Composition for inhibiting bone mineral density loss and method for imparting bone mineral density loss inhibitory effect

Abstract

The present invention provides a composition for suppressing bone mineral density loss. Specifically, the present invention provides a composition for suppressing bone mineral density loss, which contains rhamnose and is to be administered to postmenopausal women. Inhibition of bone mineral density loss in this embodiment can be suppressing the risk of bone mineral density loss in healthy postmenopausal women. The present embodiment of the composition can be a composition for administration of 0.1 to 2 g per day. The present invention can also be a composition for administration every day for at least 12 weeks. The present invention also provides a method for imparting a bone mineral density loss suppressing effect to a composition by allowing rhamnose to coexist in the composition.

Description

[Technical field]

[0001] The present invention relates to a composition for suppressing bone density loss containing rhamnose and a method for imparting an inhibitory effect on bone density loss, more particularly to a composition for suppressing bone density loss in postmenopausal women and a method for imparting an inhibitory effect on bone density loss. [Background technology]

[0002] Osteoporosis is a disease characterized by an increased risk of fracture due to increased bone fragility. The global prevalence of osteoporosis is approximately 18.3%, and 23.1% in women alone (Non-Patent Document 1). Furthermore, the number of deaths due to osteoporosis-related fractures and low bone mineral density (BMD), and disability-adjusted life years as a population health status indicating the standard life expectancy lost due to death or disability, have more than doubled from 1990 to 2019, making low BMD a global health burden.

[0003] Bone tissue is constantly remodeled to maintain the mass, structure, and quality of the skeleton. Bone metabolism is regulated by both bone formation by osteoblasts and bone resorption by osteoclasts (Non-Patent Document 2), and one of the factors that disrupt this balance is a change in the amount of estrogen. In postmenopausal women, estrogen deficiency induces turnover that favors bone resorption due to promotion of osteoclastogenesis and inhibition of osteoblastogenesis, making them more likely to develop osteoporosis (Non-Patent Document 3). Menopause is an inevitable event for women. Therefore, maintaining bone mass after menopause is an important issue for maintaining women's health throughout their lives.

[0004] Although bone resorption inhibitors and the like have been proposed for regulating bone density (Patent Document 1), it cannot be said that effective methods for inhibiting loss of bone density specifically for postmenopausal women have been sufficiently researched. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2015-38076 [Non-patent literature]

[0006] [Non-Patent Document 1] Salari N, Ghasemi H, Mohammadi L, Behzadi M hasan, Rabieenia E, Shohaimi S, Mohammadi M. 2021. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 16(1):609 [Non-Patent Document 2] Ballhause TM, Jiang S, Baranowsky A, Brandt S, Mertens PR, Frosch KH, Yorgan T, Keller J. 2021. Relevance of Notch Signaling for Bone Metabolism and Regeneration. Int J Mol Sci. 22(3):1325. doi:10.3390 / ijms22031325. [Non-Patent Document 3] Shuai Y, Zhang Z, Guo T, Yang R, Jin L, Liu W. 2019 Jul 28. Postmenopausal Osteoporosis: A Mini Review. EMJ Rheumatology.:90-100. doi:10.33590 / emjrheumatol / 10311765. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a composition for inhibiting the loss of bone density in postmenopausal women. [Means for solving the problem]

[0008] As a result of intensive research aimed at solving the above-mentioned problems, the inventors discovered that bone mineral density loss can be effectively suppressed by administering a composition containing rhamnose in a specific manner, and thus completed the present invention.

[0009] That is, the present invention includes the following inventions. [1] A composition for inhibiting loss of bone density, comprising rhamnose and to be administered to postmenopausal women.

[0010] [2] A method for imparting an inhibitory effect on bone mineral density loss to a composition by allowing rhamnose to coexist in the composition. Effect of the Invention

[0011] By using the composition for inhibiting bone density loss of the present invention, it is possible to inhibit bone density loss in postmenopausal women. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention relates to a rhamnose-containing composition for suppressing bone mineral density loss, and more particularly to a composition for suppressing bone mineral density loss in postmenopausal women.

[0013] [Composition for suppressing bone density decline] The composition for suppressing a decrease in bone mineral density of the present invention contains rhamnose (L-Rhamnopyranose monohydrate). Rhamnose is a deoxy sugar found mainly in plants, and is conjugated with various metabolites. Rhamnose is used as a sweetener in food additives, and is included in the list of existing food additives in Japan. Here, the rhamnose used in the present invention may be either α-type or β-type. It may also be in the form of a hydrate.

[0014] The content of rhamnose in the composition for suppressing a decrease in bone mineral density of the present invention is not particularly limited as long as it has an inhibitory effect on a decrease in bone mineral density, and can be appropriately set within the range of 0.001 to 100% by mass. The content of rhamnose in the composition for suppressing a decrease in bone mineral density is preferably 0.01 to 100% by mass, more preferably 0.1 to 100% by mass. The content of rhamnose in the composition for suppressing a decrease in bone mineral density can be, for example, about 10 to 90% by mass, or about 20 to 50% by mass.

