JP2009269834A - Bone resorption inhibitor, food and drink for bone resorption inhibition and quasi drug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a naturally derived bone resorption inhibitor which is safe and excellent in effects on bone diseases such as osteoporosis and periodontal diseases, food and drink for bone resorption inhibition, a bone resorption inhibition quasi drug, and an agent for preventing or treating bone diseases. <P>SOLUTION: The bone resorption inhibitor contains at least one kind of extracts of plants selected from Chaenomeles sinensis, Cinnamomum zeylanicum, Artemisia princeps, Crocus sativus, and Mallotus japonicus. The bone resorption inhibitor further contains at least either a Citrus or Citrus limon extract. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a bone resorption inhibitor. The present invention also relates to a food and drink for suppressing bone resorption, a quasi-drug for suppressing bone resorption, and a bone disease preventing or treating agent.

  Bone homeostasis is maintained by a balance between bone resorption and bone formation called bone remodeling (Non-patent Document 1). These bone resorption and bone formation are controlled by the action of osteoclasts and osteoblasts, osteoclasts play a role in bone resorption, and osteoblasts play a role in bone regeneration. Osteoclasts are tartrate-resistant acid phosphatase (TARTrate-Resistant Acid Phosphatase, hereinafter abbreviated as TRAP) positive cells derived from hematopoietic cells. Osteoclast formation involves differentiation, fusion, and activation ( It is known to proceed through a complex stage such as maturation. If the ratio of bone resorption by osteoclasts increases excessively, it causes bone destruction related to bone collapse and serious bone diseases such as osteoporosis, bone metastasis, rheumatism, and periodontal disease (Non-Patent Document 2). Improvements such as diet and pharmaceutical therapy have been required for these diseases. Therefore, suppressing excessive bone resorption by osteoclasts and adjusting the balance of bone remodeling is understood as improving bone disease.

  Currently, active vitamin D3 preparations, estrogen preparations, bisphosphonate preparations, calcium preparations and the like are used for the treatment of these bone diseases. When improvement is attempted by taking these drugs, caution is required in terms of side effects of drugs and the combined use of other drugs, and safer therapeutic drugs are required. In recent years, studies have been made to find natural-derived active ingredients having an inhibitory effect on osteoclast formation, and screening using various natural products and the like has been performed. As a result, specific natural products containing active ingredients against osteoporosis and the like have been found (Patent Documents 1 and 2). As an example, it has been found that estrogen-like substances such as daidzein and genistein, which are plant-derived components, also have an action of suppressing bone resorption (Non-patent Documents 3 and 4). Artemisia is also known to promote osteogenesis by promoting osteoblast differentiation (Patent Document 3), and citrus fruits are also known to have the effect of inhibiting osteoclast differentiation ( Patent Document 4). Patent Document 5 discloses that quercetin derived from a plant has been identified as a substance that promotes the production of a factor (Osteoprotegerin; OPG or RANKL) having an osteoclast differentiation inhibitory effect, and extraction of lemon or the like is disclosed. It is disclosed that the product contains quercetin.

  However, osteoclast formation is a complex pathway that progresses through a complex stage as described above, and few conventional screening methods have sufficient understanding of the mechanism of action in the differentiation stage. . Therefore, it is desired to identify a natural product having a bone resorption inhibitory effect with a clear mechanism of action for inhibiting differentiation in osteoclasts as an osteoclast differentiation inhibitor with very few side effects. A synergistic effect can also be expected by combining with natural products having different mechanisms of action that have been found up to now.

Manolagas, S. C. et al., Endocr. Rev., 21, 115 (2000) Rodan, G.A. et al., Science, 289, 1508 (2000) Fonseca, D. et al., Bone, 35, 489 (2004) Khalil, D. A. et al., Calcif Tissue Int., 76, 56 (2005) Japanese Patent No. 3479224 JP-T-2001-524119 International Publication No. 2004/030683 Pamphlet JP 2006-83151 A JP 2007-137775 A

  An object of the present invention is to provide a naturally-occurring bone resorption inhibitor having a safe and excellent effect on bone diseases such as osteoporosis and periodontal disease. Moreover, it is providing the food / beverage products for bone resorption suppression, the quasi-drug for bone resorption suppression, and the bone disease prevention or treatment agent similarly.

