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Clinical Application of Vitamin K2 in Osteoporosis

Clinical Application of Vitamin K2 in Osteoporosis. Dr. Suppasin Soontrapa Orthopadic department Khon Kaen University Khon Kaen Thailand. 5 Mar 09. Fractures Related to Osteoporosis. Osteoporosis accounts for more than 1.5 million fractures annually in the US 300,000 hip fractures (20%)

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Clinical Application of Vitamin K2 in Osteoporosis

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  1. Clinical Application of Vitamin K2 in Osteoporosis • Dr. Suppasin Soontrapa • Orthopadic department • Khon Kaen University • Khon Kaen • Thailand 5 Mar 09

  2. Fractures Related to Osteoporosis • Osteoporosis accounts for more than 1.5 million fractures annually in the US • 300,000 hip fractures (20%) • 700,000 vertebral fractures (45%) • 250,000 wrist fractures (15%) • 300,000 fractures at other sites (20%) US National Osteoporosis Foundation, 2002. Available at: http://www.nof.org.

  3. Osteoporotic Fractures in US Women, Compared With Other Diseases 2,000,000 1,500,000 1,200,0001 1,000,000 Annual Incidence 513,0002 500,000 228,0002 184,3003 0 Osteoporotic Fractures Heart Attack Stroke Breast Cancer 1 US National Osteoporosis Foundation, 2002. Available at: http://www.nof.org. 2 American Heart Association. Heart & Stroke Facts: 1999 Statistical Supplement. 3 American Cancer Society. Breast Cancer Facts & Figures 1999-2000.

  4. Risk Factor of Osteoporosis 1. old age 2. history of maternal hip fracture 3. menopause 4. Oophorectomy 5. Low calcium, vitamin D and vitamin K intake 6. small body frame 7.being sedentary, no regular physical activity and exercise 8. on long term steroid medications 9. drinking excessive alcohol and smoking

  5. Vitamin K and Bone

  6. Composition of Bone

  7. Major non-collagenous protein

  8. Osteocalcin (Bone Gla Protein) 24 21 17 g = glutamic acid Synthesized by osteoblast

  9. Osteocalcin and Collagen Formation Osteoblast Osteocalcin (OC) Formation Collagen Formation Inactive osteocalcin Vitamin D 49 1 OH OH ucOC , undercarboxylated OC (Glu osteocalcin) Carboxylation Vitamin K C 49 Active osteocalcin 1 N carboxylated OC (Gla osteocalcin) Ca++ Mineralization Ca++ Ca++ Ca++ Hydroxyapatite

  10. Conclusion • Vitamin D stimulate Osteoblast to synthesize osteocalcin • The initial osteocalcin is inactive osteocalcin called undercarboxylated osteocalcin • Vitamin K is the most important co-factor for carboxylation of ucOC to become active osteocalcin (carboxylated osteocalcin) • Carboxylated osteocalcin can catch up calcium into bone matrix

  11. Introduction • There are two forms of natural vitamin K • Vitamin K1 can be isolated from alfafa • Vitamin K2 derived from fermented soybean

  12. Introduction Naphthoquinone ring Vitamin K1 Vitamin K2 Isoprenoid unit Isoprenoid unit Unsaturated side chain Unsaturated side chain

  13. Source of Vitamin K • Vitamin K1 (Phylloquinone) • Is found in plants and green vegetables

  14. Source of Vitamin K • Vitamin K2 (Menaquinones) • Bacteria and intestinal flora produce menaquinones for electron transport and energy production • Menaquinone 6-10 is the major vitamin K in the animal • High concentration of menaquinone also found in fermented soybean, e.g. natto

  15. Menatetrenone (MK4) • Menaquinone-4 : not produced in significant amounts by bacteria, but appears to be synthesized by animals (including humans) from phylloquinone. • Menaquinone-4 : Found in a number of organs other than the liver at higher concentrations than phylloquinone.

