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WO2009095240A1 - Methods and compositions for the treatment of bone conditions - Google Patents

Methods and compositions for the treatment of bone conditions Download PDF

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Publication number
WO2009095240A1
WO2009095240A1 PCT/EP2009/000578 EP2009000578W WO2009095240A1 WO 2009095240 A1 WO2009095240 A1 WO 2009095240A1 EP 2009000578 W EP2009000578 W EP 2009000578W WO 2009095240 A1 WO2009095240 A1 WO 2009095240A1
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WO
WIPO (PCT)
Prior art keywords
nutritional composition
composition according
vitamin
milk
bone
Prior art date
Application number
PCT/EP2009/000578
Other languages
French (fr)
Inventor
Anne Schaafsma
Cornelis Glas
Elisabeth Gertruda Hendrika Maria Van Den Heuvel
Original Assignee
Friesland Brands B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Friesland Brands B.V. filed Critical Friesland Brands B.V.
Priority to EA201070893A priority Critical patent/EA020252B1/en
Priority to CN2009801063838A priority patent/CN101969792A/en
Priority to EP09706153A priority patent/EP2247199A1/en
Priority to MX2010008144A priority patent/MX2010008144A/en
Publication of WO2009095240A1 publication Critical patent/WO2009095240A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs

Definitions

  • the present invention relates to methods and compositions for treatment of bone conditions, especially bone loss such as osteoporosis.
  • the present invention especially relates to milk based nutritional compositions supplemented with prebiotics and a separate vitamin K 2 source, and methods using such nutritional compositions for treatment or prophylaxis of bone conditions, especially bone loss such as osteoporosis.
  • Bone conditions especially bone loss such as osteoporosis, are important diseases affecting elderly people worldwide.
  • Nutrition besides other factors, plays an important role in the prophylaxis and/or treatment of such bone conditions.
  • the nutritional intake of vitamin K appears, at least partially, to be an important nutritional component influencing the role of nutrition in the prophylaxis and/or treatment of bone conditions, such as osteoporosis
  • vitamin K is an essential co-factor in transforming specific glutamate residues (GIu) into gamma-carboxyglutamic acid (GIa) .
  • GIa residues increase the affinity of proteins for calcium.
  • Matrix GIa protein, protein S, nephrocalcin and osteocalcin are vitamin Independent proteins involved in bone metabolism.
  • Matrix GIa protein, synthesized in osteoblasts, chondrocytes and most soft tissues, is stimulated by calcitrol and does not react with hydroxyapatite . This protein appears earlier than osteocalcin and possibly prevents or inhibits calcification of arteries and cartilage through the surface coupled Rank ligand (RANKL) .
  • RNKL surface coupled Rank ligand
  • RANKL on osteoblast/stromal cells binds to RANK, a transmembrane receptor on osteoclast precursor cells. This interaction initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells.
  • OPG protein osteoprotegerin
  • OPG is produced by osteoblasts and other cell tissue types including the aorta and other large arteries. Because of this synthesis in the latter tissue, it is presently presumed that a normal function of OPG may be to prevent calcification of the large arteries.
  • Hormones and cytokines like calcitrol, PTH, PGE 2 and IL-Il appear to act through inhibition of OPG production and stimulation of RANKL synthesis.
  • the final ratio between RANKL and OPG appears to control the degree of osteoclast differentiation, activation and apoptosis.
  • Estrogen on the other hand appears to inhibit production of RANKL, but stimulates OPG synthesis.
  • Vitamin K denotes a class of related compounds having in common a methylated naphthoquinone ring structure. The variation within this group of compounds occurs in the aliphatic side chain attached at the three position of the ring structure.
  • vitamin Ki is commonly designated as vitamin Ki or phylloquinone.
  • This compound comprises an aliphatic side chain of four isoprenoid residues, of which one is saturated.
  • the other members of the vitamin K group are commonly designated as vitamins K 2 or menaquinones .
  • the aliphatic side chain of these compounds is comprised of a variable number of unsaturated isoprenoid residues.
  • vitamin K 2 compounds are also denoted as MK-n, wherein n indicates the number of unsaturated isoprenoid residues.
  • MK-4 to MK-13 are known.
  • Examples of natural food matrices of vitamin K are leafy green vegetables such as spinach and lettuce; Brassica vegetables such as kale, cabbage, cauliflower, broccoli and Brussels sprouts; wheat bran; organ meats; cereals; fruits such as avocado, kiwifruit and bananas; meats; cow milk and other dairy products; eggs; and soy products.
  • Examples of artificial food matrices of vitamin K are, for example, described in WO 02/052954, PCT/NL95/00396, and JP-2006-213627.
  • WO 02/052954 discloses a nutritional composition comprising sources of protein, carbohydrate, fat, calcium, magnesium, zinc, vitamin D and vitamin K (type of vitamin K not defined) . A beneficial effect on bone conditions is claimed.
  • PCT/NL95/00396 discloses a composition comprising a calcium source, ground eggshell in particular, in combination with macronutrients and a mineral and vitamin premix containing among others vitamin K (type of vitamin K not defined) . It is of interest to know that eggshell powder as a calcium source has shown to reduce serum PTH for a longer period as compared to standard calcium sources like calcium carbonate.
  • JP-2006-213627 discloses a composition comprising a calcium source, such as powdered fish bones, a vitamin K 2 source and citric acid. A beneficial effect on bone conditions is claimed.
  • this object is met by providing a nutritional composition as defined in appended claim 1.
  • the nutritional compositions according to the present invention comprise: a) one or more milk derived fractions and/or components; b) optionally, but preferably one or more prebiotics; c) optionally, but preferably, one or more calcium and/or magnesium salts; and d) vitamin K 2 (menaquinone) comprising 7 to 13
  • the one or more milk derived fractions and/or components are fractions or components naturally present in milk such as cow milk.
  • milk sources such as goat or horse milk, can also be considered.
  • milk fractions preferably derived from cow milk
  • skimmed milk full cream milk
  • partially skimmed milk buttermilk, cheese and yoghurt.
  • These milk fractions can be obtained using generally known milk processing techniques and, therefore, will not be further discussed in detail.
  • these milk fractions are preferable used in dry powder form.
  • milk components are whey protein derivatives, alpha-lactalbumine, beta-lactoglobuline, casein, casein-glycomacropeptide, hydrolysates of milk proteins such as casein hydrolysate and whey-protein hydrolysate, milk-calcium preparations, and lactose.
  • milk components can be obtained using generally known milk processing techniques and, therefore, will not be further discussed in detail.
  • these milk components are preferable used in a dry powder form.
  • the nutritional composition comprises one or more prebiotics.
  • prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria residing in the colon or reaching the colon as probiotic germs, thus improving host health.
