Patent Publication Number: US-2012046327-A1

Title: Method for inhibiting the induction and formation of osteoclasts

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional application of application Ser. No. 11/919,003 filed Nov. 7, 2007, which is the United States national phase application of International application PCT/JP2006/308386 filed Apr. 21, 2006. The entire contents of each of application Ser. No. 11/919,003 and PCT/JP2006/308386 are incorporated by reference herein. 
    
    
     TECHNICAL FIELD 
     The present invention relates to a medicament for preventing or treating bone metabolic diseases, comprising an angiotensin II receptor antagonist as an active ingredient 
     BACKGROUND ART 
     Bone metabolic diseases, such as osteoporosis, are increasing steadily in the modern highly aged society. The balance between bone resorption and bone formation is important in many metabolic diseases. While bone resorption by osteoclasts activates osteoblasts and stimulates the osteogenic mechanism, osteoclast activation is mediated by osteoblasts for the most part. A signal transduction system involving these osteoblasts and osteoclasts has been a target for years in the development of various drugs: 
     Use of an angiotensin II receptor antagonist for the purpose of preventing or treating osteoporosis has been known. For example, Japanese Unexamined Patent Publication No. 8-3044 discloses such use. However, no example of using specific angiotensin II receptor antagonists, such as olmesartan medoxomil, has been known yet.
     Patent Document No. 1: Japanese Unexamined Patent Publication No. 8-3044   

     DISCLOSURE OF THE INVENTION 
     Problem for Solution by the Invention 
     It is an object of the present invention to provide a medicament useful in the prevention or treatment of bone metabolic diseases. 
     Means to Solve the Problem 
     As a result of intensive and extensive researches toward the solution of the above-described problem, the present inventors have found that specific angiotensin II receptor antagonists, such as olmesartan medoxomil, are highly effective in the prevention or treatment of bone metabolic diseases such as osteoporosis. The present invention has been achieved based on this finding. 
     The present invention provides a medicament for preventing or treating bone metabolic diseases, comprising a specific angiotensin II receptor antagonist as an active ingredient. According to a preferred embodiment of the present invention, a medicament for preventing or treating osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, dental leakage or alveolar ridge resorption after tooth extraction is provided. 
     Effect of the Invention 
     According to the present invention, it becomes possible to provide a medicament useful in the prevention or treatment of bone metabolic diseases. 
     The present specification encompasses the contents described in the specification and/or drawings of Japanese Patent Application No. 2005-124374 based on which the present patent application claims priority. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows sRANKL, expression levels (pM) in human osteoblasts. Control group: non-addition group; AngII group: AngII-added group; AngII+ARB group: AngII and olmesartan were added simultaneously; AngII+AT2 group; AngII and angiotensin type 2 receptor antagonist PD (123319) were added simultaneously. 
         FIG. 2  shows TRAP activity (%) in 12-week-old female spontaneously hypertensive rats. Non-treatment group: female spontaneously hypertensive rat group where ovariectomy was not performed; Ovariectomy group: female spontaneously hypertensive rat group where ovariectomy was performed at 8 weeks of age; Ovariectomy+ARB0.5 group: female spontaneously hypertensive rat group where olmesartan was administered at 0.5 mg/kg/day with an osmotic pressure pump after ovariectomy was performed at 8 weeks of age; Ovariectomy+ARB 1 group: female spontaneously hypertensive rat group where olmesartan was administered at 1 mg/kg/day with an osmotic pressure pump after ovariectomy was performed at 8 weeks of age. 
         FIG. 3  shows bone density (g/cm 2 ) in female spontaneously hypertensive rats. Non-treatment group: female spontaneously hypertensive rat group where ovariectomy was not performed; Ovariectomy group: female spontaneously hypertensive rat group where ovariectomy was performed at 8 weeks of age; Ovariectomy+ARB0.5 group: female spontaneously hypertensive rat group where olmesartan was administered at 0.5 mg/kg/day with an osmotic pressure pump after ovariectomy was performed at 8 weeks of age; Ovariectomy+ARB 1 group: female spontaneously hypertensive rat group where olmesartan was administered at 1 mg/kg/day with an osmotic pressure pump after ovariectomy was performed at 8 weeks of age. 
     
    
    
     BEST MODE FOR CARRYING OUT THE INVENTION 
     The angiotensin II receptor antagonist, which is the active ingredient of the present invention, is a compound represented by the following general formula (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof 
     
       
         
         
             
             
         
       
     
     In the above formula, 
     R 1  represents a C 1 -C 4  alkyl group;
 
R 2  and R 3  are the same or different and each represent a hydrogen atom or a C 1 -C 4  alkyl group;
 
R 4  represents a hydrogen atom or a C 1 -C 4  alkyl group;
 
R 5  represents a hydrogen atom, a C 1 -C 4  alkyl group, a C 2 -C 5  alkanoyloxymethyl or 1-(C 2 -C 5  alkanoyloxy)ethyl group, a C 1 -C 4  alkoxycarbonyloxymethyl or 1-(C 1 -C 4  alkoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, a (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl or a phthalidyl group; and
 
R 6  represents a carboxy group or a tetrazole-5-yl group.
 