  16. Principles for vitamin K uptake in the tissues • The liver takes vitamin K in the amount that what it needs • The remainings are for other tissues • Vitamin K-deficiency mainly occurs in extra-hepatic tissue • Effects of K-deficiency will be most pronounced in bone, cartilage and arteries

  17. Dietary Sources to Vitamin K Schurgers et.al. J Nutr Env Med. 1999;9:115

  18. Enjoy Natto ! MK-7

  19. Can the intake of natto increase serum vitamin K and gamma-carboxylated osteocalcin ?

  20. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals • Eight male volunteers were given sequentially fermented soybeans (natto) containing three different contents of MK-7 at an interval of 7 days • Regular natto includingMK-7 :- 775 mcg/100 g (MK-7 x 1) • Reinforced natto including MK-7:- 1,298 mcg/100 g (MK-7 x 1.5) • Reinforced natto includingMK-7:- 1,765 mcg/100 g(MK-7 x 2) Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  21. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals • Evaluated serum MK-7, serum ucOC, andg-carboxylated osteocalcin Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  22. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals results • SerumMK-7 andg-carboxylated osteocalcin had increased in the volunteer who take reinforced natto including 1,298 mg (1.5 x regular natto) and 1,765 mg (2 x regular natto) • The serum ucOC significantly decreased in the volunteers who take reinforced natto including MK-7 1,765 mg/100g (2x regular natto) Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  23. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals • The next study was to evaluate the changes in serum MK-7 level with the frequency of dietary natto by examined in 134 healthy adults (85 men and 39 women) that could be classified into 3 subgroups • Without natto • With occasionalnatto (a few times per month) • Frequent (a few times per week) Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  24. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals Results • Serum MK-7 and gamma-carboxylated osteocalcin concentrations in subjects with the occasional or frequent dietary intake of natto were significantly higher than those without any intake. Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  25. Intake of nattocan increase circulating vitamin K2and g-carboxylated osteocalcin concentration in normal individuals Conclusion • The frequent intake of fermented soybean (natto) can increase serum levels of MK-7 and gamma-carboxylated osteocalcin in normal individuals Tsukamoto Y, et al. J Bone Miner Metab 2000;18(4): 216-22

  26. Recommended Dietary Allowance • Food and Nutrition Board of U.K. recommend daily vitamin K intake120 microgram/day Department of Healh. Report on health and social subjects No. 41: dietary reference values for food energy and nutrients for the United Kingdom. London, England: Her Majesty’s Stationery Office; 1991.

  27. VITAMIN K INTAKE (U.S.A.)

  28. Serum ucOC level in elderly womenand the risk of osteoporosis

  29. Introduction • Many studies1-4 had shown that the undercarboxylated osteocalcin (ucOC) was significantly increased in elderly women • The increase in ucOC was associated with • low BMD1 • increased risk of osteoporotic fracture3-4 • high skeletal turnover4 • Liu G, Peacock M. Calcif Tissue Int 1998 • Plantalech L. J Bone Miner Res 1991 • Vergnaud P. J Clin Endocrinol Metab 1997 • Szulc P. J Clin Invest 1993

  30. Introduction • The elevation of undercarboxylated osteocalcin concentration implied the insufficiency of vitamin K in the elderly women • It mean that vitamin K insufficiency contributed to osteoporosis development

  31. Serum ucOC level in the variety of participants Plantalech L, et al : J Bone Miner Res 1991; 6(11): 1211-6

  32. Serum ucOC level and the risk of osteoporosis fracture • Szulc P. et al (1993) • ucOC level of the elderly (age 71-101 yrs) = 1.22 + 1.00 (> young adult mean 0.65+0.5 ng/ml, p<0.01) • cut-off level of ucOC= mean + 2SD of young adult (21 cases) => 1.65 ng/ml Szulc P, et al : J Clin Invest 1993; 91(4): 1769-74

  33. Serum ucOC level and the risk of osteoporosis fracture • Szulc P. et al (1993) • The prevalence of the elderly with high ucOC ( > 1.65 ng/ml) =23 % • The elderly with higher ucOC had higher PTH and alk phos. Than the elderly with lower ucOC • After 18 mos. FU. the elderly with higher ucOChad higher risk of osteoporotic hip fracture than the elderly with lower ucOC (RR=5.9, 95%CI 1.5-22.7, p<0.001) Szulc P, et al : J Clin Invest 1993; 91(4): 1769-74

