Date Published: October 14, 2008
Publisher: Public Library of Science
Author(s): Angela M Cheung, Lianne Tile, Yuna Lee, George Tomlinson, Gillian Hawker, Judy Scher, Hanxian Hu, Reinhold Vieth, Lilian Thompson, Sophie Jamal, Robert Josse, David Torgerson
Abstract: BackgroundVitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.Methods and FindingsThis single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.ConclusionsDaily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241).
Partial Text: Vitamin K is best known for its function in the blood coagulation pathway, but recent data suggest that the K vitamins play an important role in bone metabolism, perhaps at serum levels higher than those required for normal blood coagulation. Vitamin K is the essential cofactor for the carboxylation of glutamate to gamma-carboxyglutamic acid (Gla), which confers functionality to vitamin K–dependent Gla-containing proteins. Three Gla-containing bone proteins, all synthesized by osteoblasts, have been identified: osteocalcin, matrix Gla protein, and protein S. The K vitamin family has five groups: vitamins K1 (phylloquinone) and K2 (menaquinones) occur naturally in foods, whereas K3, K4, and K5 are synthetic.
Our study showed that 5 mg of vitamin K1 supplementation daily for 2–4 y did not protect against age-related decline in BMD at the lumbar spine, total hip, femoral neck, or ultradistal radius in postmenopausal women with osteopenia who were vitamin D replete. We also showed that vitamin K1 supplementation did not decrease bone resorption, but did protect against clinical fractures and cancers. Daily supplementation with high-dose vitamin K1 significantly increased serum vitamin K levels and decreased percentage of undercarboxylated osteocalcin. It was very well tolerated with no significant adverse effects.