     The C 1 -C 4  alkyl group in R 1 , R 2 , R 3  and R 4  may be, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. The C 1 -C 4  alkyl group in R 1  is preferably ethyl, propyl or butyl group, more preferably propyl or butyl group, and especially preferably propyl group. The C 1 -C 4  alkyl group in R 2  and R 3  is preferably methyl or ethyl group, and especially preferably methyl group. The C 1 -C 4  alkyl group in R 4  is preferably a hydrogen atom or methyl group, and especially preferably a hydrogen atom. 
     R 5  may be, for example, a hydrogen atom; the above-described C 1 -C 4  alkyl group; a C 2 -C 5  alkanoyloxymethyl or 1-(C 2 -C 5  alkanoyloxy)ethyl group (where the C 2 -C 5  alkanoyl moiety may be, for example, acetyl, propyonyl, butylyl, isobutylyl, valeryl, isovaleryl or pivaloyl, preferably acetyl or pivaloyl, and especially preferably pivaloyl); a C 1 -C 4  alkoxycarbonyloxymethyl or 1-(C 1 -C 4  alkoxycarbonyloxy)ethyl group (where the C 1 -C 4  alkoxy moiety may be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy, preferably methoxy, ethoxy, propoxy or isopropoxy, and especially preferably ethoxy or isopropoxy); a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; a (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl or a phthalidyl group. Preferably, R 5  is a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group. Especially preferably, R 5  is a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group. Most preferably, R 5  is a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group. 
     The compound represented by general formula (I) of the present invention may be, if desired, converted to a corresponding pharmacologically acceptable salt by treating with acid or base according to conventional methods. Such a “pharmacologically acceptable salt” may be, for example, an alkaline metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; or an amine salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt. The pharmacologically acceptable salt is preferably an alkali metal salt, and especially preferably a sodium salt. 
     The compound represented by general formula (I) of the invention may be converted to a pharmacologically acceptable ester according to conventional methods. The types of the “pharmacologically acceptable ester” are not particularly limited. Any type of ester may be used as long as it has the same pharmaceutical applicability as the compound represented by general formula (I) and is pharmacologically acceptable. For example, a C 1 -C 4  alkoxy C 1 -C 4  alkyl group such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C 1 -C 4  alkoxylated C 1 -C 4  alkoxy C 1 -C 4  alkyl group such as 2-methoxyethoxymethyl; a C 6 -C 10  aryloxy C 1 -C 4  alkyl group such as phenoxymethyl; a halogenated C 1 -C 4  alkoxy C 1 -C 4  alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a C 1 -C 4  alkoxycarbonyl C 1 -C 4  alkyl group such as methoxycarbonylmethyl; a cyano C 1 -C 4  alkyl group such as cyanomethyl or 2-cyanoethyl; a C 1 -C 4  alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C 6 -C 10  arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C 1 -C 4  alkylsulfonyl C 1 -C 4  lower alkyl group which may be substituted with a halogen atom(s), such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C 6 -C 10  arylsulfonyl C 1 -C 4  alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a C 1 -C 7  aliphatic acyloxy C 1 -C 4  alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; a C 5 -C 6  cycloalkylcarbonyloxy C 1 -C 4  alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; a C 6 -C 10  arylcarbonyloxy C 1 -C 4  alkyl group such as benzoyloxymethyl; a C 1 -C 6  alkoxycarbonyloxy C 1 -C 4  alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; a C 5 -C 6  cycloalkyloxycarbonyloxy C 1 -C 4  alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; a [5-(C 1 -C 4  alkyl)-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl or (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a [5-(phenyl which may be substituted with a C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen atom(s))-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl; or a phthalidyl group which may be substituted with a C 1 -C 4  alkyl or C 1 -C 4  alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl may be used. It should be noted that esters of the compound represented by general formula (I) are not limited to those enumerated above. 
     A “pharmacologically acceptable salt of a pharmacologically acceptable ester” of the compound (I) of the present invention is a pharmacologically acceptable salt of the above-described “pharmacologically acceptable ester”. Such a salt may be, for example, a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C 1 -C 4  alkanesulfonic acid salt which may be substituted with a halogen atom(s), such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C 6 -C 10  arylsulfonic acid salt which may be substituted with a C 1 -C 4  alkyl group(s), such as a benzenesulfonate or p-toluenesulfonate; a C 1 -C 6  aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt, and is preferably a hydrochloride, nitrate, sulfate or phosphate, and is especially preferably a hydrochloride. 
     When the compound represented by general formula (I) of the present invention (hereinafter, referred to as the “compound (I)”) has asymmetric carbon(s) within its molecule, racemate or optically active substances thereof are also included in the present invention. 
     The compound (I) and salts thereof which are the active ingredient of the present invention, may become hydrates as a result of absorption of moisture or attachment of adsorbed water when they have been left in the air. Such salts are also included in the present invention. 
     The compound (I) and salts thereof which are the active ingredient of the present invention, may become solvates as a result of absorption of other solvents. Such salts are also included in the present invention. 
     The compound (I) is preferably: 
     (1) a compound wherein R 1  is an ethyl group, a propyl group or a butyl group,
 
