The biological responses of vitamin K2: A comprehensive review

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TL;DR

This comprehensive review examines the biological responses of vitamin K2 (menaquinones) across multiple organ systems, highlighting its roles beyond blood coagulation in osteogenesis, cardiovascular protection, neuroprotection, and hepatoprotection. The evidence suggests vitamin K2 activates vitamin K-dependent proteins (VKDPs) such as osteocalcin, matrix Gla protein, and Gas6 to regulate calcium homeostasis and inhibit pathological calcification. While preclinical and some clinical data support therapeutic potential for osteoporosis, cardiovascular calcification, and neurodegenerative diseases, the authors note inconsistent and conflicting results that warrant larger, longer-duration trials.

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**Background:** Vitamin K2 (VitK2) comprises menaquinones (MK-n) with varying isoprene side chains, predominantly MK-4, MK-7, and MK-9. MK-4 has the highest bioactivity, while MK-7 has higher bioavailability and longer half-life. VitK2 acts as a cofactor for γ-glutamyl carboxylase (GGCX), converting glutamate residues to γ-carboxyglutamate (Gla) on vitamin K-dependent proteins (VKDPs), enabling calcium binding. This review critically examines biological responses of VitK2 across multiple systems, aiming to clarify mechanistic pathways and therapeutic potential.

**Methods:** The authors conducted a literature search across PubMed, Scopus, ISI Web of Science, and CNKI from inception to 30 November 2021, updated 30 June 2022, without language restrictions. Search terms included 'vitamin K2' or 'menaquinone' combined with 'health' or 'diseases'. Original research articles (experimental, observational, clinical trials) were included. No formal quality assessment or systematic review with meta-analysis was performed due to the predominance of animal studies and case reports.

**Key Results:** - **Osteogenesis and bone homeostasis:** VitK2 activates osteocalcin (OC) and matrix Gla protein (MGP) via the VitK redox cycle. VitK2 stimulates osteoblastogenesis and inhibits osteoclastogenesis through downregulation of NF-κB activation, upregulation of osteoprotegerin (OPG), and reduction of RANKL expression. In postmenopausal women, MK-4 (45 mg/day for 3 years) improved hip bone geometry and bone mineral content (BMC) but not DXA-BMD (Knapen et al., 2007). MK-7 (100 μg/day) with calcium and vitamin D3 significantly protected lumbar spine BMD (Kanellakis et al., 2012). However, a 3-year RCT with MK-7 (375 μg/day) in 142 postmenopausal women with osteopenia showed no improvement in BMD, bone turnover, or bone microstructure (Rønn et al., 2021). A meta-analysis of 19 RCTs (6759 participants) found VitK2 beneficial for postmenopausal osteoporosis (Huang et al., 2015), while another meta-analysis found no evidence for BMD or vertebral fracture effects but suggested reduced clinical fractures (Mott et al., 2019). - **Cardiovascular calcification:** VitK2 activates MGP, the most influential natural calcification inhibitor. The inactive circulating form dp-ucMGP is independently associated with vascular calcification and cardiovascular risk. In 564 postmenopausal women, high dietary menaquinone intake (MK-4 to MK-10) was associated with reduced coronary calcification (Beulens et al., 2009). MK-7 supplementation significantly decreased carotid-femoral pulse wave velocity and stiffness index β in healthy postmenopausal women (Knapen et al., 2015). In a 1-year trial of 26 patients, MK-4 reduced brachial-ankle pulse wave velocity only in patients with baseline VitK insufficiency, but coronary artery calcification progressed by 14% (Ikari et al., 2016). Gas6/Axl pathway activation by VitK2 inhibits VSMC apoptosis and calcification. - **Hepatoprotection:** VitK2 enhanced liver regeneration in rat models and showed cytotoxic effects on hepatocellular carcinoma (HCC) cells through multiple mechanisms including G1 cell-cycle arrest via p21 upregulation, cyclin D1 suppression via IKK/NF-κB pathway, and induction of apoptosis via caspase-8 and p53 activation. - **Mitochondrial energy:** VitK2 rescued mitochondrial dysfunction due to Pink1 deficiency in D. melanogaster (Vos et al., 2012), but in human CoQ10-deficient cell lines, VitK2 did not restore electron flow or ATP synthesis (Cerqua et al., 2019). - **Neuroprotection:** MK-4 accounts for >98% of total VitK content in rat brain. VitK2 protected PC12 cells against Aβ(1-42)-induced apoptosis via p38 MAPK pathway inactivation (Hadipour et al., 2020). Long-term VitK depletion correlated with cognitive impairment in aged rats (20 months) (Carrié et al., 2011). Increased dietary VitK intake was associated with better cognition in geriatric patients (Chouet et al., 2015) and fewer subjective memory complaints (Soutif-Veillon et al., 2016). - **COVID-19:** In 100 COVID-19 patients and 50 controls, worse disease severity was independently associated with both VitK and vitamin D deficiency (Desai et al., 2021). Elevated dp-ucMGP was associated with mortality in 138 COVID-19 patients after sex- and age-adjustment (Linneberg et al., 2021). Pneumonia-induced extrahepatic VitK depletion may accelerate elastic fiber degradation and thrombosis via impaired MGP and Protein S activation (Dofferhoff et al., 2021).

**Clinical Implications:** The review supports VitK2's potential in osteoporosis prevention, cardiovascular calcification inhibition, and neuroprotection, primarily through VKDP activation and calcium homeostasis regulation. However, conflicting results across studies—particularly regarding bone density outcomes and cardiovascular benefits—highlight the need for larger, longer-duration, well-designed randomized controlled trials. The authors suggest monitoring and supplementation of VitK2 (recommended adequate daily doses: 90 μg for females >19 years, 120 μg for males >19 years) could be considered as part of COVID-19 treatment strategies, though more robust evidence is needed.