  • preferred vitamin K2 producing bacteria are species of lactic acid producing bacteria (e.g. Lactobacilli, Leuconostoc, Lactococci, Bifidobacteria) and/or propionic acid producing bacteria.
  • the vitamin K2 producing bacteria are Lactococcus lactis ssp cremoris TsH473, as a producer of predominantly MK-9, and/or Propioni bacterium FF7645, as a producer of predominantly MK-IO.
  • Prebiotics according to the present invention are preferably oligosaccharides with a defined prebiotic activity.
  • Preferred examples are inulin, fructo- polysaccharides (FPS), fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) , fuco-oligosaccharides, sialic acid comprising carbohydrates such as sialyl lactose and/or carob bean gum.
  • Suitable prebiotic ranges in the present compositions are between 3 and 40% (w/w) , such as 3, 4, 5, 6 ,7 ,8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25% or up to 40% (w/w), preferably 10 to 25% (w/w) .
  • the one or more calcium and/or magnesium salts can be any calcium and/or magnesium salt suitable for (human) consumption. Suitable, and preferred examples, of the present one or more calcium and/or magnesium salts are carbonate, chloride, hydroxide, sulphate, phosphate, citrate, lactate, short- chain fatty acid, fumarate, ascorbate, gluconate and glycerophosphate salts of calcium and/or magnesium. According to a preferred embodiment, the ratio Ca 2 VMg 2+ is maximal 10:1.
  • the present nutritional composition comprises, as a separate component, vitamin K 2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues, such as MK-7, MK-8, MK-9, MK-10, MK- 11, MK-12 and/or MK-13, preferably 8 to 13, more preferably such as 9 to 13, most preferably 10 to 13 or 9-10
  • vitamin K 2 menaquinone
  • MK-7 to MK 13 isopropenoid residues
  • a suitable and preferred MK-7 source is a K2-oil such as a MenaQ7 oil formulation sold by NattoPharma ASA, Norway.
  • the concentration of vitamin K 2 is such that preferably a daily intake is provided of between 40 micrograms to 8 milligrams vitamin K 2 (menaquinone) comprising ' 7 to 13 (MK-7 to MK 13) isopropenoid residues such as 40, 50, 60 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500 microgram, 1, 2, 3, 4 , 5 , 6, 7 , 8 mg. More preferably, a daily intake is provided of between 50 to 150 microgram/day, such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, and 150 micrograms.
  • a daily intake is provided of between 40 micrograms to 8 milligrams vitamin K 2 (menaquinone) comprising ' 7 to 13 (MK-7 to MK 13) isopropenoid residues such as 40, 50, 60 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 1
  • the indicated daily dosages of vitamin K 2 comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues are preferably provided as a single daily dosage in the form for a once daily intake of the present nutritional compositions.
  • the nutritional composition according to the present invention can be in dry powder form, a concentrate or a ready-to-use form.
  • the nutritional composition according to the present invention is dissolved, or suspended, using an aqueous solution, preferably water.
  • Preferred is to dissolve, or suspend, 5 to 35 g of the dry powder per 100 ml solution, more preferably 12 to 26 g per 100 ml, such as 12.5 or 25 g/100 ml.
  • a concentrate is suitably diluted with an aqueous solution, such as water, to provide an amount similar to the above ranges cited with respect to the dry matter (DM) .
  • vitamin K 2 menaquinone
  • MK-7 to MK 13 isopropenoid residues
  • the peak plasma levels i.e., bioavailability
  • the peak plasma levels were more than two times to more than 5 times higher, wherein a positive correlation was observed between the peak plasma levels and the number of isopropenoid residues of the vitamin K 2 source.
  • the precise mechanism (s) of action of the present nutritional compositions due to complex in vivo factors such as intestinal absorption, transport, tissue distribution is/are not known, the increased beneficial effects of the present nutritional composition, such as bioavailability, are, for example, indicated by the observation that a once daily intake, during a sufficient time-period, of the present nutritional composition provides a sufficient vitamin K source to control or to prevent negative bone conditions.
  • Examples of sufficient time-periods are from 1 month to several years.
  • the effects will further improve when the vitamin K2 is combined with a calcium source having an extended lowering effect on serum PTH, such as ground eggshell powder and low-pH milk-calcium preparations.
  • the composition is supplemented with one ore more other known calcium absorption, bone synthesis and/or recovery compounds.
  • Preferred examples are biphosphonate, casein phosphopeptides, isoflators of soy and/or vitamin D.
  • the present nutritional composition is further supplemented with a lipid-fraction.
  • a lipid fraction according to the present invention is preferably provided in the form of a mixture of animal, plant, microbial fats, and/or phospholipids.
  • the long chain polyunsaturated fatty acid (LCP) ratio of n3 to n ⁇ fatty acids is >1.
  • Preferred sources of phospholipids are soy lecithin or milk phospholipid fractions.
  • the lipid fraction of the present nutritional composition only comprises as a separate constituent phospholipids, for example obtained from the above-identified sources. It has been found within the context of the present nutritional composition that the presence of lipid fractions further increases, amongst others, the bioavailability of vitamin K.
  • Suitable concentration ranges of the present lipid fraction are between 1 to 25 % (w/w) , such as 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25% (w/w) .
  • the present nutritional composition is further supplemented with nutritionally acceptable microbial organisms, preferably lactic acid bacteria and or propionic bacteria, although other microbial organisms providing additional sources of vitamin K through de novo synthesis are contemplated within the scope of the present invention.
  • nutritionally acceptable microbial organisms preferably lactic acid bacteria and or propionic bacteria
  • preferred bacteria are the Propioni bacterium FF7645 and Lactococcus bacterium FF0429 or Lactococcus lactis ssp cremoris TsH473 as they produce relatively high levels of vitamin K2 during fermentation of skimmed milk.
  • the present invention also relates to methods for the prophylaxis or treatment of an individual, preferably a human individual, at risk of or suffering from bone conditions, such as bone loss and especially osteoporosis, comprising administering the present nutritional composition during a sufficient time-period such as from 1 month to several years.
  • administering the present nutritional composition comprises a daily intake of the present composition thereby providing 40 microgram to 8 mg vitamin K 2 (menaquinone) comprising 7 to 13 (MK-7 to MK
  • isopropenoid residues such as 40, 50, 60, 70, 80, 90,
  • the daily intake preferably comprises a single daily 'dosage .
  • the present prophylaxis or treatment is preferably supplemented with physical exercises.
  • Preferred physical exercises are directed to reinforcement of fracture sensitive bone such as preferably the vertebral column and hip, and to reinforce arthrose vulnerable joints such as knee .