(2) a compound wherein R 1  is a propyl group or a butyl group,
 
(3) a compound wherein R 1  is a propyl group,
 
(4) a compound wherein R 2  and R 3  are the same or different and each represent a hydrogen atom or a methyl group,
 
(5) a compound wherein R 2  and R 3  are the same and each represent a methyl group,
 
(6) a compound wherein R 4  is a hydrogen atom or a methyl group,
 
(7) a compound wherein R 4  is a hydrogen atom,
 
(8) a compound wherein R 5  is a hydrogen atom, a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group,
 
(9) a compound wherein R 5  is a hydrogen atom, a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group,
 
(10) a compound wherein R 5  is a hydrogen atom or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or
 
(11) a compound wherein R 6  is a tetrazole-5-yl group. It should be noted here that among groups representing the same group such as R 1  or R 2 , the greater the group number is, the greater the degree of preferability is (e.g., among R 1  groups, (1) is preferable; (2) is more preferable; and (3) is especially preferably).
 
     Alternatively, a preferable compound may be obtained by selecting R 1  from (1) to (3) described above, selecting R 2  and R 3  from (4) to (5) described above, selecting R 4  from (6) to (7) described above, selecting R 5  from (8) to (10) described above, and combining the selected ones or combining the selected ones with R 6  described in (11) above. For example, the following compounds may be enumerated. 
     (12) a compound wherein
 
R 1  is an ethyl group, a propyl group or a butyl group;
 
R 2  and R 3  are the same or different and each represent a hydrogen atom or a methyl group;
 
R 4  is a hydrogen atom or a methyl group; and
 
R 5  is a hydrogen atom, a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group;
 
(13) a compound wherein
 
R 1  is a propyl group or a butyl group;
 
R 2  and R 3  are the same and each represent a methyl group;
 
R 4  is a hydrogen atom;
 
R 5  is a hydrogen atom, a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group; and
 
R 6  is a tetrazole-5-yl group;
 
(14) a compound wherein
 
R 1  is a propyl group;
 
R 2  and R 3  are the same and each represent a methyl group;
 
R 4  is a hydrogen atom;
 
R 5  is a hydrogen atom or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; and
 
R 6  is a tetrazole-5-yl group.
 
     As specific examples of preferable compounds in general formula (I), compounds shown in Table 1 below may be given. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Compound No. 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 R 6   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 Et 
                 Me 
                 Me 
                 H 
                 H 
                 CO 2 H 
               
               
                 2 
                 Et 
                 Me 
                 Me 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 3 
                 Et 
                 Me 
                 Me 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 4 
                 Et 
                 Me 
                 Me 
                 H 
                 H 
                 Tz 
               
               
                 5 
                 Et 
                 Me 
                 Me 
                 H 
                 Pom 
                 Tz 
               
               
                 6 
                 Et 
                 Me 
                 Me 
                 H 
                 Mod 
                 Tz 
               
               
                 7 
                 Pr 
                 H 
                 H 
                 H 
                 H 
                 CO 2 H 
               
               
                 8 
                 Pr 
                 H 
                 H 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 9 
                 Pr 
                 H 
                 H 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 10 
                 Pr 
                 H 
                 H 
                 H 
                 H 
                 Tz 
               
               
                 11 
                 Pr 
                 H 
                 H 
                 H 
                 Pom 
                 Tz 
               
               
                 12 
                 Pr 
                 H 
                 H 
                 H 
                 Mod 
                 Tz 
               
               
                 13 
                 Pr 
                 H 
                 Me 
                 H 
                 H 
                 CO 2 H 
               
               
                 14 
                 Pr 
                 H 
                 Me 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 15 
                 Pr 
                 H 
                 Me 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 16 
                 Pr 
                 H 
                 Me 
                 H 
                 H 
                 Tz 
               
