Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial

Abstract

Background: Vitamin 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 findings: This 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.

Conclusions: Daily 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).

Figure 1. Flowchart of the ECKO Trial showing Participation of Women in the Study

This flow diagram shows the number of study participants remaining in the study at each time point. *Women were not invited to participate in study extension if they were enrolled after 15 March 2004. **Participation was terminated for these women because the study was terminated. All final visits occurred between March and October 2006.

Figure 2. Changes in Bone Mineral Density over Time

These graphs show mean percentage change from baseline (Δ) in bone mineral densities at the lumbar spine (L1–L4), total hip, femoral neck, and ultradistal radius sites in the vitamin K (•) and placebo (○) groups over time, with their respective 95% confidence intervals. From baseline to 2 y (left part of graphs), all 440 women were included in the analyses based on intention-to-treat principle. We used last observation carried forward for any missing data in later visits. The analyses of the 2- to 4-y outcomes in the study extension (right part of graphs) were based on observed outcomes only.

Figure 3. Changes in Biochemical Markers of Bone Turnover and Vitamin K Status Over Time

These graphs showed mean total OC levels (bone formation marker), mean CTX (bone resorption marker), mean change in percentage of ucOC, and mean serum vitamin K levels in the vitamin K (•) and placebo (○) groups over time, with their respective 95% confidence intervals. All analyses were performed using observed outcomes. Because of limited study budget, we analyzed baseline and 2-y serum vitamin K levels in almost all the participants, but only a random sample at the other time points for those in the vitamin K group and none in the placebo group beyond 2 y.

Figure 4. Cumulative Incidence of Clinical Fractures and Cancer

The cumulative incidence of clinical fractures (A) and cancer (B) are shown for the vitamin K and placebo groups (C). The relationship of the cumulative incidence of cancer according to tertiles of 2-y serum vitamin K levels (shown in brackets and expressed in nmol/l). When Cox regression analysis was performed using the 2-y serum vitamin K levels as a continuous log-transformed variable, the relationship between vitamin K levels and the cumulative incidence of cancer was statistically significant at p < 0.05.