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

Abstract

Provided is a composition for inhibiting bone density loss. Specifically, the present invention provides a composition for inhibiting bone density loss that contains rhamnose and is for administration to postmenopausal women. The inhibition of bone density loss in this embodiment can be the inhibition of the risk of bone density loss in healthy postmenopausal women. The composition of this embodiment can be a composition taken at a daily dose of 0.1-2 g. The composition can be administered daily for at least 12 weeks. The present invention also provides a method for imparting a bone density loss inhibitory effect to a composition by including rhamnose in the composition.

Description

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

[0001] The present invention relates to a composition for suppressing bone mineral density loss containing rhamnose and a method for imparting an inhibitory effect on bone mineral density loss. More specifically, the present invention relates to a composition for suppressing bone mineral density loss in postmenopausal women and a method for imparting an inhibitory effect on bone mineral density loss.

[0002] Osteoporosis is a disease characterized by increased bone fragility and an increased risk of fracture. 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), as well as disability-adjusted life years, a population health status that indicates the standard life expectancy lost due to death or disability, more than doubled from 1990 to 2019, making low BMD a global health burden.

[0003] Bone tissue is constantly remodeled to maintain skeletal mass, structure, and quality. 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 changes in estrogen levels. In postmenopausal women, estrogen deficiency induces bone turnover that favors bone resorption due to promotion of osteoclastogenesis and suppression of osteoblastogenesis, making them prone to the development of osteoporosis (Non-Patent Document 3). Menopause is an inevitable event for women. Therefore, maintaining bone mass after menopause is an important challenge for maintaining women's lifelong health.

[0004] Although bone resorption inhibitors have been proposed for regulating bone density (Patent Document 1), it cannot be said that sufficient research has been conducted into effective methods for inhibiting bone density loss specifically for postmenopausal women.

[0005] JP 2015-38076 A

[0006] 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):609Ballhause 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.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.

[0007] An object of the present invention is to provide a composition for suppressing the loss of bone mineral density in postmenopausal women.

[0008] As a result of extensive research to solve the above problems, the present 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 suppressing bone mineral density loss, which contains rhamnose and is 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.

[0011] By using the composition for suppressing bone mineral density loss of the present invention, it is possible to suppress bone mineral density loss in postmenopausal women.

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

[0013] [Composition for Suppressing Bone Mineral Density Decline] The composition for suppressing bone mineral density decline of the present invention contains rhamnose (L-Rhamnopyranose monohydrate). Rhamnose is a deoxysugar found primarily 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 the α-type or the β-type. It may also be in the form of a hydrate.

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

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

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

[0017] Examples of such carriers or additives include excipients such as 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 talc; starch, pregelatinized starch, gelatin, gum arabic, dextrin, methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, Examples of suitable binders include cellulose, carboxymethylcellulose, and salts thereof; disintegrants such as calcium carbonate, crospovidone, starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethyl starch, crystalline cellulose, and agar; lubricants such as magnesium stearate, talc, polyethylene glycol, and anhydrous silicic acid; 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 methyl phthalate; and flavoring agents such as sucrose, glucose, saccharin sodium, sorbitol, citric acid, and aspartame.In addition to the above ingredients, the present invention may contain, within the scope of not impairing the effects of the present invention, ingredients that are generally acceptable as pharmaceutical additives, such as stabilizers, surfactants, plasticizers, capsule shells, solubilizers, reducing agents, buffers, sweeteners, bases, absorption promoters, adsorbents, hardeners, antioxidants, glossing agents, flavorings, capsule shells, supports, sustaining agents, humectants, moisturizing agents, fillers, antifoaming agents, refreshing agents, adhesives, enhancers, chewing agents, antistatic agents, flavorings, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, adhesion enhancers, thickeners, Optional ingredients such as pH adjusters, floating agents, dispersants, propellants, fragrances, rust inhibitors, moisture-proofing agents, release-controlling membranes, preservatives, trapping agents, preservatives, solubilizers, solubilizers, solvents, release agents, and fluidizing agents, as well as sweeteners, colorants, preservatives, thickeners, stabilizers, gelling agents, thickening agents, antioxidants, color formers, bleaching agents, antifungal agents, emulsifiers, leavening agents, seasonings, acidulants, bittering agents, glazing agents, gum bases, nutritional fortifiers, manufacturing agents, and flavorings, which are acceptable as food additives, may also be added as desired.