  • Figure 1 plasma levels, expressed as Z-scores, of healthy adults, after intake of compositions according to the present invention
  • Figure 2 provides suitable, and illustrative, examples of physical exercises according to the present invention.
  • Figures IA to 1C show suitable knee reinforcing exercises;
  • Figures ID and IE show suitable vertebral column reinforcing exercises;
  • Figures IF to IH show suitable hip reinforcing exercises .
  • a base product was prepared by 1) standardizing full cream cow's milk (12.5% DM, 4% fat) and skimmed milk (8% DM, 1% fat) at 16% milk fat in the DM (excluded inulin) , 2) adding CaCO 3 , MgCC> 3 , vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin, and 3) concentrating this mixture by evaporation followed by drying by known methods on a wheel dryer to form a powder.
  • the base powder obtained was mixed with a vitamin and mineral premix in dry form. This product was further enriched with 7.5g inulin per lOOg by dry blending.
  • the final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% inulin, and 1079mg Ca, 152mg Mg, 375 IU D3, and l ⁇ Omcg K2.
  • the final product is dissolved in water (25 g/200 ml) and is in particularly suitable for premenopausal women, provided in one portion daily.
  • a base product was prepared by mixing liquid demineralized whey (28% DM, 3.7% protein, 23.8% lactose, 0.29% fat), a casein hydrolysate (38-40 0 DH, 87% protein), milk fat, Ca-lactate, Ca-caseinate, MgCO 3 , vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin, to provide a whey protein to casein ratio of 1 and a fat content of 16% in the DM (excluded prebiotics) .
  • This mixed product was concentrated by evaporation and dried by known methods on a wheel dryer to form a powder.
  • the base powder obtained was mixed with a vitamin and mineral premix in dry form, in combination with sialyl-lactose.
  • the final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% sialyl lactose, and 1079mg Ca, 152mg Mg, 375 IU D3, and 160mcg K2.
  • the final product is dissolved in water 25g/100 ml) .
  • the product is provided in a once-daily portion, and particularly suitable for habitual dairy consuming premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
  • a product was prepared as described in example 2, but instead of sialyl-lactose, a mixture of sialyl-lactose and galactooligosaccharides (GOS) was added.
  • the final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 2.5% sialyl lactose, 5% GOS, and 1079mg Ca, 152mg Mg, 375 IU D3, and 160mcg K2.
  • the final product is dissolved in water (25g/100 ml) .
  • the product is provided in a once-daily portion, and in particular suitable for premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
  • a product was prepared as described in example 2, but in stead of sialyl-lactose, a mixture of sialyl-lactose and fructooligosaccharides (FOS) was added.
  • the final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 2.5% sialyl lactose, 5% FOS, and 1079mg Ca, 152mg Mg, 375 IU D3, and l ⁇ Omcg K2.
  • the final product is dissolved in water (25g/100 ml) .
  • the product is provided in a once-daily portion, and in particular suitable for premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
  • a base product was prepared by mixing demineralized hydrolyzed sweet whey (28% DM, 3.7% peptides, 23.8% lactose, 0.29% vet, 5 0 DH) with a vegetable source of fat in combination with fish oil (12% DHA, 18% EPA), and furthermore with Ca-citrate, MgCO 3 , vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin. This mixture was concentrated and dried by known methods on a wheel dryer to form a powder. The base powder obtained, with 16% fat, was blended with a vitamin and mineral premix in dry form, in combination with inulin. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% inulin, and 1079mg Ca, 152mg Mg, 375 IU D3, 160mcg K2.
  • the final product is dissolved in water (25 g/200 ml) and in particular suitable for premenopausal women with sleeping problems.
  • the product is adviced to be taken once daily, preferably in the evening.
  • Example 6 of a composi tion according to the present invention A base product in accordance with example 1 was prepared, mixing low-fat skimmed milk (9.18% DM, 3.57% protein, 4.8% lactose, 0.07% fat) and demineralized whey to standardize the protein content at 31.5% in the DM. Furthermore, Ca-acetate and MgCO3 are added. The lipid fraction (containing vitamin D3-oil, vitamin K2-oil [MK-7- MK13] , and phospholipids) was added during the concentration process before spray-drying. The powder obtained was mixed with FOS, vitamin and mineral premix in dry form. The final product comprised per 100 grams: 31.5% protein, 1% lipids, 48% carbohydrates, 10% FOS, and 1079mg Ca, 152mg Mg, 375 IU D3, l ⁇ Omcg K2.
  • the final product is dissolved in water (25 g/200 ml) .
  • the product is provided in a once-daily portion, and in particular suitable for premenopausal women on a fat-low diet.
  • a ready to drink product is prepared by dissolving fat-free milk dry substances (40% protein, 52% lactose, 8% minerals) , milk fat, vanilla, CaCO 3 , MgHPO 4 , vitamin C, vitamin K2-oil (MK7-13) , vitamin D3-oil, Na-citrate, FPS, and stabilizers.
  • the product is homogenized and sterilized by known techniques.
  • the final product comprises per 200 ml: 7 g protein, 9.4g lactose, 3g fat, 2g FPS, 0.006 g vanilla, 40mcg K2, 200 IU D3, 300mg Ca, 55mg Mg, and 60mg vitamin C.
  • the product is especially prepared for teenagers and premenopausal women, and is advised to be used as one portion daily.
  • a vitamin K2 enriched yoghurt is prepared by using a mixture of whole and skimmed milk and a thermophilic yoghurt culture. Additionally, vitamin K2-oil (MK7-13) , vitamin D3-oil, CaP04, MgPO4 and GOS were added. The final product contains per 100 grams: 2g milk fat, 4.4g protein, 8.9g milk solids non fat (40% protein, 52% lactose, 8% minerals), 2 g GOS, 200 mg Ca, 55mg Mg, 2.5mcg D3, and 80mcg K2.
  • the product is especially prepared for those who cannot tolerate or do not like non-fermented sweet milk.
  • the product is advised to be consumed once-daily.
  • a vitamin K2-enriched yoghurt is produced by using whole milk and a selected yoghurt culture of high K2- producing lactic-acid bacteria. Additionally, vitamin K2-oil (MK7-13), vitamin D3-oil, MgPO 4 , and milk solids non-fat (40% protein, 52% lactose, and 8% minerals among which milk- calcium) , and GOS were added. The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, 2g GOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
  • This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
  • Example 10 of a composition according to the present invention A product as prepared in example 9, but using sialyl-lactose instead of GOS. Furthermore, the selected yoghurt culture is further enriched with Propionic bacterium (FF7645) . The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, 2g sialyl- lactose, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
  • FF7645 Propionic bacterium
  • This product is characterized by a higher natural content of vitamin K2, MK-8 and MK-10 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
  • the product is advised to be used as one portion daily.