  34. Study of Vitamin K in Thailand

  35. Histogram of premenopausal women of Thailand median mean N= 357 cases Median = 2.100 Mean = 2.693 S.E. of mean = 0.107

  36. Cut-off Level of high undercarboxylated Osteocalcin (vitamin K deficiency) The median of normal Thai premenopausal women = 2.100 ng/ml The standard error of mean = 0.107 The upper limit of ucOC for cut-off level = median+2SE • The cut-off level of high ucOC = 2.314 ng/ml Plantalech L. et al. (1991): mean ucOC = 0.65+0.5 ng/ml Szulc P. et al (1993) : mean ucOC = 0.65+0.5 ng/ml : upper limit of ucOC = 1.65 ng/ml

  37. The ucOC Level and The Prevalence of vitamin K deficiency in Khon Kaen Thai Elderly Women(median+2 SE) Elderly women N=221 cases Median = 2.0 ng/ml S.E. = 0.15 • The ucOC cut-off level = 2.314 ng/ml Prevalence of vitamin K deficiency 39.1%

  38. Comparebone marker and BMD between normal vitamin K level and vitamin K deficiency (ucOC > 2.314 ng/ml)

  39. BMD of ultradistal radius p=0.02 Mean + 95% CI Vitamin K deficiency Normal vitamin K

  40. BMD of distal 1/3 of radius P=0.006 Mean + 95% CI Vitamin K deficiency Normal vitamin K

  41. Compare PTH between low and high ucOC p<0.001 Mean + 95% CI Normal vitamin K Vitamin K deficiency

  42. Compare alkaline phosphatase between low and high ucOC p=0.014 Mean + 95% CI Vitamin K deficiency Normal vitamin K

  43. Conclusion • The suitable cut-off level of ucOC for vitamin K deficiency should be 2.314 ng/ml • The prevalence of vitamin K deficiency of Khon Kaen elderly women was 39.1% • The elderly with vitamin K deficiency had • higherbone turnover marker • Lower BMD of distal radius

  44. Conclusion • Vitamin K deficiency is the risk of osteoporosis • The prevalence of vitamin K deficiency of Thai elderly is higher than other study (39.1% vs. 23%1 ) • The supplement of vitamin K in Thai elderly is recommended especially in osteoporosis patient 1. Szulc P. J Clin Invest 1993

  45. Clinical studies of Menatetrenone

  46. Effect of combined administration of vitamin D analog and vitamin K2 on bone density Objective • Compared the effect of 1-a(OH)D and vitamin K2 on BMD of lumbar spine in postmenopausal osteoporosis with calcium, 1-a(OH)D or vitamin K2 alone • At least 5 years post-menopausal Iwamoto J, et al. J Orthop Sci 2000; 5(6): 546-51

  47. Effect of combined administration of vitamin D analog and vitamin K2 on bone density • Randomly divided into 4 administration groups • C-group: 20 cases, pure calcium lactate 2 g/day • D-group: 29 cases, pure vitamin D (1-a (OH)D3 0.75 mg/day) • K-group: 22 cases, vitamin K2(menatetrenone 45 mg/day) • DK-group: 21 cases, combined vitamin D and vitamin K • After the initial dietary assessment, all subjects were encouraged to have 1000 mg of calcium and 400 IU of vitamin D daily through food. Iwamoto J, et al. J Orthop Sci 2000; 5(6): 546-51

  48. Effect of combined administration of vitamin D analog and vitamin K2 on bone density Results • Combined vitamin D and K and adequate calcium diet, could enhance the increased in BMD of the lumbar spine in postmenopausal osteoporosis, when compared with the single administration of calcium or vitamin D or vitamin K alone Iwamoto J, et al. J Orthop Sci 2000; 5(6): 546-51

  49. Conclusion • Vitamin D induces the production of osteocalcin by osteoblast • Vitamin D is necessary prior to the carboxylation of osteocalcin by vitamin K • Vitamin D and vitamin K have synergistic effect on bone Iwamoto J, et al. J Orthop Sci 2000; 5(6): 546-51

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