[0018] The composition for suppressing bone mineral density loss of the present invention may contain, in addition to the above-mentioned components, any edible components and / or mineral components, etc., within the range that does 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 extract, coffee extract, cocoa extract, etc.), fruit juices (e.g., orange, grape, apple, peach, pineapple, tomato, strawberry, etc.), sweeteners (sweets, Examples of suitable 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), and Monk Fruit extract (e.g., mogroside), and flavorings.

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

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

[0022] The composition for suppressing bone mineral density loss of the present invention can be used as a food, drink, or pharmaceutical product having an inhibitory effect on bone mineral density loss, or as an additive for imparting an inhibitory effect on bone mineral density loss to a food, drink, or pharmaceutical product. The composition for suppressing bone mineral density loss of the present invention can be in any form, including solid forms such as powder, granules, tablets, and capsules, as well as semi-solid or liquid forms such as syrup, emulsion, liquid, and gel.

[0023] When the composition for suppressing bone mineral density loss of the present invention is a food, drink or pharmaceutical product, the subject thereof 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 compositions include milk drinks, lactic acid bacteria drinks, dairy drinks, carbonated drinks, fruit drinks (e.g., fruit juice, fruit juice mix, fruit juice drinks, fruit juice carbonated drinks, fruit juice pulp drinks, diluted drinks, etc.), vegetable drinks, vegetable and fruit drinks, tea drinks (e.g., black tea drinks, green tea drinks, oolong tea drinks, barley tea drinks, blended tea drinks, herbal tea, flavored tea, and other tea drinks), near water, powdered drinks, sports drinks, supplement drinks, nutritional drinks, functional drinks, jelly drinks, drink soups, soy milk drinks, powdered drinks such as powdered juice dissolved in water, protein-containing drinks, and other beverages; puddings such as custard pudding, milk pudding, and fruit juice pudding, desserts such as jelly, bavarois, and yogurt; frozen desserts such as ice cream, ice milk, lacto ice cream, and frozen desserts; chewing gum and bubble gum, and other gums (e.g., stick gum, sugar-coated granular 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, marble, etc.), soft candies (e.g., caramel, nougat, gummy candy, marshmallows, etc.), sugar-coated candies, drops, toffee, etc.; confectioneries such as cookies, biscuits, snacks, etc.; liquid condiments such as separate dressing, oil-free dressing, ketchup, sauces, etc.; jams such as strawberry jam, blueberry jam, marmalade, apple jam, apricot jam, preserves, syrup, etc.; fruit liquors such as red wine, and carbonated alcoholic beverages; processed fruits such as cherries, apricots, apples, strawberries, and peaches in syrup; and processed agricultural products such as pickles.