  The present invention relates to a bone resorption inhibitor containing one or more plant extracts selected from karin, cinnamon, mugwort, saffron, and akamegashiwa, which was newly found as a natural component having a bone resorption inhibitory effect. provide. Furthermore, the bone resorption inhibitor of the present invention can further contain an extract of at least one of citrus and lemon.

  Moreover, this invention provides the food-drinks for bone resorption suppression containing another 1 or more types of the extract of the plant chosen from Karin, a cinnamon, mugwort, saffron, and akamegashiwa as another aspect. Furthermore, this invention provides the quasi-drug for bone resorption suppression containing 1 or more types of the extract of the plant chosen from Karin, a cinnamon, mugwort, saffron, and akamegashiwa as another aspect.

  Furthermore, this invention provides the bone disease prevention or treatment agent containing 1 type, or 2 or more types of the extract of the plant chosen from Karin, a cinnamon, mugwort, saffron, and Akamegashiwa as another aspect. Further, the bone resorbing material and the bone disease preventing or treating agent provided in the present invention include active vitamin D3 preparation, estrogen preparation or estrogen-like substance, selective estrogen receptor modulator, bisphosphonate preparation, vitamin K2 preparation, calcium preparation. Or the bone disease therapeutic agent selected from those combination can be contained further.

  Thus, according to the present invention, a bone resorption inhibitor having a safe and excellent effect on bone diseases such as osteoporosis and periodontal disease, which has an extremely low influence on the human body, by containing an extract of a specific plant. It is possible to provide a food and drink for suppressing bone resorption and a quasi-drug. Similarly, it is possible to provide a bone disease preventive or therapeutic agent that has a very low influence on the human body and has a safe and excellent effect on bone diseases.

  The raw material plant having an inhibitory effect on bone resorption used in the present invention was identified as a natural product having an inhibitory effect on osteoclast activity by measuring tartrate-resistant acid phosphatase (TRAP) activity. Furthermore, by measuring the expression of NFATc1 by Western blotting, it was further narrowed down as a natural product having an action mechanism that suppresses the osteoclast differentiation stage.

  NFATc1 is more potent than RANKL in the signaling pathway of RANKL (William C. Dougall, et al., Genes & Dev. 13: 2412-2424), one of the proteins involved in osteoclast differentiation and activation. Induced protein. It has been shown that ES cells overexpressing NFATc1 differentiate into osteoclasts and that ES cells lacking NFATc1 cannot differentiate into osteoclasts regardless of stimulation with RANKL (Takayanagi H, et al., Dev. Cell 2002, 3, 889-901). Therefore, expression of NAFTc1 is considered to be indispensable for osteoclast formation. That is, a plant extract having an effect of suppressing the expression of NAFTc1 has an effect of suppressing differentiation into osteoclasts, and is considered to be a promising target for therapeutic intervention for bone diseases.

  As a result of earnest screening for plant-derived components in consideration of not only the bone resorption activity-suppressing effect but also such a mechanism of action, the present inventors have found that karin, saffron, and red-crowned wrinkles are newly effective. I found it. Furthermore, as described in Patent Documents 1 and 2, a cinnamon-derived component that has been considered to be ineffective in osteoporosis alone has an effect of suppressing osteoclast formation, and further an action mechanism of suppressing a differentiation stage. It became clear to have.

  Moreover, as described in Patent Document 3, it has been found that mugwort that has been known to promote osteogenesis by promoting osteoblast differentiation has an effect of inhibiting osteoclast differentiation. . In addition, by finding the difference in action mechanism between citrus fruits such as citrus and lemon having the effect of inhibiting osteoclast differentiation as described in Patent Document 4 and the above plant-derived components, and combining them The present inventors have found that the effect of inhibiting osteoclast differentiation can be further improved.

  The raw material plant discovered by the present inventors has never been found to have an effect of suppressing osteoclast activation and NAFTc1 expression. That is, the present inventors have found that karin, saffron, red-crowned wrinkle, cinnamon, mugwort, citrus, and lemon have NAFTc1 expression-suppressing effects, and are effective in preventing and treating bone diseases such as osteoporosis and periodontal disease. It was found for the first time that it had an effect.

