JPH10505091A - Phosphonates and parathyroid hormone for osteoporosis - Google Patents

Abstract

  (57) [Summary] The present invention provides: (a) administering a safe effective amount of an anti-absorbent compound to a subject for about 2 weeks to about 6 months; (b) treating a safe effective amount of parathyroid hormone for about 3 to about 12 months. There is provided a method of treating a human or other animal subject having a bone metabolic disorder, the method comprising administering to the body. Preferred anti-absorbing compounds include bisphosphonates, estrogenic compounds and anti-estrogenic compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION               Phosphonates and parathyroid hormone for osteoporosis                                 Background of the Invention   The present invention relates to a method of increasing bone mass in humans and other animals, namely osteoporosis and related methods. The present invention relates to a method for treating dysbiosis. In particular, the present invention relates to antiabsorbable compounds and parathyroid glands. It relates to such a method of treatment by administration of Lumon.   The most common metabolic bone disorder is osteoporosis. Osteoporosis is a loss of bone or skeleton It can usually be defined as tissue atrophy. Generally, there are two types, primary and secondary bone If you have osteoporosis. "Secondary osteoporosis" is a disease process or substance It is a fruit. However, about 90% of all osteoporosis cases are “primary osteoporosis”. You. Such primary osteoporosis includes postmenopausal osteoporosis and age-related osteoporosis (70 Affects the majority of individuals in their 80s and middle-aged and young men and women If you have idiopathic osteoporosis.   In some individuals with osteoporosis, loss of bone tissue is sufficient to cause mechanical damage to the bone structure Big enough. Fractures can occur, for example, in the hip and spine of women with postmenopausal osteoporosis. Often occurs in. Kyphosis (abnormal thoracic spine curvature) may also occur.   The mechanism of bone loss in osteoporosis patients is imbalanced in the process of "bone remodeling" It is thought to accompany. Bone remodeling occurs throughout life, regenerating the skeleton, To maintain. This remodeling includes details called “basic multicellular units” or “BMUs”. The bleb tissue group involves erosion and filling of discrete sites on the surface of the bone. BMU mainly Consists of "osteoclasts", "osteoblasts" and their cell precursors. For remodeling cycle In bone, the bone is resorbed at the site of BMU “activated” by osteoclasts, To form This cavity is then filled with bone by osteoblasts.   Usually in the case of adults, the remodeling cycle involves only a fraction of the bone due to incomplete filling of the bone resorption cavity. Deficiency. This results in age-related bone loss, even in healthy adults. However, in many people, especially in postmenopausal osteoporosis patients, activated B There is an increase in the number of MUs. This increased activation promotes bone remodeling and leads to abnormally high bone loss. Occurs.   The etiology is poorly understood, but many are thought to be related to osteoporosis Risk factors. These include low body weight, low calcium intake, body There is inactivity and estrogen deficiency.   Many compositions and methods have been described in the medical literature regarding "treatment" of osteoporosis. You. Many of these compositions and methods slow bone loss or reduce bone mass. It is about to make an increase. For example, R.C.Haynes, Jr. et al., "Agents affecting  Calcification ", The Pharmacological Basis of Therapeutics, 7th Edition (A. G. Gilman, L.S. Goodman et al., Editors, 1985); G. D. Whedon et al., "An Analysis of Curre nt Concepts and Research Interest in Osteoporosis ", Current Advances in S keletogenesis (A. Ornoy et al., Editors, 1985); W.A. Peck et al., Physician's Resource M See anual on Osteoporosis (1987), published by the National Osteoporosis Foundation.   Some treatments for osteoporosis shown in the literature include bisphosphonates or other bone There is administration of active phosphonates. For example, Storm et al., "Effect of Intermittent Cy clical Etidronate Therapy on Bone Mineralization and Fracture Rate in Wo men with Post-Menopausal Osteoporosis ", 322, New England Journal of Medici ne, 1265 (1990); Watts et al., "Intermittent Cyclical Etidronate Treatment of P. ost-Menopausal Osteoporosis ", 323, New England Journal of Medicine, 73 (1990 )reference. Such treatment with various bisphosphonates has been described on August 2, 1988. Flora et al., U.S. Pat. No. 4,761,406, issued on Mar. 1989; U.S. Pat. No. 4,812,30 issued to Anderson et al. Uchtman, U.S. Pat. No. 4,812, issued Mar. 14, 1989. No. 311; Flora, U.S. Pat. No. 4,822, issued Apr. 18, 1989. 