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

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

[0027] [Method for imparting an inhibitory effect on bone mineral density loss] The method for imparting an inhibitory effect on bone mineral density loss of the present invention can be carried out by adding, blending, or allowing rhamnose to coexist with 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 increase in bone mineral density of 0.7 g / cm ２ ~0.95g / cm ２ In subjects with a bone mineral density of approximately 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 in controls who did not ingest rhamnose. Here, the bone mineral density loss rate (%) is calculated by dividing the amount of bone mineral density change after a predetermined period by the initial bone mineral density and multiplying the result by 100. Although not limited thereto, it may be, for example, the value calculated 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] (Uses) The composition for suppressing bone mineral density loss of the present invention, which contains rhamnose, can suppress osteoclast differentiation and reduce the number of cells that differentiate into osteoclasts. By suppressing osteoclast differentiation, bone metabolism that is biased toward bone resorption due to increased osteoclast differentiation, as seen in osteoporosis and its precursor stages, can be restored to a normal balance. Therefore, the composition for suppressing bone mineral density loss of the present invention, which contains rhamnose, can be used to suppress bone mineral density loss. Furthermore, the composition for suppressing bone mineral density loss of the present invention, which contains rhamnose, can be administered after assessing 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), or tartrate-resistant acid phosphatase (TRACP-5b). For example, when the measured value of a bone resorption marker is higher than the reference value generally used in the art, it can be determined that bone resorption is suspected to be enhanced. For example, for NTx, the reference value measured using serum collected from postmenopausal women is 10.7 to 24.0 nmol BCE (Bone Collagen Equivalent) / L (Guide to the Proper Use of Bone Metabolic Markers in the Treatment of Osteoporosis, 2018 Edition, Japan Osteoporosis Society), and subjects with, for example, 18 nmol BCE / L or more and 24.0 nmol BCE / L or less can also be targeted. For example, the reference value for TRACP-5b measured using serum collected from postmenopausal women is set at 250 to 760 mU / dL (Guide to Proper Use of Bone Metabolic Markers in Osteoporosis Treatment, 2018 Edition, Japan Osteoporosis Society), and subjects with a reference value of 450 mU / dL or more and 760 mU / dL or less can also be included. The reference value can be set appropriately depending on the type of sample obtained from the subject (e.g., blood (serum, etc.), urine, etc.) and the age of the subject.Furthermore, for example, when the measured value of a bone formation marker is lower than the reference value commonly used in the art, it can be determined that bone resorption is suspected to be increased. For example, for OC, a reference value of 14.2 to 54.8 ng / mL can be used as the value measured using serum collected from postmenopausal women (Guide to the Proper Use of Bone Metabolic Markers in the Treatment of Osteoporosis, 2018 Edition, Japan Osteoporosis Society). For example, subjects with a BAP level of 14.2 ng / mL to 22 ng / mL can be used as the reference value. For BAP, a reference value of 3.8 to 22.6 μg / L can be used as the value measured using serum collected from postmenopausal women (Guide to the Proper Use of Bone Metabolic Markers in the Treatment of Osteoporosis, 2018 Edition, Japan Osteoporosis Society). For example, subjects with a BAP level of 3.8 to 17.5 μg / L can be used as the reference value. Furthermore, for example, the degree of bone formation can be evaluated by comparing the measured value of a bone formation marker with a reference value commonly used in the art, the degree of bone resorption can be evaluated by comparing the measured value of a bone resorption marker with a reference value commonly used in the art, and by comparing the degrees of bone formation and bone resorption, if the degree of bone resorption is greater than the degree of bone formation, it can be determined that bone resorption is increased. Therefore, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to a subject whose NTx measured using serum is, for example, 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 suppressing bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to a subject whose serum TRACP-5b level 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 rhamnose-containing composition for suppressing bone mineral density loss of the present invention can be ingested or administered to, for example, a subject whose serum OC is 14.2 to 54.8 ng / mL or less, preferably 14.2 to 22 ng / mL or less. The rhamnose-containing composition for suppressing bone mineral density loss of the present invention can be ingested or administered to, for example, a subject whose serum BAP is 3.8 to 22.6 μg / L, preferably 3.8 to 17.5 μg / L. Such subjects include, for example, postmenopausal women, preferably healthy postmenopausal women.

[0029] By inhibiting differentiation into osteoclasts, bone metabolism biased toward bone resorption is restored to a normal balance, thereby preventing bone fragility and bone mass loss. Therefore, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be used to increase bone mass. Furthermore, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to subjects who have reduced bone mass or are suspected of having reduced bone mass but are still considered healthy. For example, if the Young Adult Mean (YAM) is less than 80%, it can be determined that the subject has reduced bone mass or is suspected of having reduced bone mass. The composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to subjects whose YAM is 95%, 90%, 85%, 80%, or 75% or less, or whose YAM is 70%, 75%, 80%, or 85% or more.