               
                 17 
                 Pr 
                 H 
                 Me 
                 H 
                 Pom 
                 Tz 
               
               
                 18 
                 Pr 
                 H 
                 Me 
                 H 
                 Mod 
                 Tz 
               
               
                 19 
                 Pr 
                 Me 
                 Me 
                 H 
                 H 
                 CO 2 H 
               
               
                 20 
                 Pr 
                 Me 
                 Me 
                 H 
                 Me 
                 CO 2 H 
               
               
                 21 
                 Pr 
                 Me 
                 Me 
                 H 
                 Et 
                 CO 2 H 
               
               
                 22 
                 Pr 
                 Me 
                 Me 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 23 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Et 
                 CO 2 H 
               
               
                 24 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Et 
                 CO 2 H 
               
               
                 25 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Pr i   
                 CO 2 H 
               
               
                 26 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Pr i   
                 CO 2 H 
               
               
                 27 
                 Pr 
                 Me 
                 Me 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 28 
                 Pr 
                 Me 
                 Me 
                 H 
                 Phth 
                 CO 2 H 
               
               
                 29 
                 Pr 
                 Me 
                 Me 
                 H 
                 H 
                 Tz 
               
               
                 30 
                 Pr 
                 Me 
                 Me 
                 H 
                 Me 
                 Tz 
               
               
                 31 
                 Pr 
                 Me 
                 Me 
                 H 
                 Et 
                 Tz 
               
               
                 32 
                 Pr 
                 Me 
                 Me 
                 H 
                 Pom 
                 Tz 
               
               
                 33 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Et 
                 Tz 
               
               
                 34 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Et 
                 Tz 
               
               
                 35 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Pr i   
                 Tz 
               
               
                 36 
                 Pr 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Pr i   
                 Tz 
               
               
                 37 
                 Pr 
                 Me 
                 Me 
                 H 
                 Mod 
                 Tz 
               
               
                 38 
                 Pr 
                 Me 
                 Me 
                 H 
                 Phth 
                 Tz 
               
               
                 39 
                 Pr 
                 Me 
                 Me 
                 Me 
                 H 
                 CO 2 H 
               
               
                 40 
                 Pr 
                 Me 
                 Me 
                 Me 
                 Pom 
                 CO 2 H 
               
               
                 41 
                 Pr 
                 Me 
                 Me 
                 Me 
                 Mod 
                 CO 2 H 
               
               
                 42 
                 Pr 
                 Me 
                 Me 
                 Me 
                 H 
                 Tz 
               
               
                 43 
                 Pr 
                 Me 
                 Me 
                 Me 
                 Pom 
                 Tz 
               
               
                 44 
                 Pr 
                 Me 
                 Me 
                 Me 
                 Mod 
                 Tz 
               
               
                 45 
                 Bu 
                 H 
                 H 
                 H 
                 H 
                 CO 2 H 
               
               
                 46 
                 Bu 
                 H 
                 H 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 47 
                 Bu 
                 H 
                 H 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 48 
                 Bu 
                 H 
                 H 
                 H 
                 H 
                 Tz 
               
               
                 49 
                 Bu 
                 H 
                 H 
                 H 
                 Pom 
                 Tz 
               
               
                 50 
                 Bu 
                 H 
                 H 
                 H 
                 Mod 
                 Tz 
               
               
                 51 
                 Bu 
                 H 
                 Me 
                 H 
                 H 
                 CO 2 H 
               
               
                 52 
                 Bu 
                 H 
                 Me 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 53 
                 Bu 
                 H 
                 Me 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 54 
                 Bu 
                 H 
                 Me 
                 H 
                 H 
                 Tz 
               
               
                 55 
                 Bu 
                 H 
                 Me 
                 H 
                 Pom 
                 Tz 
               
               
                 56 
                 Bu 
                 H 
                 Me 
                 H 
                 Mod 
                 Tz 
               
               
                 57 
                 Bu 
                 Me 
                 Me 
                 H 
                 H 
                 CO 2 H 
               
               
                 58 
                 Bu 
                 Me 
                 Me 
                 H 
                 Pom 
                 CO 2 H 
               
               
                 59 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Et 
                 CO 2 H 
               
               
                 60 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Et 
                 CO 2 H 
               
               
                 61 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Pr i   
                 CO 2 H 
               
               
                 62 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Pr i   
                 CO 2 H 
               
               
                 63 
                 Bu 
                 Me 
                 Me 
                 H 
                 Mod 
                 CO 2 H 
               
               
                 64 
                 Bu 
                 Me 
                 Me 
                 H 
                 Phth 
                 CO 2 H 
               