609. Bone coarseness with abnormal calcium and phosphate metabolism The use of such phosphonates in the treatment of psoriasis and other disorders was introduced in 1972. Francis, U.S. Pat. No. 3,683,080 issued Aug. 8, 1980. Francis U.S. Pat. No. 4,330,537, issued Oct. 28, 1; US Patent No. 4,267,108 to Blum et al. Issued May 12, 981; Ebetino's European Patent Publication No. 298,553, published Jan. 11, 1989. Specification; Francis et al., "Chemical, Biochemical and Medicinal Properties of t he Diphosphonates ", The Role of Phosphonates in Living Systems, Chapter 4 ( 1983).   Estrogen administration is also used as a means to prevent osteoporosis in postmenopausal women You. This therapy typically involves about 0.625 to about 1.25 mg of conjugated estrogen or Consists of daily administration of significant amounts of other estrogen hormones. Estrogen is bone coarse May be used to treat osteoporosis (ie, actually build bone in osteoporotic patients) However, this is not well established. For example, Barzel, "Estrogens in the Pre vention and Treatment of Post-Menopausal Osteoporosis: a Review ", 85, Amer ican Journal of Medicine, 847 (1988); Barzel, "Estrogen Therapy for Osteopo rosis: Is it Effective? ", Hospital Practice, 95 (1990); Ettinger et al.," Post-M enopausal Bone Loss is Prevented by Treatment with Low-Dosage Estrogen w ith Calcium ", 106, Annals in Internal Medicine, 40 (1987); Lindsay et al.," The Minimum Effective Dose of Estrogen for Prevention of Post-Menopausal Bon e Loss ", 63, Obstetrics and Gynecology, 759 (1984);" Estrogen ", Drug Informat ion, 1765 (1990); McOsker's International Patent Publication, published September 3, 1992. See 92 14474. Furthermore, estrogen Use has been associated with certain side effects such as uterine bleeding. Rudy, "Hormone Replacem ent Therapy-How to Select the Best Preparation and Regimen ", 88, Postgra See duate Medicine 157 (1990).   Parathyroid hormone has also been suggested as a treatment for osteoporosis. Parathyroid hormone Therapies using thiophene are disclosed in the following references: Hefti et al., "Increase of Whole- Body Calcium and Skeletal Mass in Normal and Osteoporotic Adult Rats Tre ated with Parathyroid Hormone ", 62 Clin. Sci. 389-396 (1982); Hock et al.," Resor ption Is Not Essential for the Stimulation of Bone Growth by hPTH- (1-34)  in Rats In Vivo ", 4 (3) Jnl. of Bone and Mineral Res. 449-458 (1989); 199. Forssman's German Patent Publication DE 39 35738 published May 8, 2001 No. 4,698,32 to Neer et al., Issued Oct. 6, 1987. No. 8; Neer et al., US Pat. No. 4,833,1 issued May 23, 1989. U.S. Pat. No. 5,118, issued to Adams et al. On Jun. 2, 1992; No. 667; Geddes and Boyce International Patent Publication published June 24, 1993. No. 93 11786; Flora's US patent issued April 18, 1989 No. 4,822,609; Anderson et al., Issued Mar. 14, 1989. U.S. Patent No. 4,812,304; Hesch published May 24, 1984. DE 32 43 358 in Hesch et al. "Results of a Stimula ting Therapy of Low Bone Metabolism in Osteoporosis with (1-38 hPTH and D iphosphonate EHDP ", 66 (19) Klin. Wschr. 976-984 (Oct 1988); May 2, 1984. Hesch, German Patent Publication DE 32 43 358, published on 4th; Dell ing et al., "Morphologic Study of Pelvic Crest Spongiosa in Patients with Ost eoporosis during ADFR Therapy with Parathyroid Hormone and Diphosphonate s ", 128 (1) Z. Orthop. 1-5 (1990) (hereinafter" Delling et al. "); Delmas et al.," The In Vivo ".  Anabolic Effect of hPTH- (1-34) Is Blunted When Bone Resorption Is Blocked By A Bisphosphonate ", 6 (1) J.Bone Mineral Res.S 136 (# 214) (Aug. 1991).   The present inventor has recognized that administration of parathyroid hormone after administration of an anti-absorbent compound is well known in the art. Have surprisingly discovered that they have an effect that is not recognized by. Therefore, the book The method of the invention has improved potency and lower side effects as compared to methods known in the art. An effective method for preventing and treating osteoporosis having an action is provided.                                 Summary of the Invention   The invention is:   (A) administering a safe and effective amount of an anti-absorbing compound to a subject for about 2 weeks to about 6 months; Give;   (B) Applying a safe and effective amount of parathyroid hormone to a subject for about 3 to about 12 months Administer; A method for treating a human or other animal subject having a bone metabolic disorder, comprising the steps of: provide.                                 