Vitamin K2

Vitamin K exists in two main structural forms, phylloquinone (vitamin K1) and the menaquinones (vitamin K2), which differ in absorption rate, tissue distribution and bioavailability. ^[1] The menaquinones studied in bone and vascular health are mainly menaquinone-4 (MK-4) and menaquinone-7 (MK-7). ^{[2] [3]} MK-7 has a higher bioavailability and a longer half-life than the other vitamin K homologs, and is the only one shown to promote carboxylation of extrahepatic vitamin K-dependent proteins at a nutritional dose close to the recommended daily intake. ^[3] Vitamin K2 has been approved for the treatment of osteoporosis in Japan since 1995. ^[4] Vitamin K2 is also taken as a nutritional supplement, together with calcium, vitamin D and magnesium, to support bone health. ^{[5] [6]}

Vitamin K is the cofactor of gamma-glutamylcarboxylase, and only the carboxylated forms of vitamin K-dependent proteins are active, in the liver as well as in extrahepatic tissues. ^[1] For bone, the most relevant vitamin K-dependent proteins are osteocalcin and matrix Gla protein (MGP), and an adequate vitamin K status is required for their carboxylation. ^[7] Carboxylated osteocalcin binds hydroxyapatite, which promotes bone mineralization and bone strength. ^[8] In middle-aged and older adults, vitamin K supplementation shifts osteocalcin toward its carboxylated form without changing total osteocalcin or other bone turnover markers such as NTx, bone alkaline phosphatase and PINP. ^[9] Beyond carboxylation, MK-4 acts as a ligand of the nuclear steroid and xenobiotic receptor (SXR), and mechanistic work links vitamin K2 to osteoblast development through BMP/Smad and Wnt/beta-catenin signaling. ^{[7] [2]} In the vessel wall, carboxylated MGP is an inhibitor of arterial calcification, while its inactive form is associated with increased arterial stiffness

Bone density: in a meta-analysis of RCTs with 6,425 postmenopausal women, vitamin K2 significantly improved lumbar spine bone mineral density and lowered undercarboxylated osteocalcin. ^[8] Fractures: in the same meta-analysis, fracture incidence did not differ between vitamin K2 and control (RR=0.96, P=0.65), and a significant reduction (RR = 0.43) appeared only after one heterogeneous study was excluded. ^[8] A second meta-analysis of RCTs in postmenopausal women with osteoporosis (6853 participants, long-term follow-up) found larger percentage gains in lumbar (WMD 2.17) and forearm (WMD 1.57) bone mineral density with vitamin K2. ^[13] Combined with vitamin D, vitamin K increased total bone mineral density in a meta-analysis of RCTs including 971 subjects (pooled effect size 0.316), with a more favorable effect expected for vitamin K2. ^[14] Reviews still judge the bone efficacy data for vitamin K2 inconclusive and call for a larger, well-designed RCT with fractures as the primary endpoint. ^[6]

Safety signals disagree across meta-analyses: one found no difference in adverse reactions versus control (RR = 1.03), while another found higher adverse reaction rates with vitamin K2 (RR = 1.33) but no serious adverse events related to it. ^{[8] [13]} In the vascular calcification trials, adverse events did not differ significantly between vitamin K and control groups. ^[15] Current recommended daily intakes of vitamin K were set on coagulation requirements, and because vitamin K1, MK-4 and MK-7 have distinct bioactivities, it has been argued that their intakes should be set according to their relative activities. ^[3] In osteoporosis, calcium and vitamin D remain the core of supplementation, and vitamin K2 is framed as a possible adjunct that might improve bone quality and enhance their efficacy. ^[6] Even where vascular calcification can be reduced, it remains to be proven that this reduction in itself lowers cardiovascular risk. ^[10]