               
                 65 
                 Bu 
                 Me 
                 Me 
                 H 
                 H 
                 Tz 
               
               
                 66 
                 Bu 
                 Me 
                 Me 
                 H 
                 Me 
                 Tz 
               
               
                 67 
                 Bu 
                 Me 
                 Me 
                 H 
                 Et 
                 Tz 
               
               
                 68 
                 Bu 
                 Me 
                 Me 
                 H 
                 Pom 
                 Tz 
               
               
                 69 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Et 
                 Tz 
               
               
                 70 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Et 
                 Tz 
               
               
                 71 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH 2 OCO 2 Pr i   
                 Tz 
               
               
                 72 
                 Bu 
                 Me 
                 Me 
                 H 
                 CH(Me)OCO 2 Pr i   
                 Tz 
               
               
                 73 
                 Bu 
                 Me 
                 Me 
                 H 
                 Mod 
                 Tz 
               
               
                 74 
                 Bu 
                 Me 
                 Me 
                 H 
                 Phth 
                 Tz 
               
               
                 75 
                 Bu 
                 Me 
                 Me 
                 Me 
                 H 
                 CO 2 H 
               
               
                 76 
                 Bu 
                 Me 
                 Me 
                 Me 
                 Pom 
                 CO 2 H 
               
               
                 77 
                 Bu 
                 Me 
                 Me 
                 Me 
                 Mod 
                 CO 2 H 
               
               
                 78 
                 Bu 
                 Me 
                 Me 
                 Me 
                 H 
                 Tz 
               
               
                 79 
                 Bu 
                 Me 
                 Me 
                 Me 
                 Pom 
                 Tz 
               
               
                 80 
                 Bu 
                 Me 
                 Me 
                 Me 
                 Mod 
                 Tz 
               
               
                   
               
               
                 Abbreviations used in the above Table indicate the following groups. 
               
               
                 Bu: butyl group 
               
               
                 Et: ethyl group 
               
               
                 Me: methyl group 
               
               
                 Mod: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group 
               
               
                 Phth: phthalidyl group 
               
               
                 Pom: pivaloyloxymethyl group 
               
               
                 Pr: propyl group 
               
               
                 Pr i : isopropyl group 
               
               
                 Tz: tetrazole-5-yl group 
               
            
           
         
       
     
     In the above Table, preferable compounds are illustrated compounds Nos. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 79 and 80. 
     More preferable compounds are illustrated compounds Nos. 5, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 and 74. 
     Still more preferable compounds are illustrated compounds Nos. 5, 6, 8, 9, 10, 11, 12, 14, 15, 17, 18, 22, 23, 24, 25, 26, 27, 29, 32, 33, 34, 35, 36, 37, 38, 49, 50, 55, 56, 58, 63, 65, 68, 69, 70, 71, 72, 73 and 74. 
     Especially preferable compounds are:
     Illustrated compound No. 11: pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 12: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-hydroxymethyl-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 17: pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 18: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxyethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 29: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylic acid,   Illustrated compound No. 32: pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 33: ethoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,   Illustrated compound No. 34: 1-(ethoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,   Illustrated compound No. 35: isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,   Illustrated compound No. 36: 1-(isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,   Illustrated compound No. 37: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,   Illustrated compound No. 68: pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 69: ethoxycarbonyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 70: 1-(ethoxycarbonyloxy)ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 71: isopropoxycarbonyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,   Illustrated compound No. 72: 1-(isopropoxycarbonyloxy)ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate, and   Illustrated compound No. 73: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate.   

     Most preferable compounds are:
     Illustrated compound No. 29: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methylimidazole-5-carboxylic acid (Japanese designation: olmesartan), and   Illustrated compound No. 37: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl)phenyl]phenyl]methyl-imidazole-5-carboxylate (Japanese designation: olmesartan medoxomil).   