Description of the invention   The method of the present invention provides an anti-absorbing compound and parathyroid hormone for human or other animal subjects. Consists of administration of the mon compound. Therefore, the specific implementations used in these methods The compounds and compositions must be pharmaceutically acceptable. Such as used in the present invention “Pharmaceutically acceptable” ingredients are defined as excessive harmful In humans and / or animals without side effects (eg toxicity, irritation and allergic reactions) It is a component suitable for use.                               Anti-absorption compound   In the method of the present invention, one or more anti-absorbing compounds are administered. As used in the present invention, "Anti-absorbent compound" refers to the formation of osteoclasts when administered to a human or other animal subject. Prevent bone loss by direct and indirect effects on numbers and / or their metabolism Compound. Preferred anti-resorptive compounds include bone-active phosphonates, estrogens Compounds, antiestrogen compounds, calcitonin compounds and mixtures thereof. Some are selected from groups. Particularly preferred anti-absorbing compounds include bisphosphones And estrogen compounds and antiestrogenic compounds.Bone active phosphonate   Preferred anti-resorptive compounds useful in the method of the invention include bone-active phosphonates . “Bone-active phosphonates” as referred to in the present invention include one or more of the following general formulas: Compound: And pharmaceutically acceptable salts and esters thereof, wherein A, B and R are defined later. As defined.   In the formula (1), “R” is hydroxy (in the case of bisphosphonate), hydrogen or Alkyl (in the case of phosphonoalkyl phosphinates). Phosphonoalkyl In the phosphinate, R is preferably unsubstituted alkyl, especially lower alkyl. is there. When R is substituted alkyl, preferred substituents are halogen, unsubstituted or Substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted amino, one or two lower There are amino, hydroxy and carboxy substituted with alkyl groups. More preferred New substituents are fluoro, phenyl, unsubstituted amino and hydroxy; B (especially when present as trifluoromethyl) and phenyl are most preferred .   Particularly preferred R moieties in phosphonoalkyl phosphinates are unsubstituted lower An alkyl group, especially an unsubstituted straight-chain saturated lower alkyl group. Preferred R moieties are methyl , Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Tert-butyl and n-hexyl. More preferably, R is methyl, ethyl , N-propyl or n-butyl. Most preferably, R is methyl.   In the formula (1), “A” is hydrogen; halogen; nitro; alkyl; Aryl; heteroaryl; unsubstituted amino, or derived from a substituted carboxylic acid An amide substituted with one substituent or a carboxylic acid having a substituent Amides derived therefrom; independently substituted with one alkyl group and one substituent Amino; hydroxy or esters thereof derived from substituted carboxylic acids An ether having a substituent; a thiol or a carboxylic acid derived from the substituent A thiol ester thereof; a thioether having a substituent, or a sulfoxide thereof; And sulfone derivatives; -SO_ThreeH, a pharmaceutically acceptable salt thereof, an alcohol having a substituent Or its unsubstituted amide, or one or two alkyls Amide substituted with a chloro group;_TwoH, a pharmaceutically acceptable salt thereof, An ester thereof derived from an alcohol, an unsubstituted amide thereof, or 1 or 2 Amides substituted with two alkyl groups; aldehydes; ketones having substituents; A carbamate unsubstituted or substituted with one or two alkyl groups; about 1 to about 1 Is a peptide having an amino acid moiety of 00; alternatively, the A and B moieties are covalent 0 to 3 hetero atoms selected from the group consisting of nitrogen, sulfur, phosphorus and oxygen Form a ring having 3 to 7 atoms including the ring, and the ring is unsubstituted Or A is substituted with one or more of the above substituents of A; An unsubstituted or substituted bond to a gem-carbon (the carbon shown in the structure (1)) Substituted with a substituted alkyl moiety.   