PREVENTIVES/REMEDIES FOR OSTEOPOROSIS

Abstract: The prophylactic, therapeutic agent for osteoporosis of the invention is a combination of a indigestible oligosaccharide with phytoestrogen which inhibits bone loss, and the action to inhibit the reduction of bone density can be improved remarkably by combining the indigestible oligosaccharide.

Description: Technical Field This invention relates to a prophylactic, therapeutic agent capable of inhibiting bone loss which is found in osteoporosis. Background Art In Japan, the population of aged persons is sharply increasing, and various social problems occur therewith. One of the problems is in nursing of the aged persons. Most of the aged persons who require nursing are bedriddens, except for persons suffering from cranial nerve troubles, such as dementia. The greatest cause which makes aged persons bedridden is bone fracture caused by osteoporosis. Therefore, it is very important to prevent osteoporosis. Osteoporosis is caused by the trouble in the relation ship between resorption and formation of the bone, and various reasons are pointed out, such as metabolic troubles and internal secretion troubles. Various medicines have already been developed. Estrogen which is a female hormone inhibits resorption of the bone. It has already been used in clinical fields for the medical treatment of osteoporosis, and its medical effects have been confirmed. However, its relevance to uterine cancer has been pointed out, and therefore, it cannot be said that there is no problem. Thereupon, phytoestrogen is being investigated as an alternative, phytoestrogen is contained in plant, and exhibits female hormone-like action. As representative components thereof, genistein and daidzein are known which are isoflavons of soybean, and enterolactone and enterodiol are further known which are lignars contained in rye, blueberry, sesame, tea and so on. As a result, it has become apparent that phytoestrogen has also the action to inhibit bone loss, and investigations are advanced for putting it to practical use (Biol. Pharm. Ball., 21(1) 62-66 (1998), J. Nutr. 126: 161-167, 1996, J.Nutr. 126:176-182, 1996). However, its effects are still insufficient. International patent application WO 97/078111 describes the use of soy molasses for the prevention and amelioration of divers and variant pathological conditions including osteoporosis and for the provision of general well-being. According to this document, the soy molasses contains along with the oligosugars stachyrose and raffinose, the phytoestrogens isoflavones: genistein and daidzein, and other soy bean isoflavones. European patent application EP 0 753 302 describes a material for the prevention and treatment of osteoporosis containing minerals and indigestible oligosaccharides such as fructooligosaccharides. US patent 5,516,528 describes a pharmaceutical composition for oral delivery including about 1-2 mg mammalian estrogen and about 25-100 mg phytoestrogen, which is used, for example, in a therapeutic regimen designed to reduce the risk of osteoporosis in postmenopausal women. An object of the invention is to provide an agent which prevents the reduction of bone density occurring with the outbreak and progress of osteoporosis and exhibits excellent effects for the prevention and medical treatment of osteoporosis. Disclosure of Invention The inventors investigated eagerly in order to achieve the above object, and as a result, they found that the reduction of bone density can be improved remarkably by combining a indigestible oligosaccharide, namely fructooligosaccharides, with phytoestrogen. The present invention has been made based on the finding, and relates to a prophylactic, therapeutic agent for osteoporosis which comprises phytoestrogen and fructooligosaccharides as an indigestible oligosaccharide. Although the function and mechanism are not entirely clear, it can be assumed that enteric bacteria, such as Bifidobacterium bifidum having a high β -glucosidase activity, are increased by the intake of the indigestible oligosaccharide, and absorption of phytoestrogen is raised thereby steadily. That is, natural phytoestrogen is combined with a sugar chain to form a glycoside, and its absorption by an organism is not possible until the sugar chain is cut off. The cutting off of the sugar chain is made mainly by bacteria existing in large intestine. However, the type and quantity of the bacteria are greatly different between individuals, and in some persons, the absorption occurs little. It can be considered that enteric bacteria are increased or their activities are raised by the combination of the indigestible oligosaccharide, and the sugar chain is cut off phytoestogen at a high rate to raise the absorption rate of phytoestrogen. Best Mode for Carrying Out the Invention Phytoestrogen is contained in plant, and exhibits female hormone-like action. The phytoestrogen is a substance called SERM (Selective estrogen receptor modulator) contained in plants and exhibits a similar action to female hormone in an organ specificity viewpoint, such as interacting with a receptor of estrogen which is a female hormone and inhibiting resorption of the bone. The phytoestrogen is an isoflavon, such as genistein or daidzein which are isoflavons of soybean, a lignan, such as enterolactone or enterodiol, or the like. Plants containing phytoestrogen in quantity are soybean, rye, blueberry, sesame, tea and so on. The phytoestrogen applicable to the prophylactic, therapeutic agent for osteoporosis of the invention may be in a form of the above food itself or a fabricated one thereof as well as extracted semipurified one. The indigestible oligosaccharide is a disaccharide to pentacontasaccharide, preferably a disaccharide to pentasaccharide, which is not digested by the digestive enzymes in an organism, and preferred ones increase absorption of calcium in the intestines. More specifically, the indigestible