[0015] When the composition for inhibiting bone density loss of the present invention is a beverage, the content of rhamnose in the beverage can be about 0.01 to 5 mass%, preferably 0.05 to 5 mass%, more preferably 0.1 to 2 mass%, and even more preferably 0.2 to 1 mass%.

[0016] The composition for suppressing a decrease in bone mineral density of the present invention may also be blended with various carriers and additives.

[0017] Examples of such carriers or additives include monosaccharides (e.g., glucose, galactose, fructose, etc.), disaccharides (e.g., sucrose, sucrose, lactose, maltose, trehalose, etc.), sugar alcohols (e.g., xylitol, sorbitol, mannitol, etc.), oligosaccharides, starch (e.g., corn starch, partially pregelatinized starch, etc.), starch hydrolysates (e.g., dextrin, powdered sugar, etc.), cellulose or cellulose derivatives (e.g., crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, etc.), and excipients such as talc; starch, pregelatinized starch, gelatin, gum arabic, dextrin, methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl ... Examples of suitable binders include sucrose, carboxymethylcellulose or a salt thereof; disintegrating agents such as calcium carbonate, crospovidone, starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethylstarch, crystalline cellulose, agar, etc.; lubricants such as magnesium stearate, talc, polyethylene glycol, anhydrous silicic acid, etc.; suspending agents such as polysorbate 80, polyoxyethylene hydrogenated castor oil, and Pluronic (registered trademark); coating agents such as sucrose, talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, and hydroxypropyl methylphthalate, etc.; and flavoring agents such as sucrose, glucose, sodium saccharin, sorbitol, citric acid, and aspartame, etc.In addition to the above-mentioned components, the following may be added as additives generally permitted as pharmaceuticals, so long as the effects of the present invention are not impaired: stabilizers, surfactants, plasticizers, capsule shells, solubilizers, reducing agents, buffers, sweeteners, bases, absorption promoters, adsorbents, hardeners, antioxidants, glossing agents, flavorings, capsule shells, supports, sustainers, wetting agents, wetting regulators, fillers, antifoaming agents, cooling agents, adhesives, enhancers, chewing agents, antistatic agents, flavorings, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, adhesion enhancers, thickening agents, Optional ingredients such as pH adjusters, floating agents, dispersants, propellants, fragrances, rust inhibitors, moisture inhibitors, release control membranes, preservatives, trapping agents, preservatives, solubilizers, solubilizers, solvents, release agents, fluidizing agents, etc., or sweeteners, colorants, preservatives, thickeners, stabilizers, gelling agents, thickening agents, antioxidants, color formers, bleaching agents, fungicides, emulsifiers, leavening agents, seasonings, acidulants, bittering agents, gloss agents, gum bases, nutritional enhancers, manufacturing agents, fragrances, etc. that are acceptable as food additives may also be added as desired.

[0018] The composition for suppressing loss of bone mineral density of the present invention may contain, in addition to the above-mentioned components, any edible components and / or mineral components, etc., within limits that do not impair the effects of the present invention.

[0019] Examples of edible ingredients include excipients, organic acids, coloring agents, amino acids (e.g., glycine, arginine, lysine, alanine, glutamic acid, histidine, threonine, asparagine, aspartic acid, phenylalanine, leucine, valine, serine, tyrosine, isoleucine, methionine, etc.), nutrients (including vitamins and minerals), antioxidants, preservatives, antibacterial agents, bacteriostatic agents, plant extracts (e.g., tea extracts, coffee extracts, cocoa extracts, etc.), fruit juices (e.g., orange, grape, apple, peach, pineapple, tomato, strawberry, etc.), sweeteners (sweeteners, etc.), and antioxidants. Examples of such sweeteners include sugars such as sucrose, isomerized sugar, lactose, maltose, glucose, fructose, invert sugar, starch syrup, powdered starch syrup, reduced malt starch syrup, honey, trehalose, palatinose, and D-xylose; sugar alcohols such as xylitol, sorbitol, maltitol, and erythritol; high-intensity sweeteners such as saccharin sodium, cyclamate or a salt thereof, acesulfame potassium, thaumatin, aspartame, sucralose, alitame, neotame, stevia extract (e.g., stevioside, etc.), and swingle extract (e.g., mogroside, etc.), and flavorings.

[0020] Examples of mineral components include zinc, copper, calcium, manganese, and magnesium, and among these, calcium is particularly preferably used.

[0021] The calcium content in the composition for suppressing bone mineral density loss of the present invention is preferably 0.01 to 5 mass%, more preferably 0.1 to 3 mass%, and even more preferably 0.1 to 0.5 mass%. It is preferably designed to allow the intake of 300 mg to 700 mg of calcium per day.