  • the final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig GOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
  • This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
  • the product is advised to be used as one portion daily.
  • the final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig FOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
  • This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
  • the product is advised to be used as one portion daily.
  • the final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig FPS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
  • This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
  • the product is advised to be used as one portion daily.
  • a low-fat fresh cheese product was prepared, which contained 1Og milk proteins, 3.5g carbohydrates, and 8% fat per 100 gram. Under stirring, per lOOg of this product, 3g ground eggshell (as Ca and Mg source) , 2g GOS, 120mg Mg (as MgPO 4 salt), 100 meg vitamin K2-oil (MK7-13) , and 5mcg vitamin D3 oil were aseptically added until a homogeneous product of good taste was obtained. Then portion packages were filled with the thus prepared product. This product is typically for the 5O + age category, with proven effects on bone metabolism. It is advised to consume the product once daily, preferable in the evening.
  • the final product comprised per 100 gram: 29% protein, 14.7% fat 39.1% carbohydrates (lactose), 4.9g inulin, 3g ground eggshell powder, 16mg astaxanthin, 160 mgdocosahexaenoic acid, 40mg eicosapentaenoic acid, and 1070mg Ca, 152mg Mg, 375IU D3, and 160mcg K2.
  • the final product is dissolved in water
  • the product is designed to be consumed once daily, and in particular by those who suffer from arthrose or have an increased risk to develop arthrose.
  • Emmenthaler-like cheese was produced according to the state of the art applying K2-producing propionic bacteria, low-pH milk calcium preparation, MgPO 4 , vitamin D3- oil, and GOS.
  • the final product comprised per 100 gram: 29g protein, 3Og fat, 2g GOS, llOOmg Ca, 115mg Mg, 130mcg K2, 5mcg D3.
  • the product was developed typically for those who have a low consumption of liquid dairy, and is preferable consumed as two slides during breakfast or lunch.
  • Example 11 Appearance and clearance of vitamin Kl and K2 vitamins
  • a vitamin Kl and vitamin K2 (MK-7, 9, and 10) enriched serving of buttermilk was orally consumed by 12 adult volunteers (20-45 years of age) , in the laboratory in combination with a standard breakfast.

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Abstract

The present invention relates to methods and compositions for treatment of bone conditions, especially bone loss such as osteoporosis. The present invention especially relates to milk based nutritional compositions preferably supplemented with prebiotics and a separate vitamin K2 source, and methods using such nutritional compositions for treatment or prophylaxis of bone conditions especially bone loss such as osteoporosis. The present composition comprises: one or more milk derived fractions and/or components; preferably one or more prebiotics; preferably one or more calcium and/or magnesium salts; and vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF BONE
CONDITIONS .
Description
The present invention relates to methods and compositions for treatment of bone conditions, especially bone loss such as osteoporosis. The present invention especially relates to milk based nutritional compositions supplemented with prebiotics and a separate vitamin K2 source, and methods using such nutritional compositions for treatment or prophylaxis of bone conditions, especially bone loss such as osteoporosis.
Bone conditions, especially bone loss such as osteoporosis, are important diseases affecting elderly people worldwide. Nutrition, besides other factors, plays an important role in the prophylaxis and/or treatment of such bone conditions. The nutritional intake of vitamin K appears, at least partially, to be an important nutritional component influencing the role of nutrition in the prophylaxis and/or treatment of bone conditions, such as osteoporosis
Studies have shown that in postmenopausal women, 1 to 10 years past menopause, undercarboxylated osteocalcin was correlated with lower bone mineral density (BMD) of
Wards' s triangle and femoral neck in particular. In another study in women, an inverse association between dietary vitamin K intake and the risk of hip fractures was observed. In another study, it was shown that a normalization of carboxylated osteocalcin levels (to about 72% of total osteocalcin) in postmenopausal women occurred following daily supplementation of vitamin K in combination with vitamin D during 12 months. In yet another study, it was shown that daily vitamin K intake during a period of three years reduced bone loss of the femoral neck.
Although the underlying mechanism (s) of the relation between nutritional vitamin K intake and bone loss, such as osteoporosis, is not completely understood, a number of studies have been performed providing some insight in a possible candidate mechanism (s ), although other yet unexplored mechanisms cannot be excluded.
It has been shown that vitamin K is an essential co-factor in transforming specific glutamate residues (GIu) into gamma-carboxyglutamic acid (GIa) . GIa residues increase the affinity of proteins for calcium. Matrix GIa protein, protein S, nephrocalcin and osteocalcin are vitamin Independent proteins involved in bone metabolism. Matrix GIa protein, synthesized in osteoblasts, chondrocytes and most soft tissues, is stimulated by calcitrol and does not react with hydroxyapatite . This protein appears earlier than osteocalcin and possibly prevents or inhibits calcification of arteries and cartilage through the surface coupled Rank ligand (RANKL) .
RANKL on osteoblast/stromal cells binds to RANK, a transmembrane receptor on osteoclast precursor cells. This interaction initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells. It has been found that the naturally occurring protein osteoprotegerin (OPG) also binds to RANK and acts as an inhibitor of osteoclastogenesis . OPG is produced by osteoblasts and other cell tissue types including the aorta and other large arteries. Because of this synthesis in the latter tissue, it is presently presumed that a normal function of OPG may be to prevent calcification of the large arteries. Hormones and cytokines like calcitrol, PTH, PGE2 and IL-Il appear to act through inhibition of OPG production and stimulation of RANKL synthesis. The final ratio between RANKL and OPG appears to control the degree of osteoclast differentiation, activation and apoptosis. Estrogen on the other hand appears to inhibit production of RANKL, but stimulates OPG synthesis.
Vitamin K denotes a class of related compounds having in common a methylated naphthoquinone ring structure. The variation within this group of compounds occurs in the aliphatic side chain attached at the three position of the ring structure.
One member of this class of compounds is commonly designated as vitamin Ki or phylloquinone. This compound comprises an aliphatic side chain of four isoprenoid residues, of which one is saturated. The other members of the vitamin K group are commonly designated as vitamins K2 or menaquinones . The aliphatic side chain of these compounds is comprised of a variable number of unsaturated isoprenoid residues. Considering this variability, vitamin K2 compounds are also denoted as MK-n, wherein n indicates the number of unsaturated isoprenoid residues. Presently, at least vitamin K2 compounds MK-4 to MK-13 are known.
Despite this variability in the class of vitamin K compounds, it is generally believed that the naphthoquinone ring structure provides the observed mechanism of action and this mechanism is generally assumed to be similar for all vitamin K compounds.
However, substantial differences can be found with respect to intestinal absorption, transport, tissue distribution and bioavailability. Factors influencing these differences are, amongst others, different lipophilicities of the various side chains of the compounds and the different food matrices in which vitamin K compounds are presented and consumed. Known food matrices of vitamin K are both of natural and artificial origin.
