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

Int J Vitam Nutr Res. 2020 Jan;90(1-2):42-48. doi: 10.1024/0300-9831/a000554. Epub 2019 Feb 28.


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.

Keywords: Carboxylation of osteocalcin; Dose-finding; Postmenopausal osteoporosis; Vitamin K2 (MK-4); hip or vertebral compression fractures.

MeSH terms

  • Female
  • Fractures, Compression*
  • Humans
  • Osteocalcin / blood*
  • Osteocalcin / chemistry
  • Osteoporosis*
  • Prospective Studies
  • Spinal Fractures*
  • Vitamin K 2 / administration & dosage
  • Vitamin K 2 / analogs & derivatives*
  • Vitamin K 2 / metabolism*
  • Vitamin K 2 / therapeutic use
  • Vitamins / administration & dosage
  • Vitamins / metabolism


  • Vitamins
  • Osteocalcin
  • Vitamin K 2
  • menatetrenone