[0022] The composition for suppressing a decrease in bone density of the present invention can be used as a food, drink, or medicine having an inhibitory effect on a decrease in bone density, or as an additive for imparting an inhibitory effect on a decrease in bone density to a food, drink, or medicine. The composition for suppressing a decrease in bone density of the present invention can be in any form, and can have a solid form such as a powder, granule, tablet, or capsule, as well as a semi-solid or liquid form such as a syrup, emulsion, liquid, or gel.

[0023] When the composition for suppressing bone mineral density loss of the present invention is a food, drink, or medicine, its target is not particularly limited.

[0024] Specifically, in addition to general foods and beverages, various compositions such as supplements and quasi-drugs can be mentioned. Examples of the food and beverage composition include milk beverages, lactic acid bacteria beverages, dairy beverages, carbonated beverages, fruit beverages (e.g., fruit juice, mixed fruit juice, beverages containing fruit juice, carbonated beverages containing fruit juice, fruit pulp beverages, diluted beverages, etc.), vegetable beverages, vegetable and fruit beverages, tea beverages (e.g., black tea beverages, green tea beverages, oolong tea beverages, barley tea beverages, blended tea beverages, herbal tea, flavored tea, and other tea beverages), near water, powdered beverages, sports beverages, supplement beverages, nutritional beverages, functional beverages, jelly beverages, drink soups, soy milk beverages, powdered beverages such as powdered juices dissolved in water, and protein-containing beverages; Puddings such as custard pudding, milk pudding, and fruit juice pudding, as well as desserts such as jelly, bavarois, and yogurt; Frozen desserts such as ice cream, ice milk, lacto ice cream, and frozen desserts; Chewing gum, bubble gum and other gums (e.g. gum sticks, sugar-coated gum); Chocolates such as coated chocolate (e.g. marble chocolate, etc.) and flavored chocolate (e.g. strawberry chocolate, blueberry chocolate, melon chocolate, etc.); Candies such as hard candies (e.g. bonbons, butterballs, marbles, etc.), soft candies (e.g. caramel, nougat, gummy candy, marshmallows, etc.), sugar-coated candies, drops, taffy, etc.; Confectionery such as cookies, biscuits, snacks, etc.; Liquid condiments such as separate dressings, non-oil dressings, ketchup, sauces, and other sauces; Jams such as strawberry jam, blueberry jam, marmalade, apple jam, apricot jam, preserves, syrups, etc.; Red wine and other fruit wines, carbonated alcoholic drinks; Fruits for processing, such as cherries, apricots, apples, strawberries, peaches, etc. in syrup; processed agricultural products such as pickles; Includes:

[0025] Examples of the food and beverage products also include semi-finished products and intermediate products of these products.

[0026] Further, examples of foods, beverages, and medicines include those in the form of powders, granules, tablets (including lozenges and chewable tablets), pills, capsules, films, and liquids (drinks), including nutritional supplements, various supplements, anti-bad breath agents, mouth fresheners, etc.

[0027] [Method of imparting an inhibitory effect on bone density loss] The method of the present invention for imparting an inhibitory effect on bone mineral density loss can be carried out by adding, blending, or allowing rhamnose to be present in a food, drink, or pharmaceutical product. The content of rhamnose and other conditions are as described in [Composition for inhibiting bone mineral density loss]. Here, the inhibition of bone mineral density loss means, for example, an inhibition of bone mineral density loss when the bone mineral density is less than 0.7 g / cm. 2 ~0.95g / cm 2 In subjects with a bone mineral density of about 100 mg / kg, the bone mineral density loss rate after 24 weeks is preferably suppressed by 5% or more, more preferably 8% or more, and even more preferably 10% or more, compared to the bone mineral density loss rate of a control who does not ingest rhamnose. Here, the bone mineral density loss rate (%) is the value obtained by dividing the amount of bone mineral density change after a predetermined period of time by the initial bone mineral density and multiplying the result by 100. It is not limited to this, but may be, for example, the value obtained by dividing the amount of bone mineral density change after 24 weeks by the initial bone mineral density and multiplying the result by 100.