[0030] Furthermore, it is known that when differentiation into osteoclasts is promoted in the bone that supports the teeth (alveolar bone), bone metabolism becomes biased toward bone resorption, resulting in alveolar bone resorption and periodontal diseases such as periodontitis. For this reason, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be used for the treatment or prevention of periodontal disease. Furthermore, the composition for inhibiting bone mineral density loss of the present invention, which contains rhamnose, can be ingested or administered to subjects with or suspected of having periodontal disease.

[0031] (Dosage, etc.) The intake amount of the composition for suppressing bone mineral density loss of the present invention may vary depending on the subject's body weight, age, condition, or other factors. The administration dose, route, interval, and amount and interval of intake can be determined appropriately by those skilled in the art. Generally, for an adult, the daily amount of rhamnose 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. Furthermore, the daily amount 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] (Subjects for Administration or Ingestion) The subjects for administration or ingestion of the composition for suppressing bone mineral density loss 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 subject's body weight 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 subject's body weight 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 weigh 40 to 55 kg, 41 to 52 kg, 41 to 50 kg, or 43 to 48 kg. The subject's BMI is preferably 24 kg / m ２ More preferably 22 kg / m or less ２ or less, and even more preferably 20 kg / m ２ Below 19 kg / m, most preferably ２ The subject's BMI is preferably 13 kg / m ２ More preferably, 14 kg / m ２ or more, and even more preferably 15 kg / m ２ The subject's BMI is preferably between 13 and 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 / m２ As shown in the examples, the effects of the present invention are more pronounced in subjects with lower BMI values. The present invention can also be targeted at those who wish to ingest foods that contribute to bone health by maintaining bone components. Foods that contribute to the maintenance of bone components in women, and those who wish to maintain strong bones, can also be targeted. Postmenopausal women refer to subjects who have completely stopped menstruating and have "not menstruated for more than one year." There are no age restrictions, but typically the subjects are 45 years of age or older, 47 years of age or older, or 50 years of age or older. There is no upper age limit, but the subjects are preferably 75 years of age or younger, more preferably 70 years of age or younger, and even more preferably 65 years of age or younger.

[0033] (Method for producing the composition for suppressing bone mineral 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 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] (Method for inhibiting bone mineral density loss, 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 inhibiting bone mineral density loss, details of related diseases, recipients of administration or intake, dosage, etc. are the same as those described above in the section on the composition for inhibiting bone mineral density loss.

[0035] (Use of rhamnose for producing a composition for suppressing bone mineral density loss) The present invention also relates to the use of rhamnose for producing a composition or a drug for suppressing bone mineral density loss. Here, the definition of suppression of bone mineral density loss, details of related diseases, recipients of administration or intake, dosage, etc. are the same as those 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 producing a composition for suppressing bone mineral density loss in postmenopausal women. [2] The use according to [1], wherein the suppression of bone mineral density loss is suppressing the risk of bone mineral density loss in healthy postmenopausal women. [3] The use according to [1] or [2], wherein the composition for suppressing bone mineral density loss is for administering 0.1 to 2 g of rhamnose per day. [4] The use according to [3], wherein the composition for suppressing bone mineral density loss is for administering 0.5 to 1 g of rhamnose per day. [5] The use according to any of [1] to [4], wherein the composition for suppressing bone mineral density loss is for administering rhamnose for at least 12 weeks. [6] The use according to any of [1] to [5], wherein the composition for suppressing bone mineral density loss is for preventing osteoporosis. [7] The use according to any of [1] to [5], wherein the composition for suppressing bone mineral density loss is for administering rhamnose for at least 12 weeks. ２ The use according to any one of [1] to [6], which is for a subject.

[0037] (Composition for suppressing bone mineral density loss) The present invention also includes the following aspects: [8] A composition for suppressing bone mineral density loss, comprising rhamnose as an active ingredient. [9] The composition for suppressing bone mineral density loss according to [8], wherein the suppression of bone mineral density loss is suppressing the risk of bone mineral 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 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 for administration of 0.5 to 1 g of rhamnose per day.

