Role of Vitamin K Supplement in Increasing Bone Mineral Density in Postmenopausal Women

Growing evidence supports the fact that hip fractures occur at an earlier age in developing countries compared with western countries. The peak age for hip fractures in India is in the 60s compared to the 80s in western countries. (2)

Since osteoporosis is closely related to estrogen deficiency, during the menopausal transition period, the drop of estrogen leads to more bone resorption than formation, lowering Bone Mineral Density (BMD) and the resulting in osteoporosis, which left untreated can cause major osteoporotic fractures. (3)

An increasing focus has been put on worldwide studies indicating the role of vitamin K in bone metabolism, helping in elevating the Bone Mineral Density (BMD), thus reducing the postmenopausal fracture risks. (4,5)

Vitamin K, specifically K2 (menaquinone) also functions as a cofactor required for the formation of gamma-carboxyglutamate (Gla) residues by osteocalcin, aggravating the rates of new bone formation. (6) It is well documented that Vitamins K2 and D work synergistically on bone metabolism, the form of osteocalcin that osteoblasts produce is undercarboxylated osteocalcin, and this process is upregulated by vitamin D, while carboxylation of osteocalcin is mediated by vitamin K.(7)

Though a deficiency in vitamin K2 has been linked to greater circulating levels of undercarboxylated osteocalcin (UcOC) (8), some studies have come across with very limited and controversial findings on the effects of vitamin K on bone mineral density (BMD) and osteoporotic fracture susceptibility.

To achieve a greater understanding of the biological linkages between vitamin K and osteoporotic fractures risks in postmenopausal Korean women over sixty years old, in 2011, a study was conducted by Sang Hyeon Je and team from the Department of Family Practice and Community, Health, Ajou University School of Medicine, Suwon. (9)

The findings were published in the Journal of Korean medical science.

The study evaluated the effect in subjects over 60-yr-old who did not want to take anti-resorptive agent such as bisphosphonate for osteoporosis. Forty-five women completed the study.

For 6 months, the treatment group received 15 mg of vitamin K2 (menatetrenone) three times a day after every meal, combination form containing 400 IU of active vitamin D3 once a day, and 315 mg of calcium carbonate twice daily. During the same period, the control group received 400 IU of vitamin D and 315 mg of calcium twice daily. The vitamin K group and the control group were randomly assigned.

The BMD in the lumbar spine (L1- L4) and femur neck, and ward measurements were performed using a QDR 4500 apparatus (Hologic, Waltham, MA, USA) at baseline and 6 months. The serum UcOC was assayed by an enzyme-linked immunosorbent assay using two monoclonal antibodies. Fasting blood (10 hr of fasting in the morning) was collected at baseline and months 3 and 6. Total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were measured.

On data analysis, results highlighted the following key points.

• During the six months of treatment, seventy-eight women participated (38 in the vitamin K group and 40 in the control group) and 45 women completed the study.

• The baseline characteristics of study participants did not differ between the vitamin K and the control groups.

• It was noted that In a per-protocol analysis after 6 months, L3 bone mineral density increased statistically significantly in the vitamin K group compared to the control group (0.01 ± 0.03 g/cm2 vs -0.008 ± 0.04 g/cm2, P = 0.049).

• Osteocalcin was also non-significantly increased in the vitamin K group (1.6 ± 5.8 ng/dL), but not in the control group (-1.1 ± 6.0 ng/dL). Triglyceride levels decreased in the vitamin K group (-10.0 ± 59.1 ng/dL).

• UcOC concentration was also significantly decreased in the vitamin K group (-1.6 ± 1.6 ng/dL vs-0.4 ± 1.1 ng/dL, P = 0.008).

The team observed some important facts as follows.

1. In this study, supplementation with vitamins K and D, and with calcium for 6 months of treatment significantly improved the L3 BMD compared to supplementation with vitamin D and calcium in postmenopausal Korean women over sixty years old.

2. Also, femur BMD was increased in the vitamin K group (vitamin K + vitamin D + calcium), but a similar increase was observed in the control group (vitamin D + calcium supplementation).

3. The UcOC concentration significantly decreased in the vitamin K group compared to the control group (P < 0.01), and the osteocalcin level increased nonsignificantly in the vitamin K group (P =0.14).

4. The triglyceride level decreased in the vitamin K group but was not statistically different from the control group. Similar results were observed in the ITT analysis.

5. Further, a study design involving a longer duration of vitamin K supplementation and with postmenopausal women having a short duration of menopause may prove valuable.

1. Kanis J.A., Melton L.J., 3rd, Christiansen C., Johnston C.C., Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994 Aug;9:1137–1141

2. Cauley J.A. Defining ethnic and racial differences in osteoporosis and fragility fractures. Clin Orthop Relat Res. 2011;469:1891–1899.

3. Ji, M. X., & Yu, Q. (2015). Primary osteoporosis in postmenopausal women. Chronic diseases and translational medicine, 1(1), 9–13.https://doi.org/10.1016/j.cdtm.2015.02.006

4. Vermeer C, Jie KS, Knapen MH. Role of vitamin K in bone metabolism. Annu Rev Nutr. 1995;15:1-22

5. Heiss C, Hoesel LM, Wehr U, Wenisch S, Drosse I, Alt V, et al. Diagnosis of osteoporosis with vitamin k as a new biochemical marker. Vitamins and Hormones. 2008;78:417-434

6. Booth SL. Roles for vitamin K beyond coagulation. Annual Review of Nutrition. 2009;29:89-110

7. Masterjohn C. Vitamin D toxicity redefined: Vitamin K and the molecular mechanism. Medical Hypotheses. 2007;68(5):1026-1034

8. Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. The American Journal of Medicine. 2013;126(3):243-248

9. Je, S. H., Joo, N.-S., Choi, B., Kim, K.-M., Kim, B.-T., Park, S.-B., … Lee, D.-J. (2011). Vitamin K Supplement Along with Vitamin D and Calcium Reduced Serum Concentration of Undercarboxylated Osteocalcin While Increasing Bone Mineral Density in Korean Postmenopausal Women over Sixty-Years-Old. Journal of Korean Medical Science, 26(8), 1093. doi:10.3346/jkms.2011.26.8.1093