[0028] (Application) The composition for suppressing a decrease in bone mineral density of the present invention, which contains rhamnose, can suppress differentiation into osteoclasts and reduce the number of cells differentiated into osteoclasts. By suppressing differentiation into osteoclasts, bone metabolism biased toward bone resorption due to enhanced differentiation into osteoclasts, as seen in osteoporosis and its precursor stage, can be improved to a normal balance, so the composition for suppressing a decrease in bone mineral density of the present invention, which contains rhamnose, can be used to suppress a decrease in bone mineral density. In addition, the composition for suppressing a decrease in bone mineral density of the present invention, which contains rhamnose, can be administered after evaluating the state of bone resorption in a subject by measuring bone formation markers such as osteocalcin (OC) or bone-specific alkaline phosphatase (BAP), or bone resorption markers such as total type I procollagen N-terminal propeptide, type I collagen cross-linked N-telopeptide (NTx), type I collagen cross-linked C-telopeptide (CTx), and tartrate-resistant acid phosphatase (TRACP-5b). For example, when the measured value of the bone resorption marker is higher than the standard value generally used in the technical field, it can be judged that bone resorption is suspected to be enhanced. For NTx, for example, the standard value is 10.7 to 24.0 nmol BCE (Bone Collagen Equivalent) / L as a value measured using serum collected from a postmenopausal woman (Guide to the Proper Use of Bone Metabolic Markers in Osteoporosis Treatment, 2018 Edition, Japan Osteoporosis Society), and for example, subjects with 18 nmol BCE / L or more and 24.0 nmol BCE / L or less can be targeted. For TRACP-5b, for example, the standard value is 250 to 760 mU / dL as a value measured using serum collected from a postmenopausal woman (Guide to the Proper Use of Bone Metabolic Markers in Osteoporosis Treatment, 2018 Edition, Japan Osteoporosis Society), and subjects with 450 mU / dL or more and 760 mU / dL or less can be targeted. The reference value can be set appropriately depending on the type of sample obtained from the subject (eg, blood (serum, etc.), urine, etc.) and the age of the subject.In addition, for example, when the measured value of the bone formation marker is lower than the standard value generally used in the technical field, it can be judged that bone resorption is suspected to be enhanced. For OC, for example, the standard value can be 14.2 to 54.8 ng / mL as a value measured using serum collected from postmenopausal women (Guide to Proper Use of Bone Metabolic Markers in Osteoporosis Treatment, 2018 Edition, Japan Osteoporosis Society), and for example, subjects with 14.2 ng / mL or more and 22 ng / mL or less can be targeted. For BAP, for example, the standard value can be 3.8 to 22.6 μg / L as a value measured using serum collected from postmenopausal women (Guide to Proper Use of Bone Metabolic Markers in Osteoporosis Treatment, 2018 Edition, Japan Osteoporosis Society), and for example, subjects with 3.8 to 17.5 μg / L can be targeted. In addition, for example, the degree of bone formation can be evaluated by comparing the measured value of the bone formation marker with a standard value generally used in the art, the degree of bone resorption can be evaluated by comparing the measured value of the bone resorption marker with a standard value generally used in the art, and the degree of bone formation can be compared with the degree of bone resorption, and if the degree of bone resorption is greater than the degree of bone formation, it can be determined that bone resorption is enhanced. Therefore, the composition for suppressing a decrease in bone mineral density of the present invention containing rhamnose can be taken or administered to a subject whose NTx measured using serum is 18 nmol BCE / L or more, 19 nmol BCE / L or more, 20 nmol BCE / L or more, 21 nmol BCE / L or more, 22 nmol BCE / L or more, or 23 nmol BCE / L or more. Furthermore, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to a subject whose TRACP-5b measured using serum is, for example, 400 mU / dL or more, 450 mU / dL or more, 500 mU / dL or more, 600 mU / dL or more, 650 mU / dL or more, 700 mU / dL or more, 750 mU / dL or more and 760 mU / dL or less.Furthermore, the composition for suppressing a decrease in bone mineral density of the present invention, which contains rhamnose, can be ingested or administered to a subject having an OC measured using serum of 14.2 to 54.8 ng / mL or less, preferably 14.2 to 22 ng / mL or less. The composition for suppressing a decrease in bone mineral density of the present invention, which contains rhamnose, can be ingested or administered to a subject having an BAP measured using serum of 3.8 to 22.6 μg / L, preferably 3.8 to 17.5 μg / L. The subject is, for example, a postmenopausal woman, preferably a healthy postmenopausal woman.

[0029] By inhibiting differentiation into osteoclasts, bone metabolism biased toward bone resorption is improved to a normal balance, and bone fragility or a decrease in bone mass can be inhibited. For this reason, the composition for inhibiting a decrease in bone density of the present invention, which contains rhamnose, can be used to increase bone mass. The composition for inhibiting a decrease in bone density of the present invention, which contains rhamnose, can be ingested or administered to subjects who have a decreased bone mass or are suspected to have a decreased bone mass but are included in the category of healthy subjects. For example, if the Young Adult Mean (YAM) is less than 80%, it can be determined that the bone mass is decreased or is suspected to have a decreased bone mass. The composition for inhibiting a decrease in bone density of the present invention, which contains rhamnose, can be ingested or administered to subjects who have a YAM of 95%, 90%, 85%, 80%, or 75% or less, or a YAM of 70%, 75%, 80%, or 85% or more.

[0030] It is also known that when differentiation into osteoclasts is promoted in the bone (alveolar bone) that supports the teeth, bone metabolism becomes biased toward bone resorption, causing resorption of the alveolar bone and resulting in periodontal disease such as periodontitis. For this reason, the composition for inhibiting a decrease in bone density of the present invention, which contains rhamnose, can be used for treating or preventing periodontal disease. The composition for inhibiting a decrease in bone density of the present invention, which contains rhamnose, can be ingested or administered to a subject who has or is suspected of having periodontal disease.