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

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

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

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

[14] The composition for inhibiting bone mineral density loss is for a patient with a BMI of 13 to 24 kg / m ２ The composition for inhibiting bone mineral density loss according to 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] A method for suppressing bone mineral density loss in a subject, comprising administering rhamnose to a healthy postmenopausal female.

[16] The method according to

[15] , wherein the suppression of bone mineral density loss is suppressing the risk of bone mineral density loss in a healthy postmenopausal female.

[17] The method according to

[15] or

[16] , wherein the administration comprises administering 0.1 to 2 g of 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] , wherein the method is for preventing osteoporosis.

[20] A method according to any one of

[15] to

[18] , wherein the method is for preventing osteoporosis.

[21] A method according to any one of

[15] to

[18] , wherein the method is for preventing osteoporosis in a subject having a BMI of 13 to 24 kg / m ２ The method according to any one of

[15] to

[19] , which is for the following subjects:

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

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

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

[0042] (Test Method) The effect of rhamnose on bone mineral density (BMD) was examined in healthy postmenopausal women when they ingested 1.0 g / day or 0.5 g / day of rhamnose for 24 consecutive weeks. Furthermore, the effect of rhamnose on human bone metabolism, particularly bone resorption, was investigated 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 to 65 years, and the following: (1) those who had not had a menstrual period for at least one year and were considered to be menopausal, (2) those whose lumbar spine total mass was 70% or more of the young adult mean (YAM) at screening and before intake (Scr), and (3) those who were deemed eligible for this study by the investigator. Patients with osteoporosis and those undergoing hormone therapy were excluded from this study.

[0045] (Evaluation) Based on the intervention effect evaluation period for bone resorption markers, the intake period was set to 24 weeks (approximately 6 months), and evaluations were conducted at 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] (Results) Frontal images of the lumbar spine were taken using a dual-energy bone X-ray absorptiometry (Discovery X-ray bone densitometry, Toyo Medic Co., Ltd., Tokyo, Japan). Bone mineral density (BMD) at L2, L3, and L4 was measured using dual-energy X-ray absorptiometry (DEXA). The mean BMD values ​​at L2, L3, and L4 were summed to calculate the total BMD at the front of the lumbar spine at 24 weeks.

[0047] BMD Measurement. Using a Discovery X-ray bone densitometer, the change in BMD of the total lumbar spine frontal volume from Scr at 24 weeks, as measured by DEXA, and the actual measured values ​​and changes from Scr at 12 weeks were evaluated. Furthermore, the actual measured BMD values ​​of L2, L3, and L4, as well as the bone area, bone mineral content, T-score, YAM score, and Z-score of each L2, L3, and L4, and the total volume and changes from Scr at 12 and 24 weeks were evaluated. For the lumbar spine, a Discovery X-ray bone densitometer was used to evaluate the actual measured BMD, bone area, bone mineral content, T-score, YAM score, and Z-score of the left femur (neck, trochanter, and total volume), as well as the changes from Scr at 12 and 24 weeks.

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

[0049] Bone metabolism markers. Deoxypyridinoline and pentosidine were measured at 12 and 24 weeks, and the changes and percentage changes from Scr were measured by urine analysis. Measurements of each parameter were performed according to standard methods at LSI Medience Corporation (Tokyo, Japan). Blood tests were also performed to measure the actual values ​​of 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, as well as the changes and percentage changes from Scr. Measurements of each parameter were performed according to standard methods at LSI Medience Corporation. After registering this study protocol with UMIN-CTR, we decided to calculate the percentage changes of only these markers to determine the significance of the intervention effect on bone metabolism.

[0050] Physical measurements, urinalysis, and blood tests were conducted as safety evaluation items. Body weight, body mass index (BMI), body fat percentage, and systolic and diastolic blood pressure were measured during physical measurements. Height was measured at the information session and used to calculate BMI. In addition, urinary protein, glucose, pH, and occult blood were measured by urinalysis. Each item was measured according to standard methods at LSI Medience Corporation.