     Olmesartan medoxomil (illustrated compound No. 37) is a prodrug in which the carboxylic acid at position 5 of the imidazole ring of olmesartan (illustrated compound No. 29) is medoxomil ester. Upon oral administration, this prodrug is hydrolyzed by esterase mainly in the small intestinal epithelium and thus converted to olmesartan, an active substance. 
     The compound (I) which is the active ingredient of the present invention, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof are known (see, for example, Japanese Unexamined Patent Publication No. Hei 5-78328) or may be prepared by known methods (see, for example, Japanese Unexamined Patent Publication No. Hei 5-78328). 
     The medicament of the present invention may be used in the prevention or treatment of bone metabolic diseases. The term “prevention or treatment” used herein encompasses not only improvement or curing of such diseases but also inhibition of the progress of such diseases, prevention of onset of such diseases, and prevention of recurrence of such diseases. The term “prevention or treatment” should not be interpreted in a limitative manner in any meaning. This term must be in interpreted more broadly. 
     Bone metabolic diseases are diseases of which the major pathology is enhancement of bone resorption by osteoclasts. For example, osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, alveolar ridge resorption after tooth extraction and the like are included. 
     Briefly, the medicament of the present invention comprising a specific angiotensin II receptor antagonist (such as olmesartan medoxomil) as an active ingredient may be used in the prevention or treatment of bone metabolic diseases such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, or alveolar ridge resorption after tooth (preferably osteoporosis). 
     Since the above-described angiotensin II receptor antagonist is generally administered orally, it is desirable to administer the medicament of the present invention orally. However, the administration route of the medicament of the present invention is not limited to oral administration. It may also be administered parenterally, such as intravenously, intrarectally, percutaneously, transmucosally or subcutaneously. Examples of dosage forms suitable for oral administration include, but are not limited to, powder, granules, tablets and capsules. In the preparation of each dosage form, pharmacologically acceptable additives for formulation such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, correctives or diluents may be used appropriately. 
     As “excipients”, for example, organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan; and inorganic excipients including silicate derivatives such as light anhydrous silicic acid, synthetic aluminium silicate, calcium silicate or magnesium aluminometasilicate; phosphates such as calcium hydrogenphosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate may be used. 
     As “lubricants”, for example, stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride and silicic hydrate; or the starch derivatives described above may be used. 
     As “binders”, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or compounds similar to the above-described excipients may be used. 
     As “disintegrants”, for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; and chemically modified starch/cellulose derivatives such as carboxymethylstarch or sodium carboxymethylstarch may be used. 
     As “emulsifiers”, for example, colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminium hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylenealkylether, polyoxyethylene sorbitan fatty acid ester or sucrose esters of fatty acids may be used. 
     As “stabilizers”, for example, p-hydroxybenzoate esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid may be used. 
     As “correctives”, for example, sweeteners such as saccharin sodium or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon or orange may be used. 
     As “diluents”, conventionally used diluents, for example, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinyl-pyrrolidone, magnesium aluminometasilicate or a mixture of these compounds may be used. 
     Doses of the medicament of the present invention may be appropriately selected depending on various factors such as the administration route, the type of the active ingredient, the age, body weight or symptoms of the patient, the purpose of administration (prevention or treatment), etc. Generally, the medicament of the present invention is administered at 0.001 mg/kg (preferably 0.01 mg/kg) per day with an upper limit of 10 mg/kg (preferably 1 mg/kg) per day. This dose may be administered once or may be divided into 2 to 6 times a day depending on the symptoms. 
     The medicament of the present invention may be used in combination with other preparations which are effective for bone metabolic diseases such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, or alveolar ridge resorption after tooth extraction. 
     EXAMPLES 
     Hereinbelow, the present invention will be described in more detail with reference to the following Examples and Preparation Examples. However, the scope of the present invention is not limited to these Examples and Preparation Examples. 
     Test Example 1 
     Purpose: Using a domestic rabbit bone marrow culture system, the number of osteoclasts which were differentiation-induced by active vitamin D3 was measured. Then, inhibitory effect of olmesartan medoxomil was examined. 
     Methods: A three-day-old domestic rabbit (New Zealand White Rabbit) was sacrificed, followed by removal of the thigh bone and the tibia. After collection of the bone marrow, the leukocyte (granulocyte-monocyte) fraction was isolated and cultured under conditions of α-MEM, 10% FBS, 5% CO 2 , 37° C. 24-well culture plates were used for the culture. The cell count was adjusted to 5×10 4  cells/well. Active vitamin D3 (10 −8 M) was added to the culture system. On day 3, 7 and 10 of the culture, cells were fixed with 4% paraformaldehyde and stained with tartarate-resistant acid phosphatase (TRAP staining) under acidic conditions (pH 5.0). The number of multinucleated cells stained with red (osteoclasts) was measured. Similar measurement was performed with addition of olmesartan at concentrations of 10 −8 , 10 −7  and 10 −6 M. With respect to TRAP positive cells (generally, containing 1 to 100 nuclei in one cell), they were divided into three groups depending on the degree of fusion: small cells (containing 1 to 2 nuclei), medium cells (containing 3 to 9 nuclei) and large cells (containing 10 or more nuclei). 