[0031] (Dose, etc.) The intake amount of the composition for suppressing a decrease in bone mineral density of the present invention may vary depending on the body weight, age, condition, or other factors of the subject. The dosage, route, interval, and amount and interval of intake may be appropriately determined by those skilled in the art, but generally, the amount of rhamnose per day for an adult is preferably 5 mg / kg body weight or more, more preferably 10 mg / kg body weight or more, even more preferably 15 mg / kg body weight or more, and preferably 100 mg / kg body weight or less, more preferably 75 mg / kg body weight or less, and even more preferably 50 mg / kg body weight or less. In addition, the amount per day may be preferably 0.1 g to 2 g or less, more preferably 0.3 g to 1.5 g or less, and even more preferably 0.5 to 1 g or less.

[0032] (Those to be administered or ingested) The subjects for administration or ingestion of the composition for suppressing a decrease in bone mineral density of the present invention are not particularly limited as long as they are postmenopausal women who need or desire it. Preferably, they are healthy postmenopausal women. The body weight of the subject is preferably 60 kg or less, more preferably 55 kg or less, even more preferably 52 kg or less, even more preferably 50 kg or less, and most preferably 48 kg or less. The body weight of the subject is preferably 40 kg or more, more preferably 41 kg or more, and even more preferably 43 kg or more. For example, the subject may be 40 to 55 kg, 41 to 52 kg, 41 to 50 kg, or 43 to 48 kg. The BMI of the subject is preferably 24 kg / m 2 More preferably, 22 kg / m 2 Less than or equal to 20 kg / m 2 Less than or equal to 19 kg / m 2 The subject's BMI is preferably less than or equal to 13 kg / m 2 More preferably, 14 kg / m 2 More preferably, 15 kg / m 2 The BMI of the subject is preferably 13 to 24 kg / m 2 , more preferably 14 to 22 kg / m 2, and even more preferably 15 to 20 kg / m 2 , particularly preferably 15 to 19 kg / m 2 As shown in the examples, the effect of the present invention is more pronounced in subjects with lower BMI values. The present invention can also be applied to those who wish to ingest foods that are beneficial for bone health by maintaining bone components. The present invention can also be applied to women who wish to maintain strong bones and foods that are beneficial for maintaining bone components. A postmenopausal woman refers to a subject who has "not had menstruation for one year or more" in a state where menstruation has completely stopped. In addition, the age is not limited, but is typically 45 years old or older, 47 years old or older, or 50 years old or older. There is no upper age limit, but the subject can be preferably 75 years old or younger, more preferably 70 years old or younger, and even more preferably 65 years old or younger.

[0033] (Method of producing a composition for inhibiting bone density loss) The method for producing the composition for suppressing bone mineral density loss of the present invention is not limited, and the composition can be produced by any known method. In these production methods, the content and amount of each component are the same as those described above for the composition for suppressing bone mineral density loss.

[0034] (Methods for suppressing bone density decline, etc.) The present invention also relates to a method for inhibiting bone mineral density loss by administering or ingesting a composition containing rhamnose. Here, the definition of inhibition of bone density loss, details of associated diseases, subjects for administration or ingestion, dosage, etc. are in accordance with the contents described in the section on composition for inhibiting bone density loss above.

[0035] (Use of rhamnose for producing a composition for inhibiting bone mineral density loss) The present invention also relates to use of rhamnose for producing a composition or drug for suppressing bone mineral density loss, in which the definition of suppression of bone mineral density loss, details of related diseases, subjects to which the composition is administered or taken, dosage, etc. are as described above in the section on the composition for suppressing bone mineral density loss.

[0036] That is, the present invention includes the following aspects. [1] Use of rhamnose for the manufacture of a composition for inhibiting bone mineral density loss in postmenopausal women. [2] The use described in [1], wherein the inhibition of bone density loss is to inhibit the risk of bone density loss in healthy postmenopausal women. [3] The use according to [1] or [2], wherein the composition for suppressing bone mineral density loss contains 0.1 to 2 g of rhamnose per day. [4] The use according to [3], wherein the composition for suppressing bone mineral density loss contains 0.5 to 1 g of rhamnose per day. [5] The use of the composition for suppressing bone mineral density loss described in any one of [1] to [4], wherein the composition is rhamnose administered for at least 12 weeks. [6] The use according to any one of [1] to [5], wherein the composition for suppressing bone mineral density loss is for preventing osteoporosis. [7] The composition for inhibiting bone mineral density loss is also for use in a patient with a BMI of 13 to 24 kg / m 2 The use according to any one of [1] to [6], wherein the use is for a subject.

[0037] (Composition for suppressing bone density decline) The present invention also includes the following aspects: [8] A composition for inhibiting bone mineral density loss, comprising rhamnose as an active ingredient. [9] The composition for suppressing bone density loss described in [8], wherein the suppression of bone density loss is to suppress the risk of bone density loss in healthy postmenopausal women.

[10] The composition for suppressing bone mineral density loss according to [8] or [9], wherein the composition for suppressing bone mineral density loss is for administration of 0.1 to 2 g of the rhamnose per day.

