1. Vitamin K: Tool to control osteoporosis Muhammad Yasin, Masood Sadiq Butt and Faqir Muhammad Anjum National Institute of Food Science and Technology University of Agriculture Faisalabad 12/28/10

2. Road map

• Introduction

• Functions of vitamin K

• Osteoporosis and vitamin K

• Vitamin K-dependent carboxylation reaction

• Vitamin K supplementation and bone health

• Observations related to osteoporosis

• Conclusions

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3. Vitamin K: Introduction

• Vitamin K, a fat-soluble vitamin is needed for the post-translational modification of certain proteins

• • blood coagulation

• • metabolism pathways in bone and other tissue

• Vitamin K exist naturally in multiple dietary forms

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4. Types and sources Phylloquinone (K 1 ) Menaquinone (K 2 ) Menadione (K 3 )

• Leafy green vegetables (spinach, Brassica,

• Some fruits (avocado)

• Colonic bacteria Staphylococcus aureus

• Egg,

• Fermented soybean (Natto)

• Chicken meat

• Cheese

• Synthetic analogue

• Menadion Sodium Bisulfie

• Mendione Nictinamide Bisulfite

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5. Functions of vitamin K

• Blood coagulation

• • Vitamin k is a factor for promoting blood coagulation by helping post-trancriptional modifications of blood factors

• • Vitamin K is responsible for the carboxylation or activation of clotting factors II, VII, IX, and X in the liver.

• • Vitamin K reductase enzymes keep the vitamin in an active (reduced) state

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6. Cont

• Calcium binding proteins (CBP)

• • Vitamin K is found to carboxylated specific glutamate residues of CBP of bones, spleen, placenta and kidneys

• Vitamin K-dependent protein

• • Matrix Gla-protein (mgp)

• • Growth arrest-specific gene 6 (gas6),

• • Endothelial protein C receptor (EPCR)-

• • Protease activated receptor 1 (PAR-1)

• • Thrombin (f2)

• • Growth arrest-specific gene 6 (gas6)

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7. Cont

• Poor vitamin K status is associated

• • increased postmenopausal bone loss

• • bone fractures

• • artery calcification

• Inverse correlation between dietary vitamin K intake and

• • bone fracture risk

• • cardiovascular mortality

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8. Vitamin K dosage and toxicity

• There is no known toxicity associated with high doses

• • phylloquinone

• • menaquinone

• • menadione

• • its derivatives

• High intake of vitamin K is not recommended

12/28/10 Age RDI Males and females, 0-6 months 2g Males and females, 7-12 months 2.5g Males and females, 1-3 years 30g Males and females, 4-8 years 55g Males and females, 9-13 years 60g Males and females, 14-18 years 75g Males, 19 years and older 120g Females, 19 years and older 90g

9. Osteoporosis and vitamin K

• Osteoporosis is a disease of skeleton characterizes by decrease bone power and the bone are more vulnerable to fracture

• Menaquinone reduce and stop

• • bone loss

• • helpful to control the disorders of bone

• Vitamin K

• • decreases the vertebral the hip fractures

• • rising bone mass

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10. Cont

• Pakistan has a rapidly growing population, with the percentage of elderly steadily increasing

• Osteoporosis- medical fraternity as a significant health problem

• Hip fractures in 2008

• • estimates based on ultrasound study

• • 9.91 million people suffer with osteoporosis

• • • 7.19 million women

• • • 2.71 million men

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11. Cont

• • These numbers are estimated to rise

• • • 11.3 million in 2020

• • • 12.91 million in 2050

• Women aged (45-70 years)

• • osteoporosis -16%

• • osteopenia - 34%

• Postmenopausal women in Peshawar- 75% at risk of osteoporosis (2002)

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12. Cont

• Vitamin k dependent proteins

• • Osteocalcin

• • Matrix Gla-protein

• • activated and play role in bone metabolism

• • reduce the threat of hip breakage

• Incomplete carboxylation of osteocalcin results in

• • an increased risk of osteoporosis

• • bone fractures

• Gla residues binds Ca 2+ ions and promotes a protein-Ca 2+ -phospholipid interaction