  As described above, osteoporosis having a very low influence on the human body by containing a specific plant extract having the effect of commonly suppressing the two factors related to the control of bone resorption “differentiation and activation of osteoclasts” It is possible to provide a bone resorption inhibitor that is safe and has an excellent effect on bone diseases such as periodontal disease and the like.

  The karin used in the present invention is a plant belonging to the genus Rosaceae, and includes varieties such as karin, defocus, and blur.

  The cinnamon used in the present invention is a plant belonging to the genus Nikkei belonging to the family Camphoraceae. Including varieties such as Ogasawara Nikkei, Nikkei, Shibayabu Nikkei and Ceylon Nikkei.

  The artemisia used in the present invention is a plant belonging to the genus Artemisia, Artemisia, Artemisia, Tarragon, Nitro Artemisia, Japanese Artemisia, Chinese Artemisia, Japanese Artemisia, Japanese Artemisia, Chinese Artemisia, Japanese Artemisia, Japanese Art Sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush, sagebrush Including.

  The saffron used in the present invention is a plant belonging to the genus Crocodidae, and includes varieties such as saffron.

  The red-crowned wrinkle used in the present invention is a plant belonging to the genus Red-tailedaceae, and includes varieties such as red-crowned wrinkles.

  Citrus used in the present invention refers to citrus fruits belonging to the genus Citrus, and includes plants such as orange, Daidai, sweet orange, and bitter orange.

  The lemon used in the present invention is a plant belonging to the genus Citrus mandarin and includes varieties such as lemon.

  The plant used as a raw material of this invention uses the extract created using the solvent which can extract an active ingredient from the said plant body effectively.

  The solvent used in this extraction is not particularly limited as long as it can effectively extract the active ingredient. For example, water, methanol, ethanol, propanol, isopropanol, 1,3 butylene glycol, propylene One or two of glycol, dipropylene glycol, chloroform, DMSO, glycerin, ethyl ether, propyl ether, ethyl acetate, butyl acetate, acetone, ethyl methyl ketone, physiological saline, phosphate buffer and phosphate buffered saline It is preferable to select and use seeds or more.

  As an extraction method, it is preferable to extract after raw or shredded, dried, pulverized or the like. Further, the extraction can be performed by immersing in an extraction solvent. Stirring may be performed to increase extraction efficiency, and homogenization may be performed in an extraction solvent. Furthermore, the extraction can be repeated 2 to 4 times to increase the extraction efficiency. The extraction temperature is suitably about 5 ° C. to the boiling point of the extraction solvent. The extraction time varies depending on the type of solvent and the extraction temperature, but is preferably about 1 hour to 14 days.

  In addition, although the extract contained in this invention may be obtained from a single plant, it is also possible to apply the said extraction method, after mixing 2 or more types of plants.

  Extracts of these plants with the above solvents can be used as they are, but they can be decolorized, deodorized and desalted as long as the concentrated / dried solid is dissolved again in water or a polar solvent, or the microbial lipase inhibitory action is not impaired. It can also be obtained by performing a purification treatment or performing fraction extraction by column chromatography.

  To produce a bone resorption inhibitor, a bone resorption suppressing food or drink, or a bone resorption suppressing quasi-drug, etc., using as an active ingredient an extract obtained from a raw material plant alone or a combination of two or more, The extract obtained as described above may be formulated as an active ingredient in combination with a known pharmaceutical, food or beverage, or quasi drug carrier according to a conventional method.

  Since the plant extract selected from Karin, Cinnamon, Artemisia, Saffron, and Akamegashi of the present invention has a bone resorption inhibitory effect, by suppressing an increase in the rate of bone resorption in the body, bone collapse or serious Bone diseases related to osteoporosis, bone metastasis, rheumatism, periodontal disease, arthritis and the like, which are bone diseases, can be prevented or treated. Since these plant extracts are safe for the human body, they can be used in bone resorption inhibitors, foods for bone resorption and quasi drugs for bone resorption, and their benefits are very high. .