     Results: As a result of induction using active vitamin D3, in the control group (olmesartan non-addition group), fusion of bone marrow mononuclear cells was observed in the coexistence of mesenchymal cells on day 3; TRAP positive cells were observed sporadically on day 7; and a large number of TRAP positive, multinucleated cells were observed on day 10 (degree of fusion; average cell count: small 101.6, medium 68.6, large 80.6). In olmesartan addition groups, while no remarkable change was recognized in 10 −8  M addition group compared to the control group, a reduction in TRAP positive cell count was recognized on day 10 in 10 −7  M addition group and a significant reduction was recognized in 10 −6  M addition group (small 192.8, medium 50.2, large 23.0). In 10 −6  M addition group, it was also observed that fusion of mononuclear cells observed in the control group on day 3 was significantly reduced. In any of the groups, no remarkable change was observed in the growth of coexisting mesenchymal cells. Although no statistically significant difference was observed in the total number of TRAP positive, multinucleated cells (control group: 250.8; olmesartan addition groups: 265.0), it was observed that fusion into medium or large cells was inhibited in olmesartan addition groups and fusion into small cells was increased. It has been demonstrated that mononuclear TRAP positive cells belonging to the above “small cell” have no bone resorption ability. Therefore, taking all things into consideration, it is judged that osteoclasts contributing to bone resorption are significantly (p&lt;0.05) decreased in olmesartan addition groups (73.2) compared to the control group (149.2). 
     Discussion: From the above-described experimental results, it is believed that olmesartan and its prodrug olmesartan doxomil inhibit the induction and formation of osteoclasts in a concentration dependent manner. Further, while olmesartan inhibited the fusion of bone marrow mononuclear cells at effective concentrations, it did not affect the growth of other mesenchymal cells coexisting in the culture system. Therefore, it is believed that this compound specifically inhibits the formation of osteoclasts and that this effect is not caused by cytotoxicity. 
     Specificity: Based on the above results, it is believed that this compound is effective for bone metabolic diseases (such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, or alveolar ridge resorption after tooth extraction; preferably osteoporosis) by inhibiting the formation of osteoclasts. In view of the mode of action of this compound, it is believed that its preventive or therapeutic effect will be further enhanced by a combined use with other preparations. 
     Test Example 2 
     Purpose: Using human osteoblasts, expression of RANKL (Receptor Activator of NK-κB Ligand) which increases with angiotensin 2 (AngII) was measured. Then, inhibitory effect of olmesartan doxomil was examined. 
     Methods: Human osteoblasts (Clonetics Corp., Palo Alto, Calif.) were cultured in DMEM medium under conditions of 10% FCS, 5% CO 2  and 37° C. AngII (1 μM) (Sigma) was added to the culture. After two-day cultivation, sRANKL (soluble Receptor Activator of NK-κB Ligand) contained in the culture supernatant was examined by ETA assay (Biomedica). Further, effect produced by simultaneous administration of olmesartan (1 μM) or angiotensin type II receptor antagonist PD (123319) (chemical name: (S)-1-(4-[dimethylamino]-3-methylphenyl)methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate) (1 μM) (Sigma-aldrich) was also examined. 
     Results: Significant increase of sRANKL was observed by AngII addition (AngII group: 1.045±0.129 pM) compared to non-addition group (Control group: 0.133±0.0271 pM) ( FIG. 1 ). This increase was almost completely inhibited by simultaneous administration of olmesartan (AngII+ARB group: 0.0442±0.0328 pM), but not by PD (123319) (AngII+AT2 group: 0.747±0.0855 pM). 
     Discussion: From the results described above, it is believed that AngII increases RANKL expression in osteoblasts to thereby promote the activation of osteoclasts indirectly. On the other hand, it has been found that olmesartan almost completely inhibits this RANKL expression increasing effect of AngII in osteoblasts. 
     Specificity: Based on the above results, it is believed that olmesartan and its prodrug olmesartan medoxomil are effective for bone metabolic diseases (such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, or alveolar ridge resorption after tooth extraction; preferably osteoporosis) by inhibiting the activation of osteoclasts by AngII. In view of the mode of action of these compounds, it is believed that their preventive or therapeutic effect will be further enhanced by a combined use with other preparations. 
     Test Example 3 
     Purpose: Using spontaneously hypertensive rats, increase in TRAP (tartarate-resistant acid phosphatase) activity in the thigh bone and decrease in the bone density after ovariectomy were measured. Then, inhibitory effects of olmesartan medoxomil against TRAP activity increase and bone density decrease were examined. TRAP is a marker enzyme for osteoclasts, and TRAP activity increases when osteoclasts are activated. When osteoclasts are activated, bone is resorbed and thus bone density is decreased. 
     Methods: The ovary was removed from 8-week-old female spontaneously hypertensive rats (SHR) (Charles River). After one month observation, the thigh bone was removed, followed by measurement of TRAP activity in the bone (Walter K., et al., Method of Enzymatic Analysis, Academic Press, New York &amp; London: 1974; 856-870) and simultaneous measurement of bone density (Venken K., et al., Bone 2005; 36: 663-670). Further, from immediately after the ovariectomy, olmesartan was administered subcutaneously at two different concentrations of 0.5 mg/kg/day and 1 mg/kg/day using an osmotic pressure pump (Alzet model 2004; Alza Corp). 
     Results: The TRAP activity in the thigh bone in SHR one month after ovariectomy (Ovariectomy group: 76.9±9.9 U/L) was significantly increased compared to non-treatment group (59.6±1.0 U/L) ( FIG. 2 ). Although administration of olmesartan brought no changes in the length and weight of the bone, concentration dependent decrease was recognized in TRAP activity in the thigh bone (Ovariectomy+ARB0.5 group: 71.7±8.7 U/L; Ovariectomy+ARB 1 group: 66.1±3.6 U/L). Concentration dependent decrease in blood pressure was also recognized as a result of administration of olmesartan (Table A). In the measurement of bone density (dual-energy X-ray absorptiometry), bone density in ovariectomy groups (0.1438±0.003445 g/cm 2 ) was significantly decreased compared to non-treatment group (0.1685±0.002684 g/cm 2 ). However, the administration of olmesartan significantly inhibited the decrease in bone density resulted from ovariectomy (Ovariectomy+ARB0.5 group: 0.15273±0.003454 g/cm 2 ; Ovariectomy+ARB1 group: 0.15386±0.004365 g/cm 2 ) ( FIG. 3 ). 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE A 
               