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13. The vitamin K-dependent carboxylation reaction 12/28/10 The enzyme is located at the luminal surface of the endoplasmic reticulum, and post-translationally carboxylates specific Glu residues of a limited number of proteins to -carboxyglutamyl (Gla) residues during protein processing glutamyl (Glu) 7-carboxyglutamyl (Gla) residues The vitamin K-dependent carboxylation reaction

14. Osteocalcin

• Osteocalcin

• • low-molecular-weight protein (49-50 residues)

• • three Gla residues

• • mineral-binding properties

• Osteocalcin is produced by

• • osteoblasts during bone matrix formation

• Osteocalcin concentration in bone

• • is directly proportional to calcium in bone

• Osteocalcin indication of bone formation

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15. Relationship between vitamin K status and bone health

• Circulating and bone vitamin K concentrations

• Vitamin K status and os teoporosis

• • reduced plasma concentrations of

• • • Phylloquinone

• • • MK-7

• • • MK-8

• • patients with recent femoral fractures or prior vertebral compression fractures

• Serum vitamin K concentration in elderly women after hip fracture

• • significantly lowers than those in age-matched healthy control

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16. Under- -carboxylated osteocalcin ( ucOC )

• Circulating osteocalcin

• • Adsorbed ca-phosphate (hydroxyapatite) gel

• • oral anticoagulant is less adsorbed hydroxyapatite in the presence of warfarin

• Osteocalcin converted in to fully -carboxylate in normal vitamin K-sufficient subjects

• Circulating ucOC increase with advancing age in women

• Serum osteocalcin and extent of its carboxylation is a

• • marker of vitamin K status in

• • • pregnant women

• • • newborn babies

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17. Vitamin K supplementation and bone health

• Phylloquinone (1 mg/d)

• • undercarboxylated osteocalcin to normal level in a postmenopausal (55- to 75 years old) women

• • elevated ratios of urinary hydroxyprolinexreatinine and urinary calciumxreatinine,

• • rapid bone turnover

• Vitamin K supplementation led to significant reductions in both urinary calcium and hydroxyproline excretion

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18. Cont

• MK-4 (45 mg) increase in

• • metacarpal bone mineral density,

• • serum osteocalcin

• • reduced urinary calcium excretion

• Renal vitamin K-dependent protein activity decreased by insufficient vitamin K

• • leading to excessive calcium loss in the urine

• Supplementation with MK-4 has positive effect in an in vitro bone mineralization system

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19. Observations relating to osteoporosis

• Low concentration of circulating vitamin K in patients with bone fractures

• Concentration of circulating under- -carboxylated osteocalcin associated with age, low bone mineral density, and hip fracture risk

• Anticoagulant therapy associated with decreased bone density

• Vitamin K supplementation decreases bone loss and calcium excretion

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20. Conclusions

• Vitamin K should be mandatory to control osteoporosis

• It is also indispensable for the formation of thrombin

• Osteoporosis is not recognized by the government as a health problem

• There are no policies or programs for prevention of osteoporosis and associated fractures in Pakistan

• The level of awareness among allied heath professionals as well as the general population

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21. References

• Binkley, N. C and Suttie, J. W. 1995. Vitamin K Nutrition and Osteoporosis. Journal of nutrition, 125: 1812-1821.

• Katarzyna Billing-Marczak, Marcin Krotkiewski. 2008. The role of vitamin K in bone metabolism.Terapia;16(5):41-46.

• Habiba U, Ahmed S, Hassan L. 2002. Predisposition to osteoporosis in postmenopausal women. J Coll Physicians Surg Pak;12:297-301

• Riaz S, Alam M, Umer M. 2006.Frequency of osteomalacia in elderly patients with hip fractures. J Pak Med Assoc;56:273-276

• Lowe N, Bano Q, Bangash S A, et al. 2008.Dietary calcium intake and bone health in postmenopausal women in Nahaqi, North West Frontier Province, Pakistan. Proceedings of the Nutrition Society; 67:(OCE8), E369

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