[11] The composition for suppressing bone mineral density loss according to

[10] , wherein the composition for suppressing bone mineral density loss is administered in an amount of 0.5 to 1 g per day.

[12] The composition for suppressing bone mineral density loss described in any one of [8] to

[11] , wherein the composition for suppressing bone mineral density loss is administered for at least 12 weeks.

[13] The composition for suppressing bone mineral density loss according to any one of [8] to

[12] , wherein the composition for suppressing bone mineral density loss is for preventing osteoporosis.

[14] The composition for inhibiting bone mineral density loss is 2 The composition for suppressing bone mineral density loss described in any one of [8] to

[13] , which is intended for the following subjects:

[0038] (Treatment Method) The present invention also includes the following aspects:

[15] 13. A method for inhibiting bone mineral density loss in a subject, comprising administering rhamnose to a healthy postmenopausal female.

[16] The method according to

[15] , wherein the inhibition of bone mineral density loss is to inhibit the risk of bone mineral density loss in healthy postmenopausal women.

[17] The method according to

[15] or

[16] , wherein the administration comprises administering 0.1 to 2 g of the rhamnose per day.

[18] The method according to any one of

[15] to

[17] , wherein the administration comprises administering rhamnose for at least 12 weeks.

[19] The method according to any one of

[15] to

[18] , which is a method for preventing osteoporosis.

[20] BMI between 13 and 24 kg / m 2 The method according to any of

[15] to

[19] , wherein the method is for the following subjects: EXAMPLES

[0039] The present invention will be described below with reference to examples, but the present invention is not limited thereto. In the examples, unless otherwise specified, the blend amounts and other information are based on mass.

[0040] (Preparation Example) Rhamnose (purity 98.0% or more) was purified from the Japanese pagoda tree (Sophora japonica L.) by a conventional method. This product met the specifications of the 10th edition of the Japanese Food Additives Official Standards "L-Rhamnose".

[0041] Participants consumed one pack per day containing either 1.0 g or 0.5 g rhamnose per day (1.0 g rhamnose per day group and 0.5 g rhamnose per day group, respectively) or a placebo food pack (placebo group) with water after breakfast (all products were in powder form). The 1.0 g rhamnose per day group contained only 1.0 g rhamnose, while the 0.5 g rhamnose per day group and the placebo group contained dextrin instead of rhamnose. An ethical review conducted prior to the start of the study confirmed that the test products were indistinguishable in terms of color, odor and flavor.

[0042] (Test Method) We investigated the effect of rhamnose on bone mineral density (BMD) in healthy postmenopausal women when they ingested 1.0 g / day or 0.5 g / day for 24 consecutive weeks. Furthermore, we investigated the effect of rhamnose on human bone metabolism, particularly bone resorption, by evaluating bone metabolism markers such as TRAP isoform 5b (TRACP-5b), which is secreted into the human blood and correlates with osteoclast numbers.

[0043] This study was a randomized, placebo-controlled, double-blind, parallel-group comparative study. This example was conducted in accordance with the Declaration of Helsinki (2013) and in strict compliance with the "Ethical Guidelines for Life Science and Medical Research Involving Human Subjects" of the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Ministry of Economy, Trade and Industry.

[0044] The inclusion criteria were healthy Japanese women aged 20 years or older and younger than 65 years and the following: (1) Those who have not had a menstrual period for more than one year and are considered to be in menopause, (2) Subjects whose total lumbar spine volume is 70% or more of the young adult mean (YAM) at screening and before intake (Scr); (3) Those who the investigator judges to be eligible for this study. This study excluded patients with osteoporosis and those undergoing hormone therapy.

[0045] (evaluation) Based on the intervention effect evaluation period for bone resorption markers, the intake period was set at 24 weeks (approximately 6 months), and evaluations were performed 12 weeks (approximately 3 months) and 24 weeks (approximately 6 months) after the start of intake. Efficacy and safety evaluation items were examined at Scr, 12 weeks (12 weeks), and 24 weeks (24 weeks) after intake.

[0046] (result) A dual-energy X-ray absorptiometry integrated device (Discovery X-ray bone densitometry device, Toyo Medic Co., Ltd., Tokyo, Japan) was used to take frontal images of the lumbar spine. BMD was measured at L2, L3, and L4 using dual-energy X-ray absorptiometry (DEXA). The average BMD values ​​at L2, L3, and L4 were added together to calculate the total BMD of the frontal lumbar spine at 24 weeks.

[0047] BMD measurement. Using a Discovery X-ray bone densitometer, we evaluated the change in BMD of the total lumbar spine volume from Scr at 24 weeks, as measured by DEXA, and the actual measured value and change from Scr at 12 weeks. In addition, we evaluated the actual BMD values ​​of L2, L3, and L4, as well as the bone area, bone mineral content, T-score, YAM value, and Z-score of L2, L3, and L4, and the total volume and change from Scr at 12 and 24 weeks. For the evaluation of the lumbar spine, a Discovery X-ray bone density analyzer was used to measure the BMD, bone area, bone mineral content, T-score, YAM value, and Z-score of the left femur (neck, trochanter, and total mass), as well as the changes from Scr at 12 and 24 weeks.