               
                   
               
               
                   
                 Blood  
                 Blood  
                 Blood  
                   
               
               
                   
                 Pressure 
                 Pressure 
                 Pressure 
                 Heart  
               
               
                 Group 
                 (systolic) 
                 (diastolic) 
                 (average) 
                 Rate 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Non-treatment group (n = 3) 
                 147.667 
                 105.667 
                 119.333 
                 322.333 
               
               
                 Ovariectomy group (n = 3) 
                 131.667 
                 94.6667 
                 107 
                 312.667 
               
               
                 Ovariectomy + ARB 0.5  
                 107 
                 68.3333 
                 81.3333 
                 314 
               
               
                 group 
                   
                   
                   
                   
               
               
                 Ovariectomy + ARB1  
                 70.8 
                 45.8 
                 56.25 
                 358.6 
               
               
                 group (n = 3) 
               
               
                   
               
               
                 The numerical values shown in Table A are average values. 
               
            
           
         
       
     
     Discussion: From the above-described experimental results, it was suggested that olmesartan has inhibitory effect against osteoclast activation even in in vivo systems. 
     Specificity: Based on the above results, it is believed that olmesartan and its prodrug olmesartan medoxomil are effective for bone metabolic diseases (such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea, or alveolar ridge resorption after tooth extraction; preferably osteoporosis) by inhibiting the activation of osteoclasts even in in vivo systems. In view of the mode of action of these compounds, it is believed that their preventive or therapeutic effect will be further enhanced by a combined use with other preparations. 
     Preparation Example 1 
     Capsules 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Olmesartan medoxomil 
                  20.0 mg 
               
               
                   
                 Lactose 
                 158.7 mg 
               
               
                   
                 Corn starch 
                  70.0 mg 
               
               
                   
                 Magnesium stearate 
                  1.3 mg 
               
               
                   
                 Total 
                 250.0 mg 
               
               
                   
                   
               
            
           
         
       
     
     The above prescribed powders are mixed and passed through a 60-mesh sieve. The resultant mixture is packed in 250 mg No. 3 gelatin capsules to thereby prepare capsules. 
     Preparation Example 2 
     Tablets 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Olmesartan medoxomil 
                  20.0 mg. 
               
               
                   
                 Lactose 
                 154.0 mg 
               
               
                   
                 Corn starch 
                  25.0 mg 
               
               
                   
                 Magnesium stearate 
                  1.0 mg 
               
               
                   
                 Total 
                 200.0 mg 
               
               
                   
                   
               
            
           
         
       
     
     The above prescribed powders are mixed and tableted with a tableting machine to thereby prepare 200 mg tablets. These tablets may be coated with sugar, if necessary. 
     All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety. 
     INDUSTRIAL APPLICABILITY 
     The medicament of the present invention comprising a specific angiotensin II receptor antagonist (such as olmesartan medoxomil) is useful in the prevention or treatment of bone metabolic diseases such as osteoporosis, rheumatoid arthritis, Paget&#39;s disease, bone metastasis of malignant tumor, osteoarthritis, osteomalacia, hyperparathyroidism, periodontal disease, alveolar pyorrhea or alveolar ridge resorption after tooth extraction (preferably osteoporosis). The above-described medicament is preferably for use in warm-blooded animals, and more preferably for use in human.