Examples of natural food matrices of vitamin K are leafy green vegetables such as spinach and lettuce; Brassica vegetables such as kale, cabbage, cauliflower, broccoli and Brussels sprouts; wheat bran; organ meats; cereals; fruits such as avocado, kiwifruit and bananas; meats; cow milk and other dairy products; eggs; and soy products.
Examples of artificial food matrices of vitamin K are, for example, described in WO 02/052954, PCT/NL95/00396, and JP-2006-213627.
WO 02/052954 discloses a nutritional composition comprising sources of protein, carbohydrate, fat, calcium, magnesium, zinc, vitamin D and vitamin K (type of vitamin K not defined) . A beneficial effect on bone conditions is claimed.
PCT/NL95/00396 discloses a composition comprising a calcium source, ground eggshell in particular, in combination with macronutrients and a mineral and vitamin premix containing among others vitamin K (type of vitamin K not defined) . It is of interest to know that eggshell powder as a calcium source has shown to reduce serum PTH for a longer period as compared to standard calcium sources like calcium carbonate. JP-2006-213627 discloses a composition comprising a calcium source, such as powdered fish bones, a vitamin K2 source and citric acid. A beneficial effect on bone conditions is claimed.
Despite these available food matrices of vitamin K, especially considering the bioavailability and the recognized beneficial effect of vitamin K supplementation on bone conditions, such as osteoporosis, there is still a need in the art to provide improved artificial food matrices as a source of vitamin K.
It is an object of the present invention to provide such improved artificial food matrices for vitamin K supplementation.
According to the present invention, this object, amongst others, is met by providing a nutritional composition as defined in appended claim 1.
The nutritional compositions according to the present invention comprise: a) one or more milk derived fractions and/or components; b) optionally, but preferably one or more prebiotics; c) optionally, but preferably, one or more calcium and/or magnesium salts; and d) vitamin K2 (menaquinone) comprising 7 to 13
(MK-7 to MK 13) isopropenoid residues. According to the present invention, the one or more milk derived fractions and/or components are fractions or components naturally present in milk such as cow milk. However, other milk sources, such as goat or horse milk, can also be considered.
Suitable, and preferred, examples of milk fractions, preferably derived from cow milk, are: skimmed milk, full cream milk, partially skimmed milk, buttermilk, cheese and yoghurt. These milk fractions can be obtained using generally known milk processing techniques and, therefore, will not be further discussed in detail. When formulating the present nutritional compositions, these milk fractions are preferable used in dry powder form.
Suitable, and preferred, examples of milk components are whey protein derivatives, alpha-lactalbumine, beta-lactoglobuline, casein, casein-glycomacropeptide, hydrolysates of milk proteins such as casein hydrolysate and whey-protein hydrolysate, milk-calcium preparations, and lactose. These milk components can be obtained using generally known milk processing techniques and, therefore, will not be further discussed in detail. When formulating the present nutritional compositions, these milk components are preferable used in a dry powder form.
According to the present invention, the nutritional composition comprises one or more prebiotics. In general, prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria residing in the colon or reaching the colon as probiotic germs, thus improving host health.
According to the present intervention, preferred vitamin K2 producing bacteria are species of lactic acid producing bacteria (e.g. Lactobacilli, Leuconostoc, Lactococci, Bifidobacteria) and/or propionic acid producing bacteria.
According to a particularly preferred embodiment, the vitamin K2 producing bacteria are Lactococcus lactis ssp cremoris TsH473, as a producer of predominantly MK-9, and/or Propioni bacterium FF7645, as a producer of predominantly MK-IO.
Prebiotics according to the present invention are preferably oligosaccharides with a defined prebiotic activity. Preferred examples are inulin, fructo- polysaccharides (FPS), fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) , fuco-oligosaccharides, sialic acid comprising carbohydrates such as sialyl lactose and/or carob bean gum. Suitable prebiotic ranges in the present compositions are between 3 and 40% (w/w) , such as 3, 4, 5, 6 ,7 ,8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25% or up to 40% (w/w), preferably 10 to 25% (w/w) .
Optionally, a part of the preferred oligosaccharides may be replaced within the context of the present invention by nucleotides and/or nucleosides and/or specific peptides. According to the present invention, the one or more calcium and/or magnesium salts can be any calcium and/or magnesium salt suitable for (human) consumption. Suitable, and preferred examples, of the present one or more calcium and/or magnesium salts are carbonate, chloride, hydroxide, sulphate, phosphate, citrate, lactate, short- chain fatty acid, fumarate, ascorbate, gluconate and glycerophosphate salts of calcium and/or magnesium. According to a preferred embodiment, the ratio Ca2VMg2+ is maximal 10:1. As separate vitamin K source, besides a possible vitamin K source, for example, provided by the one or more milk derived fractions and/or components, the present nutritional composition comprises, as a separate component, vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues, such as MK-7, MK-8, MK-9, MK-10, MK- 11, MK-12 and/or MK-13, preferably 8 to 13, more preferably such as 9 to 13, most preferably 10 to 13 or 9-10
According to the present invention, a suitable and preferred MK-7 source is a K2-oil such as a MenaQ7 oil formulation sold by NattoPharma ASA, Norway.
According to the present invention, the concentration of vitamin K2 is such that preferably a daily intake is provided of between 40 micrograms to 8 milligrams vitamin K2 (menaquinone) comprising' 7 to 13 (MK-7 to MK 13) isopropenoid residues such as 40, 50, 60 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500 microgram, 1, 2, 3, 4 , 5 , 6, 7 , 8 mg. More preferably, a daily intake is provided of between 50 to 150 microgram/day, such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, and 150 micrograms. The indicated daily dosages of vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues are preferably provided as a single daily dosage in the form for a once daily intake of the present nutritional compositions.
The nutritional composition according to the present invention can be in dry powder form, a concentrate or a ready-to-use form. In case of a dry powder form, the nutritional composition according to the present invention is dissolved, or suspended, using an aqueous solution, preferably water.
Preferred is to dissolve, or suspend, 5 to 35 g of the dry powder per 100 ml solution, more preferably 12 to 26 g per 100 ml, such as 12.5 or 25 g/100 ml. A concentrate is suitably diluted with an aqueous solution, such as water, to provide an amount similar to the above ranges cited with respect to the dry matter (DM) .
It has surprisingly been found by the present inventors that vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues, provided as a component of the nutritional compositions according to the present invention, provides an beneficial bioavailability, as compared to the vitamin K sources, both natural and artificial, according to the prior art.
