases milk vitamin K levels and can improve vitamin K status in breastfed infants who also receive intramuscular vitamin K shortly after birth. Although exclusively breastfed infants are at higher risk of vitamin K deficiency bleeding (VKDB), a condition that can involve intracranial hemorrhage, sometimes leading to infant death, maternal vitamin K supplementation alone is not an adequate or safe substitute for vitamin K administered directly to the newborn after birth to prevent VKDB.[1-3]

Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis

Low concentrations of serum vitamin K accompany high concentrations of undercarboxylated osteocalcin (ucOC) and osteoporotic fractures. Although vitamin K2 (MK-4) is approved as a therapeutic agent for the treatment of osteoporosis in some countries, the dose-response is unknown. The objective of this study was to assess the improvement in carboxylation of osteocalcin (OC) in response to escalating doses of MK-4 supplementation. A nine-week, open-labeled, prospective cohort study was conducted in 29 postmenopausal women who suffered hip or vertebral compression fractures. Participants took low-dose MK-4 (0.5 mg) for 3 weeks (until the second visit), then medium-dose MK-4 (5 mg) for 3 weeks (until the third visit), then high-dose MK-4 (45 mg) for 3 weeks. The mean ± SD age of the participants was 69 ± 9 years. MK-4 dose (p < 0.0001), but neither age nor other relevant medications (e.g. bisphosphonates) correlated with improvement in %ucOC. As compared to baseline concentrations (geometric mean ± SD) of 16.8 ± 2.4, 0.5 mg supplementation halved %ucOC to 8.7 ± 2.2 (p < 0.0001) and the 5-mg dose halved %ucOC again (to 3.9 ± 2.2; p = 0.0002 compared to 0.5-mg dose). However, compared to 5 mg/day, there was no additional benefit of 45 mg/day (%ucOC 4.6; p = NS vs. 5-mg dose). MK-4 supplementation resulted in borderline increases in γ-carboxylated osteocalcin (glaOC; p = 0.07). There were no major side effects of MK-4 supplementation. In postmenopausal women with osteoporotic fractures, supplementation with either 5 or 45 mg/day of MK-4 reduces ucOC to concentrations typical of healthy, pre-menopausal women.