  Further, the bone resorption inhibitor of the present invention can be administered in various dosage forms. For example, as oral administration agents, tea agents, capsules, tablets, granules, fine granules, syrups, and dry syrups can be used. Etc.

  The production of the bone resorption inhibitor of the present invention is usually carried out by blending a plant extract with a pharmaceutically acceptable liquid or solid carrier, and optionally a solvent, a dispersant, an emulsifier, a buffer, a stabilizer. , Excipients, binders, disintegrants, lubricants, etc., to add solids such as tablets, granules, powders, powders, capsules, etc., liquids such as normal solutions, suspensions, emulsions, etc. be able to.

  The pharmaceutical carrier can be selected according to the administration form and dosage form of the bone resorption inhibitor. In the case of an oral preparation comprising a solid composition, it can be a tablet, pill, capsule, powder, fine granule, granule, etc., for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch Inorganic salts are used. In preparation of the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be further added. For example, in the case of a tablet or pill, if desired, it may be coated with a sugar coating such as sucrose, gelatin or hydroxypropylcellulose, or a film of a gastric or enteric substance. In the case of an oral preparation comprising a liquid composition, it can be a pharmacologically acceptable emulsion, solution, suspension, syrup, etc. For example, purified water, ethanol, etc. are used as a carrier. Is done. Further, if desired, auxiliary agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, preservatives and the like may be added.

  On the other hand, in the case of a parenteral preparation, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil as the diluent is used as the active ingredient of the present invention according to a conventional method. It can be prepared by dissolving or suspending in propylene glycol, polyethylene glycol or the like, and adding a bactericidal agent, stabilizer, isotonic agent, soothing agent, etc., if necessary. In addition, a solid composition can be produced and dissolved in sterile water or a sterile solvent for injection before use.

  Further, each of the above preparations may contain a pharmaceutically acceptable additive such as a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as desired.

  In formulating, it is preferable to add a stabilizer. Examples of the stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.

  The dry weight that is the basis of the plant extract as the active ingredient of the bone resorption inhibitor of the present invention is usually 3.1 mg / kg (body weight) or more per day for an adult, preferably 4.6 mg / kg (body weight) or more. It is preferable to do this. Specifically, Karin is preferably 23.1 mg / kg (body weight) or more, cinnamon is preferably 16.4 mg / kg (body weight) or more, mugwort is preferably 21.6 mg / kg (body weight) or more, and saffron is 3 .1 mg / kg (body weight) or more is preferable, Akamegawashi is preferably 30.7 mg / kg (body weight) or more, Citrus is preferably 25.2 mg / kg (body weight) or more, and Lemon is preferably 39 mg / kg (body weight) or more. . Generally, it is a dose of the active ingredient contained in the preparation. Of course, the dose varies depending on various conditions such as the type of extraction solvent, the amount of solvent used, etc. The amount may be sufficient, or it may be required beyond the range. Administration may be performed once or within several days within a desired dose range, or may be performed over a predetermined period. The upper limit of the dose is preferably 240 mg / kg (body weight) or less per day, and more preferably 480 mg / kg (body weight) or less.

  Examples of the bone resorption inhibitor of the present invention include those prepared by combining the active ingredient according to the present invention with a known medicine. The active ingredient of the present invention can be used together with, for example, an active vitamin D3 preparation, an estrogen preparation or an estrogen-like substance, a selective estrogen receptor modulator, a bisphosphonate preparation, a vitamin K2 preparation, a calcium preparation or a combination thereof. Thereby, a synergistic effect regarding bone resorption suppression can be expected.

  As described above, the bone resorption-suppressing food or drink according to the present invention can be blended together with optional components that are usually used in food and drink. Examples of such human or animal foods and drinks include breads, confectionery, noodles, processed meat products / fishery products, processed cereal products, processed vegetables / processed fruits, processed eggs, dairy products, flours, Examples include instant confectionery ingredients, edible fats and oils, soup ingredients, powdered drinks, seasonings, beverages, and feeds.

  The food and drink for suppressing bone resorption according to the present invention includes, for example, nutritional supplements such as vitamins, nutritional supplement beverages, animal health foods, etc., and various commonly used forms such as powders and granules. It is formulated as an agent, a tablet, a capsule, a liquid, a film or the like. For formulation, together with plant extract having bone resorption inhibitory effect, excipient, binder, disintegrant, disintegration inhibitor, absorption enhancer, adsorbent, lubricant, colorant, preservative, flavor, flavor Agents, sweeteners, etc. are blended.