[0048] The YAM score is the study participant's BMD expressed as a percentage of the mean BMD of the young participants, which is set at 100%. The T-score is the YAM score divided by the standard deviation (SD) of the BMD of the study participant compared to the mean BMD of the young participants, which is set at 0. The Z-score is the YAM score divided by the SD of the BMD of the age group compared to the mean BMD of the age group, which is set at 0.

[0049] Bone metabolism markers. The measured values ​​of deoxypyridinoline and pentosidine at 12 and 24 weeks, as well as the change and rate of change from Scr, were measured by urine analysis. Each item was measured by standard methods at LSI Medience Corporation (Tokyo, Japan). In addition, blood tests were performed to measure the actual values ​​and the change and rate of change from Scr in osteocalcin, bone-specific alkaline phosphatase, total type I procollagen N-terminal propeptide, type I collagen cross-linked N-telopeptide, type I collagen cross-linked C-telopeptide (CTx), and TRACP-5b at 12 and 24 weeks. Each item was measured according to standard methods at LSI Medience Corporation. After registering this study protocol in UMIN-CTR, we decided to calculate the change rate of only these markers to determine the significance of the intervention effect on bone metabolism.

[0050] Physical measurements, urine tests, and blood tests were performed as safety evaluation items. Weight, body mass index (BMI), percentage of body fat, systolic and diastolic blood pressure were measured during anthropometric measurements. Height was measured at the information session and was used to calculate BMI. In addition, urine protein, glucose, pH, and occult blood were measured by urine analysis. Each item was measured by standard methods at LSI Medience Corporation.

[0051] The total sample size was 36 (12 per group). In particular, Julious SA (2005) recommends that the number of patients in a pilot study be 12 per group, and the sample size in this example was appropriate. Enrollment, randomization, and blinding

[0052] All statistical analyses were two-sided, with a significance level of 5%. Data analysis was performed using the Statistical Package for the Social Sciences (version 23, IBM Japan, Tokyo, Japan). Participants who significantly deviated from the protocol were excluded from the analysis population. Multiplicity across multiple items and time points was not considered, except for outcomes other than actual BMD measurements. In this study, the per protocol analysis set (PPS) was used as the analysis dataset for efficacy evaluation, and the safety analysis population (SAF) was used as the analysis dataset for safety evaluation.

[0053] Baseline characteristics of participants were summarized using demographics (PPS, SAF) for age, height, weight, BMI, systolic and diastolic blood pressure, years since menopause, parity, fracture history, past exercise history, and total lumbar frontal BMD. Chi-square test was used for fracture history and past exercise history, and Student's t-test was used for the other items to compare the rhamnose intervention group and the placebo group.

[0054] Outcomes were presented as means and SD, between-group differences, and 95% confidence intervals for between-group differences. Between-group differences were presented as baseline means and estimated marginal means after intervention. Scr data were defined as baseline, and between-group comparisons were performed using analysis of variance. Meanwhile, baseline values ​​were compared between groups for measurements and changes (and rates of change) from Scr after intervention using a linear mixed model with factors of covariates, time point, group, presence or absence of heavy drinking habits, time point and group interactions, baseline value and time point interactions, and study participants. The statistical methods used in the subgroup analyses performed in this example were similar to those used in the analysis of the PPS dataset.

[0055] Baseline characteristics of participants in each analysis dataset are shown in Table 1. All study participants had undergone natural menopause. [Table 1]

[0056] The results for lumbar total frontal BMD, bone area, bone mineral content, T-score, YAM value, and Z-score are shown in Table 2. No significant differences were observed between the 1.0 g / day rhamnose group and the placebo group at 12 weeks, but significant differences were observed in the measured values ​​and changes in BMD, T-score, and YAM value at 24 weeks, with the 1.0 g / day rhamnose group showing significantly higher values. [Table 2]

[0057] There was a significant difference between the groups for TRACP-5b (Table 3). The actual TRACP-5b values ​​at 24 weeks were significantly lower in both the rhamnose 1.0 g / day group and the 0.5 g / day group compared with the placebo group. Similar results were observed for the amount and percentage change from baseline. [Table 3]

[0058] (Subgroup analysis) Subgroups were created based on the weight and BMI of the PPS analysis subjects, and an additional study was conducted. As there was no clear standard for weight, the standard was set at less than the mean PPS weight in the Scr (52.19 kg) (defined as SG1). Regarding BMI, a BMI of 20 kg / m 2 The following criteria were used (defined as SG2): The participant backgrounds for SG1 and SG2 are shown in Table 4. [Table 4]

[0059] The results of lumbar frontal total BMD measurements and each parameter for SG1 are shown in Table 5. In comparison with the placebo group, the actual values ​​and changes from baseline in BMD, T-score, YAM value, and Z-score at 12 and 24 weeks were significantly higher in the rhamnose 1.0 g / day group. Furthermore, the actual values ​​and changes from baseline in bone mineral content at 24 weeks were significantly higher in the rhamnose 1.0 g / day group (Table 5).