As compared to a vitamin Kl intake, the peak plasma levels, i.e., bioavailability, were more than two times to more than 5 times higher, wherein a positive correlation was observed between the peak plasma levels and the number of isopropenoid residues of the vitamin K2 source. Although the precise mechanism (s) of action of the present nutritional compositions, due to complex in vivo factors such as intestinal absorption, transport, tissue distribution is/are not known, the increased beneficial effects of the present nutritional composition, such as bioavailability, are, for example, indicated by the observation that a once daily intake, during a sufficient time-period, of the present nutritional composition provides a sufficient vitamin K source to control or to prevent negative bone conditions.
Examples of sufficient time-periods are from 1 month to several years. The effects will further improve when the vitamin K2 is combined with a calcium source having an extended lowering effect on serum PTH, such as ground eggshell powder and low-pH milk-calcium preparations.
According to a further preferred embodiment of the present composition, the composition is supplemented with one ore more other known calcium absorption, bone synthesis and/or recovery compounds. Preferred examples are biphosphonate, casein phosphopeptides, isoflavons of soy and/or vitamin D.
According to an especially preferred embodiment of the present invention, the present nutritional composition is further supplemented with a lipid-fraction. A lipid fraction according to the present invention is preferably provided in the form of a mixture of animal, plant, microbial fats, and/or phospholipids. Preferably, the long chain polyunsaturated fatty acid (LCP) ratio of n3 to nβ fatty acids is >1. Preferred sources of phospholipids are soy lecithin or milk phospholipid fractions. Within the scope of the present invention, it is contemplated that the lipid fraction of the present nutritional composition only comprises as a separate constituent phospholipids, for example obtained from the above-identified sources. It has been found within the context of the present nutritional composition that the presence of lipid fractions further increases, amongst others, the bioavailability of vitamin K.
Suitable concentration ranges of the present lipid fraction are between 1 to 25 % (w/w) , such as 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25% (w/w) .
According to another preferred embodiment, the present nutritional composition is further supplemented with nutritionally acceptable microbial organisms, preferably lactic acid bacteria and or propionic bacteria, although other microbial organisms providing additional sources of vitamin K through de novo synthesis are contemplated within the scope of the present invention. Within the context of the present invention, it has been found that preferred bacteria are the Propioni bacterium FF7645 and Lactococcus bacterium FF0429 or Lactococcus lactis ssp cremoris TsH473 as they produce relatively high levels of vitamin K2 during fermentation of skimmed milk.
Considering the beneficial properties of the present composition such as, amongst others, a reduced bone loss, the present invention also relates to methods for the prophylaxis or treatment of an individual, preferably a human individual, at risk of or suffering from bone conditions, such as bone loss and especially osteoporosis, comprising administering the present nutritional composition during a sufficient time-period such as from 1 month to several years.
In a preferred embodiment, administering the present nutritional composition comprises a daily intake of the present composition thereby providing 40 microgram to 8 mg vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK
13) isopropenoid residues such as 40, 50, 60, 70, 80, 90,
100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300,
400, 500 micrograms, 1, 2, 3, 4, 5, 6, 7, 8 mg, more preferably 50 to 150 micrograms/day. The daily intake preferably comprises a single daily 'dosage .
The present prophylaxis or treatment is preferably supplemented with physical exercises. Preferred physical exercises are directed to reinforcement of fracture sensitive bone such as preferably the vertebral column and hip, and to reinforce arthrose vulnerable joints such as knee .
Below, examples of suitable and preferred embodiments of the present invention are presented. In the examples reference is made to the appended figure wherein:
Figure 1: plasma levels, expressed as Z-scores, of healthy adults, after intake of compositions according to the present invention;
Figure 2: provides suitable, and illustrative, examples of physical exercises according to the present invention. Figures IA to 1C show suitable knee reinforcing exercises; Figures ID and IE show suitable vertebral column reinforcing exercises;
Figures IF to IH show suitable hip reinforcing exercises . Examples
Example 1 of a composition according to the present invention
A base product was prepared by 1) standardizing full cream cow's milk (12.5% DM, 4% fat) and skimmed milk (8% DM, 1% fat) at 16% milk fat in the DM (excluded inulin) , 2) adding CaCO3, MgCC>3, vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin, and 3) concentrating this mixture by evaporation followed by drying by known methods on a wheel dryer to form a powder. The base powder obtained was mixed with a vitamin and mineral premix in dry form. This product was further enriched with 7.5g inulin per lOOg by dry blending. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% inulin, and 1079mg Ca, 152mg Mg, 375 IU D3, and lβOmcg K2.
The final product is dissolved in water (25 g/200 ml) and is in particularly suitable for premenopausal women, provided in one portion daily.
Example 2 of a composition according to the present invention
A base product was prepared by mixing liquid demineralized whey (28% DM, 3.7% protein, 23.8% lactose, 0.29% fat), a casein hydrolysate (38-40 0DH, 87% protein), milk fat, Ca-lactate, Ca-caseinate, MgCO3, vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin, to provide a whey protein to casein ratio of 1 and a fat content of 16% in the DM (excluded prebiotics) . This mixed product was concentrated by evaporation and dried by known methods on a wheel dryer to form a powder. The base powder obtained was mixed with a vitamin and mineral premix in dry form, in combination with sialyl-lactose. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% sialyl lactose, and 1079mg Ca, 152mg Mg, 375 IU D3, and 160mcg K2.
The final product is dissolved in water 25g/100 ml) . The product is provided in a once-daily portion, and particularly suitable for habitual dairy consuming premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
Example 3 of a composition according to the present invention
A product was prepared as described in example 2, but instead of sialyl-lactose, a mixture of sialyl-lactose and galactooligosaccharides (GOS) was added. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 2.5% sialyl lactose, 5% GOS, and 1079mg Ca, 152mg Mg, 375 IU D3, and 160mcg K2.
The final product is dissolved in water (25g/100 ml) . The product is provided in a once-daily portion, and in particular suitable for premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
Example 4 of a composition according to the present invention
A product was prepared as described in example 2, but in stead of sialyl-lactose, a mixture of sialyl-lactose and fructooligosaccharides (FOS) was added. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 2.5% sialyl lactose, 5% FOS, and 1079mg Ca, 152mg Mg, 375 IU D3, and lβOmcg K2.
The final product is dissolved in water (25g/100 ml) . The product is provided in a once-daily portion, and in particular suitable for premenopausal women under stressful conditions, and stimulates as well the intestinal vitamin K2 production.