  These dietary supplements, dietary supplement beverages, and the like are produced by conventional methods commonly known in the art.

  The addition amount of the plant extract having the bone resorption inhibitory effect in such a food or drink may be added so as to have the above-described intake amount in a range corresponding to each raw material plant or each form of the food or drink. Is preferably added in the range of 0.001 wt% to 20.0 wt%. For example, 0.01 to 20.0% by weight for liquid food and drink, 0.001 to 20.0% by weight for solid food and drink, and 0.001 to 20.0 for tablet food and drink. It is preferable to add within the range of% by weight. More specifically, for coffee milk, 0.01-20.0% by weight, for coffee soymilk, 0.01-20.0% by weight, for soymilk, 0.01-20.0% by weight, For milk tea, 0.01-20.0 wt%, for pudding 0.001-20.0 wt%, for candy 0.001-20.0 wt%, for yogurt 0.001 ~ 20.0 wt%, for health drinks 0.01-20.0 wt%, for yogurt flavored acidic milk drinks 0.001-20.0 wt%, for functional oolong tea, 0.01 It is preferable to add within a range of ˜20.0% by weight, hard capsules within a range of 0.001 to 20.0% by weight, and soft capsules within a range of 0.001 to 20.0% by weight.

  Further, the quasi drug for inhibiting bone resorption of the present invention includes moss, toothpastes, liquid toothpastes, gel toothpastes, gums and the like. Moreover, the quasi-drug for bone resorption can be blended together with optional components usually used in quasi-drugs.

  These quasi-drugs for inhibiting bone resorption are produced by conventional methods commonly known in the art.

  The addition amount of the plant extract in such a quasi-drug for bone resorption inhibition may be added so as to be the above-mentioned intake amount in a range corresponding to each raw material plant and each form of the quasi-drug. The quasi drug is preferably added in the range of 0.001 to 20.0% by weight. For example, 0.001 to 20.0% by weight for solid quasi drugs, 0.001 to 10.0% by weight for liquid quasi drugs, gel or paste quasi drugs It is preferable to add in the range of 0.001 to 20.0% by weight to the product. More specifically, 0.001 to 20.0% by weight for beverages, 0.001 to 20.0% by weight for candy, 0.001 to 20.0% by weight for toothpaste, and liquid toothpaste. 0.001 to 20.0% by weight for agents, 0.001 to 10.0% by weight for gel dentifrices, and 0.001 to 10.0% by weight for gums It is preferable to do.

  Hereinafter, the present invention will be further described with reference to production examples, test examples and examples. In addition, these do not limit this invention at all.

(Production example)
These plants are dried. 200 parts by weight of 99.5% ethanol or DMSO was added to 10 parts by weight of the dried product, extracted for 3 days with occasional stirring at room temperature, filtered, and the solvent was distilled off to obtain an extract. Using these as samples, the ability to inhibit osteoclast differentiation and activation was measured by the method of the following test example. The results regarding the ability to inhibit osteoclast activation are shown in Table 1, and the results concerning the ability to inhibit osteoclast differentiation are shown in FIG.

(Test method and evaluation method)
(Measurement of tartrate alkaline phosphatase activity)
The activity of tartrate alkaline phosphatase (TRAP) was measured as osteoclast activation, and the inhibitory effect was evaluated by calculating the inhibition rate (%) of each plant extract. In measuring the TRAP activity, the technique of Woo et al. Was slightly modified. That is, RAW264.7 cells were suspended in MEM-α medium containing FBS, seeded in a 48-well plate at 50,000 cells / well, and incubated as it was for 24 hours. Next, they added each plant extract to a final concentration of 50 μg / ml. After incubation for 2 hours, the cells were stimulated by adding RANKL (Receptor Activator for Nuclear Factor kB Ligand) to a final concentration of 50 μg / ml and incubated for 2 days. When the culture was completed, the medium was removed, and the cell monolayer was gently washed twice with phosphate buffer. Thereafter, the cells were lysed with 0.2% Triton X-100. A citrate buffer solution (50 mM, pH 4.6) containing 10 mM tartaric acid and 5 mM p-nitrophenyl phosphate was added to the aqueous layer of the cell lysate and incubated at 37 ° C. for 30 minutes. The reaction was stopped by adding 0.1 N sodium hydroxide, and the absorbance at 405 nm was measured with a 1420 ARVO series multi-label counter.