oligosaccharide are fructooligosaccharides. Other known indigestible oligosaccharides are raffinose, galactooligosaccharides, xylooligosaccharides and the like. The fructooligosaccharides are a designation of a mixture of sugars having a similar structure to sucrose which are formed by bonding 1 to 3 fructose molecules to the fructose residue of sucrose. Each sugar is named 1-kestose (GF 2 ), nystose (GF 3 ) and fructo-furanosyl nystose (GF 4 ) from the shortened chain length one. The galactooligosaccharide is a generic term of 2 to 6 sugar oligosaccharides formed by acting β -galactosidase on lactose (disaccharide composed of galactose and glucose bonded by a β-1,4-bond). A representative component of the galactooligosaccharide is 4'-galactosyl lactose (hereinafter abbreviated as 4'-GL) having a structure composed of lactose and galactose bonded through a β-1,4-bond. As the other components, there are tetra to hexasaccharides formed by further bonding galactose molecule(s) to 4'-GL through β -1,4-bond(s), disaccharides composed of galactose and glucose bonded through a β -1,3-bond, and so on. The structure of the galactooligosaccharide is shown below: The xylooligosaccharide is a sugar derived from hemicellulose having a structure composed of about 2 to 7 xylose molecules bonded through β -1,4-bond(s). Some xylooligosaccharides have a side chain of arabinose, glucuronic acid, etc. The indigestible oligosaccharide may be a crude product as well as a purified one. A suitable content ratio of phytoestrogen and the indigestible oligosaccharide is about 1:10 to 1:1,000, preferably about 1:100 to 1:500. The prophylactic, therapeutic agent of the invention may not contain calcium. The prophylactic, therapeutic agent of the invention is taken orally, and a suitable ingestion per once is about 1 to 100 mg, preferably about 10 to 50 mg as the weight of phytoestorogen per 1 kg of body weight. Examples Example 1 The prophylactic, therapeutic effects of the invention on osteoporosis were evaluated using ovariectomized female rats which are commonly used as a model animal for osteoporosis (reference: Nippon Eiyo · Shokuryo Gakkai-shi, vol. 43, No. 6, pp437-443). That is, 20 SD strain female rats of 15 weeks old were divided into 5 groups each consisting of 4 rats. The ovaries of the rats of 4 groups were removed, and a counterfeit operation was applied to the remaining one group, under ether anesthesia, respectively. The test feed shown in Table 1 was fed to the rats of each group. In this example, soybean flour containing isoflavon in quantity (containing 2.6 mg isoflavon per 1 g soybean flour, reference: Shokuhin to Kaihatsu, Vol. 31, No. 6 pp 44-47, 1996) was used as phytoestrogen. Pure fructooligosaccharides was used having a purity of 95 wt. % or more (trade name: "Mei-Oligo-P Powder, Meiji Seika Kaisha, Ltd.). Using the above soybean flour and fructooligosaccharides, a standard purified feed (control feed), a fructooligosaccharides-containing feed, a soybean flour-containing feed, and a fructooligoscchaide-soybean flour mixture-containing feed which is the prophylactic, therapeutic agent for osteoporosis of the invention, having a composition described in Table 1 were prepared, and the rats were bred for one month using these feeds. When breeding was finished, the rats were slaughtered and dissected, and the right femur was taken out. After removing the soft tissues, the bone density (BMD) of the femur taken out was measured by a double X-ray bone density measuring apparatus (made by Aroka). The results shown in Table 2 indicate that a remarkable increase of bone density was not found in the case of taking fructooligosaccharide or soybean flour alone compared with the bone density of the counterfeit operation group. However, the reduction of bone density was inhibited remarkably in the group of taking the prophylactic, therapeutic agent for osteoporosis of the invention which is a mixture of both materials, and the bone density was in a similar degree to the bone density of the counterfeit operation group. From the above results, it was confirmed that the agent of the invention is effective against the prophylaxis and medical treatment of osteoporosis. Feed Composition (%) Control Feed Soybean flour feed Fructooligosaccharides feed The agent of the invention containing feed Casein 25 22.5 25 22.5 Corn starch 49.6 49.5 49.5 49.5 Corn oil 6 6 6 6 Vitamin mixture 1 1 1 1 Mineral mixture 3.5 3.5 3.5 3.5 Cellulose powder 5 5 5 5 Sucrose 10 10 8 8 Soybean flour 0 2.5 0 (Prophylactic of the invention) 2.5 Fructooligosaccharides 0 0 2 2 Industrial Applicability By taking orally the prophylactic, therapeutic agent of the invention, it is possible to inhibit the reduction of bone density and to prevent and remedy osteoporosis. The prophylactic, therapeutic agent of the invention is effective not only against human but also other animals, such as domestic animals and pets. The prophylactic, therapeutic agent of the invention can be eaten as it is, drunk by suspending it is a suitable drink or eaten by adding it to a suitable food.

Claims: A prophylactic, therapeutic agent for osteoporosis which comprises phytoestrogen and an indigestible oligosaccharide, wherein the indigestible oligosaccharide is fructooligosaccharides. The prophylactic, therapeutic agent for osteoporosis as set forth in claim 1 wherein the content ratio of phytoestrogen and indigestible oligosaccharide is 1:10 to 1:1000 by weight ratio. The prophylactic, therapeutic agent for osteoporosis as set forth in claim 1 wherein the phytoestrogen is isoflavon.

Inventors: ADACHI TAKASHI, HIRAYAMA MASAO, OHTA ATSUTANE, ADACHI, TAKASHI, HIRAYAMA, MASAO, OHTA, ATSUTANE, ADACHI, Takashi, Bioscience Labs., HIRAYAMA, Masao, Bioscience Labs., OHTA, Atsutane, Bioscience Labs.
Applicants: MEIJI SEIKA KAISHA, MEIJI SEIKA KAISHA, LTD.
Application year: 1999
Main classification: A61K31
IPC codes: C07J1, A61K36, A61K31, C07H3