[0051] The total sample size was 36 (12 per group). In particular, Julio SA (2005) recommended 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 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 of data across multiple items and time points was not considered 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] Participants' baseline characteristics were summarized demographically using PPS and 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. The rhamnose intervention group and placebo group were compared using the chi-square test for fracture history and past exercise history, and the other items were compared using the Student's t-test.

[0054] Outcomes were presented as means and SDs, 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 post-intervention Scr measurements and changes (and rates of change) using a linear mixed model with factors including covariates: time point, group, presence or absence of heavy drinking, time point-group interaction, baseline value-time point interaction, and study participant. The statistical methods used in the subgroup analyses performed in this study 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 were at natural menopause.

[0056] The results for the total lumbar 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.

[0057] Significant differences were observed between the groups for TRACP-5b (Table 3). Measured TRACP-5b levels at 24 weeks were significantly lower in both the rhamnose 1.0 g / day and 0.5 g / day groups compared with the placebo group. Similar results were observed for the change and percent change from baseline.

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

[0059] The results of lumbar spine total frontal BMD measurements and each parameter for SG1 are shown in Table 5. Compared with the placebo group, the actual measured 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 measured values ​​and changes from baseline in bone mineral density at 24 weeks were significantly higher in the rhamnose 1.0 g / day group (Table 5).

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

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

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

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

[0064] TRACP-5b. The 24-week observed 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).

[0065] The purpose of this example was to examine the effect of 24 weeks of continuous intake of rhamnose at 1.0 g / day or 0.5 g / day on BMD in healthy postmenopausal women. Actual BMD measurements in frontal lumbar spine measurements at 24 weeks showed that the mean value for 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, demonstrating that 1.0 g / day rhamnose intake contributes to the maintenance of BMD in postmenopausal women.

[0066] Based on the above, participants with a weight below the average (52.19 kg) or a BMI of 20 kg / m ２ In the following subgroups of participants, the actual BMD measured in frontal measurements of the lumbar spine at 24 weeks was 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 is 20 kg / m ２ Individuals aged 65 years and 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 underweight (BMI < 20.0 kg / m ２ ) (Armstrong et al. 2012) Considering subgroup analysis, the effect of rhamnose intake may be more sensitively reflected in individuals prone to underweight.

[0068] In this example, the percent change in TRACP-5b was calculated to evaluate the significance of the test food intervention in accordance with the Japan Osteoporosis Society's guidelines for the use of bone metabolic markers (Nishizawa et al. 2019). Interestingly, after 24 weeks of intake, the 1.0 g / day and 0.5 g / day rhamnose groups had significantly lower TRACP-5b levels compared to the placebo group. The between-group difference in percent change relative to the placebo group was -18.82% for the 1.0 g / day rhamnose group and -18.11% for the 0.5 g / day rhamnose group. According to the guidelines (Nishizawa et al. 2019), the minimally significant change (MSC) for TRACP-5b was 12.4%, and in this study, the between-group difference in TRACP-5b exceeded the MSC. Therefore, it appears that rhamnose inhibited osteoclast proliferation and controlled bone resorption in the participants in this study.

[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 was considered sufficient to prevent BMD decline in the study population.

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

Claims

1. A composition containing rhamnose for administering to postmenopausal women to inhibit bone mineral density loss.

2. A composition for suppressing bone mineral density loss according to claim 1, wherein the suppression of bone mineral density loss is to suppress the risk of bone mineral density loss in healthy postmenopausal women.

3. A composition for inhibiting bone mineral density loss according to claim 1 or 2, for taking 0.1 to 2 g of rhamnose per day.

4. A composition for inhibiting bone mineral density loss according to claim 1 or 2, for taking rhamnose daily for at least 12 weeks.

5. A method for imparting to a composition an inhibitory effect on bone mineral density loss by allowing rhamnose to coexist in the composition.

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