(Measurement of NFATc1 expression by Western blotting)
It is known that the expression of NFATc1 protein increases when macrophages, which are immune cells, differentiate into osteoclasts. That is, the expression of NFATc1 was used as an index to measure by the Western blotting method, and the inhibitory action of each plant extract was evaluated. Further, Glyceraldehyde-3-phosphate dehydrogenase (hereinafter referred to as GAPDH), which is known to be expressed constantly, was measured as a standard protein.

RAW cells buffer for cell lysis _{(10nM HEPES, pH7.8, 150mMNaCl,} 2mM EDTA, 1.5mM MgCl 2, 0.5mM dithiothreitol, and protease inhibitors) and lysed by. The eluate of each cell was fractionated on a polyacrylamide-SDS gel, and the protein was transferred to a nitrocellulose membrane using a BIO CRAFT semi-drive lotter. Thereafter, the cells were incubated for 1 hour in a blocking solution (5% non-fat dry milk in which phosphate buffer containing 0.1% Tween-20 was also dissolved). Membranes were incubated overnight at 4 degrees with primary antibody. The membrane was washed and exposed to a horseradish-conjugated secondary antibody for 1 hour, and finally detected with an ECL Plus Western Blotting Detection System from GE Healthcare Bio-sciences.

(Test results)
As shown in Table 1, the specific plant extract of the present invention has been confirmed to have an action of suppressing differentiation and activation of osteoclasts, although there is a slight difference, bone disease, and periodontal disease. Can be used as an improving agent.

(Prescription example)
Bone resorption inhibitor for the prevention or improvement of bone diseases such as periodontal disease and osteoporosis, the bone resorption suppression food and drink, the quasi drug for bone resorption suppression, or the bone disease prevention or treatment containing the plant extract of the present invention According to the above evaluation results, examples of its formulation are shown below, but each example of formulation may be manufactured by a conventional method for manufacturing each product, and only the blending amount is shown. The present invention is not limited to these.

It is also possible to add the plant extract obtained as described above to a quasi drug. The quasi drug for suppressing bone resorption obtained in this way can be expected to have an effect of preventing or improving bone disease, and is useful as a quasi drug.

Moreover, it is also possible to add the plant extract obtained as mentioned above in normal food and drink. The bone resorption-suppressing food and drink obtained as described above can be ingested on a daily basis, can be expected to prevent or improve bone disease, and is useful as a food or beverage for preventing or improving bone disease. .

Moreover, it is also possible to add the plant extract obtained as mentioned above to a bone disease preventive or therapeutic agent. The bone disease preventive or therapeutic agent thus obtained can be expected to have a bone disease preventive or ameliorating effect and is useful as a pharmaceutical composition.
The following ingredients were coated with a gelatin film.

The following ingredients were coated with gelatin and glycerin films.

  The plant extract contained in the bone resorption inhibitor and the like of the present invention is already used as a food or folk medicine, and has no particular problem in safety.

It is the photograph data which showed the expression measurement result of NFATc1 by the western blotting method.

Claims (5)

  A bone resorption inhibitor comprising at least one plant extract selected from karin, cinnamon, mugwort, saffron, and akamegashiwa.   The bone resorption inhibitor according to claim 1, further comprising an extract of at least one of citrus and lemon.   A food and drink for suppressing bone resorption, containing one or more plant extracts selected from karin, cinnamon, mugwort, saffron and akamegashiwa.   A quasi-drug for inhibiting bone resorption, comprising one or more plant extracts selected from Karin, Cinnamon, Artemisia, Saffron, and Akamegasiwa.   A bone disease preventive or therapeutic agent comprising one or more plant extracts selected from karin, cinnamon, mugwort, saffron, and akamegashiwa.