Example 5 of a composition according to the present invention
A base product was prepared by mixing demineralized hydrolyzed sweet whey (28% DM, 3.7% peptides, 23.8% lactose, 0.29% vet, 5 0DH) with a vegetable source of fat in combination with fish oil (12% DHA, 18% EPA), and furthermore with Ca-citrate, MgCO3, vitamin A-acetate, vitamin D3-oil, vitamin K2-oil (MK-7-MK13) , and lecithin. This mixture was concentrated and dried by known methods on a wheel dryer to form a powder. The base powder obtained, with 16% fat, was blended with a vitamin and mineral premix in dry form, in combination with inulin. The final product comprised per 100 grams: 29% protein, 14.7% fat, 39.1% carbohydrates (lactose), 7.5% inulin, and 1079mg Ca, 152mg Mg, 375 IU D3, 160mcg K2.
The final product is dissolved in water (25 g/200 ml) and in particular suitable for premenopausal women with sleeping problems. The product is adviced to be taken once daily, preferably in the evening.
Example 6 of a composi tion according to the present invention A base product in accordance with example 1 was prepared, mixing low-fat skimmed milk (9.18% DM, 3.57% protein, 4.8% lactose, 0.07% fat) and demineralized whey to standardize the protein content at 31.5% in the DM. Furthermore, Ca-acetate and MgCO3 are added. The lipid fraction (containing vitamin D3-oil, vitamin K2-oil [MK-7- MK13] , and phospholipids) was added during the concentration process before spray-drying. The powder obtained was mixed with FOS, vitamin and mineral premix in dry form. The final product comprised per 100 grams: 31.5% protein, 1% lipids, 48% carbohydrates, 10% FOS, and 1079mg Ca, 152mg Mg, 375 IU D3, lβOmcg K2.
The final product is dissolved in water (25 g/200 ml) . The product is provided in a once-daily portion, and in particular suitable for premenopausal women on a fat-low diet.
Example 7 of a composition according to the present invention
A ready to drink product is prepared by dissolving fat-free milk dry substances (40% protein, 52% lactose, 8% minerals) , milk fat, vanilla, CaCO3, MgHPO4, vitamin C, vitamin K2-oil (MK7-13) , vitamin D3-oil, Na-citrate, FPS, and stabilizers. The product is homogenized and sterilized by known techniques. The final product comprises per 200 ml: 7 g protein, 9.4g lactose, 3g fat, 2g FPS, 0.006 g vanilla, 40mcg K2, 200 IU D3, 300mg Ca, 55mg Mg, and 60mg vitamin C. The product is especially prepared for teenagers and premenopausal women, and is advised to be used as one portion daily. Example 8 of a composition according to the present invention
A vitamin K2 enriched yoghurt is prepared by using a mixture of whole and skimmed milk and a thermophilic yoghurt culture. Additionally, vitamin K2-oil (MK7-13) , vitamin D3-oil, CaP04, MgPO4 and GOS were added. The final product contains per 100 grams: 2g milk fat, 4.4g protein, 8.9g milk solids non fat (40% protein, 52% lactose, 8% minerals), 2 g GOS, 200 mg Ca, 55mg Mg, 2.5mcg D3, and 80mcg K2.
The product is especially prepared for those who cannot tolerate or do not like non-fermented sweet milk. The product is advised to be consumed once-daily.
Example 9 of a composition according to the present invention
A vitamin K2-enriched yoghurt is produced by using whole milk and a selected yoghurt culture of high K2- producing lactic-acid bacteria. Additionally, vitamin K2-oil (MK7-13), vitamin D3-oil, MgPO4, and milk solids non-fat (40% protein, 52% lactose, and 8% minerals among which milk- calcium) , and GOS were added. The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, 2g GOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
Example 10 of a composition according to the present invention A product as prepared in example 9, but using sialyl-lactose instead of GOS. Furthermore, the selected yoghurt culture is further enriched with Propionic bacterium (FF7645) . The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, 2g sialyl- lactose, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
This product is characterized by a higher natural content of vitamin K2, MK-8 and MK-10 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production. The product is advised to be used as one portion daily.
Example 11 of a composition according to the present invention
A product as prepared in example 9, but using sialyl-lactose in combination with GOS, instead of GOS only. The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig GOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production. The product is advised to be used as one portion daily.
Example 12 of a composition according to the present invention
A product as prepared in example 9, but using sialyl-lactose in combination with FOS instead of GOS only. The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig FOS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production. The product is advised to be used as one portion daily.
Example 13 of a composition according to the present invention
A product as prepared in example 9, but using sialyl-lactose in combination with FPS instead of GOS only.
The final product contains per 100 grams: 3g milk fat, 4.6g milk protein, 4.6 g carbohydrates, Ig sialyl-lactose, Ig FPS, 175 mg Ca, 55mg Mg, 2.5mcg D3, and 80 meg K2.
This product is characterized by a higher natural content of vitamin K2, MK-8 in particular, and as well is a vehicle to stimulate the intestinal vitamin K2 production.
The product is advised to be used as one portion daily.
Example 14 of a composition according to the present invention
A low-fat fresh cheese product was prepared, which contained 1Og milk proteins, 3.5g carbohydrates, and 8% fat per 100 gram. Under stirring, per lOOg of this product, 3g ground eggshell (as Ca and Mg source) , 2g GOS, 120mg Mg (as MgPO4 salt), 100 meg vitamin K2-oil (MK7-13) , and 5mcg vitamin D3 oil were aseptically added until a homogeneous product of good taste was obtained. Then portion packages were filled with the thus prepared product. This product is typically for the 5O+ age category, with proven effects on bone metabolism. It is advised to consume the product once daily, preferable in the evening.
Example 15 of a composition according to the present invention
A product as prepared in example 1, but 2.6g of the inulin is replaced by the combination of astaxanthin and a dried blend of fish-oil fatty acids, whereas the CaCO3 is replaced by ground eggshell powder. The final product comprised per 100 gram: 29% protein, 14.7% fat 39.1% carbohydrates (lactose), 4.9g inulin, 3g ground eggshell powder, 16mg astaxanthin, 160 mgdocosahexaenoic acid, 40mg eicosapentaenoic acid, and 1070mg Ca, 152mg Mg, 375IU D3, and 160mcg K2.
The final product is dissolved in water
(25g/200ml) . The product is designed to be consumed once daily, and in particular by those who suffer from arthrose or have an increased risk to develop arthrose.
Example 16 of a composition according to the present invention
An Emmenthaler-like cheese was produced according to the state of the art applying K2-producing propionic bacteria, low-pH milk calcium preparation, MgPO4, vitamin D3- oil, and GOS. The final product comprised per 100 gram: 29g protein, 3Og fat, 2g GOS, llOOmg Ca, 115mg Mg, 130mcg K2, 5mcg D3.
The product was developed typically for those who have a low consumption of liquid dairy, and is preferable consumed as two slides during breakfast or lunch. Example 11 Appearance and clearance of vitamin Kl and K2 vitamins
A vitamin Kl and vitamin K2 (MK-7, 9, and 10) enriched serving of buttermilk was orally consumed by 12 adult volunteers (20-45 years of age) , in the laboratory in combination with a standard breakfast.