[0060] In comparison with the placebo group, the actual values ​​and changes from baseline in BMD, T-score, and YAM values ​​at 12 and 24 weeks were significantly higher in the rhamnose 0.5 g / day group. Furthermore, the actual values ​​and changes from baseline in bone mineral density and Z-score at 24 weeks were significantly higher in the rhamnose 0.5 g / day group (Table 5).

[0061] TRACP-5b. In the rhamnose 1.0 g / day and 0.5 g / day groups, the actual values ​​and changes from baseline at 12 and 24 weeks were significantly lower than in the placebo group (Table 5). [Table 5]

[0062] The results of lumbar frontal total volume BMD measurements and each parameter in SG2 are shown in Table 6. The actual measured values ​​and changes from baseline of BMD, T-score, and YAM values ​​at 12 and 24 weeks were significantly higher in the rhamnose 1.0 g / day group. Furthermore, the actual measured values ​​and changes from baseline of Z-score at 24 weeks were significantly higher in the rhamnose 1.0 g / day group compared to the placebo group (Table 6).

[0063] In comparison with the placebo group, the rhamnose 0.5 g / day group showed significantly higher actual YAM values ​​and changes from baseline at 12 and 24 weeks. Furthermore, the rhamnose 0.5 g / day group showed significantly higher actual bone mineral density, T-score, and Z-score at 24 weeks and changes from baseline compared with the placebo group (Table 6).

[0064] TRACP-5b. The 24-week actual values ​​and changes from baseline in the rhamnose 1.0 g / day and 0.5 g / day groups were significantly lower than those in the placebo group (Table 6). [Table 6]

[0065] In this example, the purpose was to verify the effect of 1.0 g / day or 0.5 g / day of rhamnose on BMD in healthy postmenopausal women when they were given 1.0 g / day or 0.5 g / day for 24 consecutive weeks. The actual BMD measured in the frontal measurement of the lumbar spine at 24 weeks showed that the mean value of the 0.5 g / day rhamnose group was higher than that of the placebo group, but this was not statistically significant. On the other hand, the 1.0 g / day rhamnose group showed a significantly higher value than the placebo group, indicating that 1.0 g / day rhamnose intake contributes to the maintenance of BMD in postmenopausal women.

[0066] Based on the above, participants with body weight below the average (52.19 kg) or BMI below 20 kg / m 2 In the following subgroups of participants, the actual BMD values ​​in frontal measurements of the lumbar spine at 24 weeks were significantly higher in the rhamnose 1.0 g / day group as well as the rhamnose 0.5 g / day group than in the placebo group:

[0067] BMI 20 kg / m 2 Individuals aged 65 years or older are classified as malnourished (Ministry of Health, Labour and Welfare 2020), and in Japan the target BMI range for individuals aged 50–64 is 20.0–24.9 kg / m 2 (Ministry of Health, Labour and Welfare 2019). Previous studies of postmenopausal women have shown that low body weight (BMI ≤ 20.0 kg / m 2 ) (Wu and Du 2016) and thin (BMI < 20.0 kg / m 2)(Armstrong et al. 2012) Considering subgroup analyses, the effects of rhamnose intake may have been more sensitive in individuals prone to underweight.

[0068] In this example, the change rate of TRACP-5b was calculated to evaluate the significance of the test food intervention according to the guidelines for the use of bone metabolism markers from the Japan Osteoporosis Society (Nishizawa et al. 2019). Interestingly, TRACP-5b values ​​were significantly lower in the rhamnose 1.0 g / day group and the 0.5 g / day group compared to the placebo group after 24 weeks of intake. The intergroup difference in the change rate relative to the placebo group was -18.82% in the rhamnose 1.0 g / day group and -18.11% in the 0.5 g / day group. According to the guidelines (Nishizawa et al. 2019), the minimal significant change (MSC) of TRACP-5b was 12.4%, and in this study, the intergroup difference in TRACP-5b exceeded the MSC. Therefore, it was considered that rhamnose suppressed osteoclast proliferation in the participants of this study and controlled bone resorption.

[0069] The results of BMD and TRACP-5b measurements consistently indicated that rhamnose administration contributed to the maintenance of BMD. Therefore, rhamnose was reasonably considered to be a food that maintains BMD in healthy postmenopausal women. In particular, an intake of 1.0 g / day of rhamnose would be sufficient to prevent the decline of BMD in the study population.

[0070] Furthermore, it has been shown that ingesting 0.5 g / day of rhamnose may be able to prevent BMD loss in certain populations.

Claims

1. A composition for inhibiting bone mineral density loss, which contains rhamnose and is to be administered to postmenopausal women at a dose of 0.1 to 2 g per day.

2. The composition for suppressing bone mineral density loss according to claim 1, wherein rhamnose is administered daily for at least 12 weeks.