The buttermilk contained about 100 μg of each of the K-vitamins per serving. Blood samples were taken just before supplementation (T=O), and after 2, 4, 6, 8 and 24 hours. During the study period the volunteers remained in the laboratory and received the same meals that were very restricted in K-vitamins. K vitamins were measured in serum as described by
Schurgers LJ & Vermeer C. (Determination of phylloquinone and menaquinones in food: effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000;30:298-307) . In short, samples were extracted with hexane and after a prepurification on silica columns they were analyzed by high-performance liquid chromatography (HPLC) using a reversed-phase column with online zinc reduction and fluorescence detection. Vitamin Kl-25 (a synthetic form of vitamin Kl containing 5 isoprenoid residues) was used as internal standard. The data obtained are shown in Figure 1.
The data show that K2-vitamins are absorbed into human blood as quickly as Kl but at a higher level. Furthermore, the data also show that the longer the chain of isopropenoid residues, the higher the peak level in blood and also the higher the level after 24 hours. There was no return to baseline values after 24 hours, except for vitamin Kl. Example 18
The preferred daily intake of the nutritional compositions of any of the examples 1 to 17 is recommended to be combined with physical exercises such as physical exercises directed to reinforcement of fracture and or arthrose sensitive bone and joints such as the vertebral column, hip, and knee. Reference is made to the accompanying Figure 2 wherein suitable examples of such exercises are presented as outlined below.
Knee
Figure imgf000022_0001
Figure imgf000023_0001
Vertebral column
Figure imgf000024_0001
Hip
Figure imgf000024_0002
Figure imgf000025_0001

Claims

1. Nutritional composition comprising: a) one or more milk derived fractions and/or components; b) optionally one or more prebiotics; c) optionally one or more calcium and/or magnesium salts; and d) vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK-13) isopropenoid residues.
2. Nutritional composition comprising: a) one or more milk derived fractions and/or components; b) one or more prebiotics; c) one or more calcium and/or magnesium salts; and d) vitamin K2 (menaquinone) comprising 7 to 13
(MK-7 to MK-13) isopropenoid residues.
3. Nutritional composition according to claim 1 or claim 2, comprising one or more milk derived fractions and one or more milk derived components.
4. Nutritional composition according to any of the claims 1 to 3, wherein the one or more milk derived fractions are selected from the group consisting of skimmed milk, full cream milk, partially skimmed milk, buttermilk, cheese, yoghurt, fractions obtained by microfiltration of milk and/or skimmed milk.
5. Nutritional composition according to any of the claims 1 to 4, wherein the one or more milk derived components are selected from the group consisting of whey protein derivatives, alpha-lactalbumine, beta- lactoglobuline, casein, casein-glycomacropeptide, hydrolysates of milk proteins, casein hydrolysate, whey- protein hydrolysate, and lactose.
6. Nutritional composition according to any of the claims 1 to 5, wherein the one or more prebiotics are selected from the group consisting of inulin, FPS, FOS, GOS, fuco-oligosaccharides, carob bean gum, or sialic acid comprising compounds, sialic acid comprising carbohydrates and sialyl lactose.
7. Nutritional composition according to any of the claims 1 to 6, wherein vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues is at least partially provided as a K2 oil.
8. Nutritional composition according to any of the claims 1 to 7, wherein vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues is at least partially provided as a component of viable or dead bacteria.
9. Nutritional composition according to any of the claims 1 to 8, wherein vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues is at least partially provided as a component of lysed bacteria.
10. Nutritional composition according to any of the claims 1 to 9, wherein the calcium source is ground eggshell powder, and or a milk-calcium preparation with a pH<6.
11. Nutritional composition according to any of the claims 1 to 10, comprising: e) a lipid fraction
12. Nutritional composition according to claim 11, wherein the lipid fraction comprises a mixture of animal, plant, microbial fats, and/or phospholipids.
13. Nutritional composition according to claim 11 or claim 11, wherein the lipid fraction is chosen from the group consisting of lecithin or phospholipid fractions.
14. Nutritional composition according to claim 13, wherein the lecithin fraction is soy derived.
15. Nutritional composition according to claim 13, wherein the phospholipid fraction is milk derived.
16. Nutritional composition according to any of the claims 1 to 15 comprising: f) one or more microbial organisms.
17. Nutritional composition according to claim 16, wherein the one or more microbial organisms are chosen from the group consisting of vitamin K-producing lactic acid bacteria and propionic acid producing bacteria.
18. Nutritional composition according to claim 17, wherein the microorganism is Lactococcus lactis ssp cremoris
TsH473.
19. Nutritional composition according to claim 17, wherein the microorganism is Propioni bacterium FF7645.
20. Nutritional composition according to claim 18 or claim 19, wherein the microorganism is Lactococcus lactis ssp cremoris TsH473 and Propioni bacterium FF7645.
21. Nutritional composition according to any of the claims 1 to 20, comprising: g) one or more calcium absorption, bone synthesis or recovery compounds.
22. Nutritional composition according to claim 21, wherein the one or more calcium absorption, bone synthesis or recovery compounds are chosen from the group consisting of biphosphonate, casein phosphopeptides, isoflavons of soy, and vitamin D.
23. Nutritional composition according to any of the claims 1 to 22, comprising, per daily doses, 50 to 150 micrograms vitamin K2 (menaquinone) comprising 7 to 13 (MK-7 to MK 13) isopropenoid residues.
24. Use of a nutritional composition according to any of the claims 1 to 23 for the preparation of a medicament for the prophylaxis or treatment of specific bone and joint conditions.
25. Use according to claim 24, wherein the condition is osteoporosis.
26. Use according to claim 24, wherein the condition is arthrosis.
27. Use according to any of the claims claim 24 to 26, wherein the treatment further comprises physical exercises .
28. Use according to claim 27, wherein the physical exercises are directed to one or more body bone structures selected from the group consisting of the vertebrate column, knee, joints and hip.
29. Method for treating an individual suffering from or at risk of a bone condition, comprising: a) once daily intake of a nutritional composition according to any of the claims 1 to 22; b) physical exercises;
30. Method according to claim 29, wherein the bone condition is osteoporosis.
31. Method according to claim 29, wherein the bone condition is arthrosis.
32. Method according to any of the claims 29 to 31, wherein the physical exercises are directed to one or more body bone structures selected from the group consisting of the vertebrate column, knee, joints and hip
PCT/EP2009/000578 2008-01-28 2009-01-27 Methods and compositions for the treatment of bone conditions WO2009095240A1 (en)

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