Preferably, A is one of the following parts: (1) Hydrogen (2) halogen (preferably fluoro or chloro, more preferably fluoro) (3) a substituted or unsubstituted alkyl having the following general structure: In the above formula:   (A) n is 1 to 10, preferably 1 to 5, more preferably 1 or 2, more preferably Or an integer of 1;   (B) Each R¹Are independently hydrogen, halogen, lower alkyl, unsubstituted amino or low Amides derived from carboxylic acids of lower alkyl groups, with one lower alkyl group Amides thereof derived from substituted amino or lower alkyl carboxylic acids, Amino, hydroxy or lower alkyl independently substituted with two lower alkyl groups Ester derived from a carboxylic acid of the_TwoH, its pharmaceutically acceptable Salts, their esters derived from alcohols of lower alkyl groups, their unsubstituted Amides or amides thereof substituted by one or two lower alkyl groups, lower alkyl Ether having a kill group, -PO_ThreeH_TwoOr a pharmaceutically acceptable salt thereof, and nitro Or two R on the same carbon atom¹Is = O or = NR⁹(R⁹ Is lower alkyl, or ＮＲNR⁹Another moiety attached to the same carbon atom as the moiety May be hydrogen if one nitrogen atom is present) or Two Rs on the carbon atom¹May be replaced by an additional bond between carbon atoms Or R on the first carbon atom (from the right side of structure (2) above)¹When B (see structure (1) above) may be replaced by an additional bond; and   (C) Y is halogen; nitro; cyano; heterocycle; aryl; Unsubstituted amino and alkyl, heterocyclic, aryl or heteroaryl groups; Amides derived therefrom; one alkyl, heterocycle, aryl or Heteroaryl substituted amino and alkyl groups derived from carboxylic acids An amide thereof; one alkyl group and one alkyl, heterocycle, aryl or Amino independently substituted with a heteroaryl group; hydroxy, and alkyl, Esters derived from carboxylic acids of telocycles, aryl or heteroaryl groups Ether having an alkyl, heterocyclic, aryl or heteroaryl group; All and carboxylic acids of alkyl, heterocycle, aryl or heteroaryl groups Thiol esters derived therefrom; alkyl, heterocycle, aryl or hetero A thioether having a loaryl group and its sulfoxide and sulfone derivatives; SO_ThreeH, its pharmaceutically acceptable salts, alkyl alcohols derived from alcohols. An unsubstituted amide thereof, and an ester thereof substituted with one or two alkyl groups. Amide; -CO_TwoH, its pharmaceutically acceptable salts, alkyl alcohols Substituted with its ester, its unsubstituted amide, and one or two alkyl groups The amide; PO_ThreeH_Two, Its pharmaceutically acceptable salts, alkyl alcohols Ester thereof, its unsubstituted amide, and one or two alkyl The amide substituted with a group;-(R⁸) PO_TwoH (R⁸Is hydrogen or unsubstituted lower alkyl ), Its pharmaceutically acceptable salts, derived from alkyl alcohols Ester, its unsubstituted amide, and substituted with one or two alkyl groups Amide; aldehyde; ketone having alkyl group; unsubstituted or 1 or 2 Carbamates substituted with two alkyl groups; or peptidyl. Bisho In the case of a sulfonate, Y is preferably a heterocycle (preferably one or two nitrogen atoms A 5- to 7-membered heterocyclic ring), amino and substituted amino. Particularly preferred Y part In some cases, pyridyl, amino, and one or two lower alkyl groups are substituted. There is amino. Preferably, for a phosphonoalkyl phosphinate, Y is ha Rogen (preferably fluoro); trifluoromethyl; having a lower alkyl group Ethers; unsubstituted amino, their aminos derived from carboxylic acids of lower alkyl groups Amino, substituted with one lower alkyl group, and carboxyl of a lower alkyl group Amides derived therefrom; amides independently substituted with two lower alkyl groups Or peptidyl having 1 to about 6 amino acid moieties. (4) Cycloalkyl having 4 to 10 carbon atoms, preferably 5 or 6 carbon atoms kill (5) 5 or 6 atoms in the ring, more preferably 1 or 2 nitrogen atoms in the ring, More preferably a heterocycle having one nitrogen atom in the ring. Particularly preferred heterocycle Is unsubstituted or substituted piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl It is. (6) Unsubstituted and substituted phenyl and naphthyl (7) Unsubstituted and substituted 5 having 1 or 2 heteroatoms (particularly nitrogen heteroatoms) And 6-membered heteroaryl, preferably pyridinyl (8) an amine-containing moiety having the following general structure: In the above formula   (A) m is 0 to 10, preferably 0 to 5, more preferably 0 or 1, and still more preferably Or an integer of 0;   (B) R¹And Y are as described above; and   (C) R^TwoIs derived from hydrogen, a lower alkyl or a lower alkyl carboxylic acid. Is acyl (9) An oxygen-containing moiety having the following general structure: In the above formula   (A) m is 0 to 10, preferably 0 to 5, more preferably 0 or 1, and still more preferably Or an integer of 0; and   (B) R¹And Y are as described above (10) A sulfur-containing portion having the following general structure: In the above formula   (A) m is 0 to 10, preferably 0 to 5, more preferably 0 or 1, and still more preferably Or an integer of 0; and   (B) R¹And Y are as described above.   In the formula (1), “B” is hydrogen; halogen; unsubstituted or substituted lower alkyl; Unsubstituted or substituted cycloalkyl having 3 to 7 atoms in the ring; 3 to 7 atoms in the ring Unsubstituted or substituted heterocycle having an atom of the formula: unsubstituted or substituted phenyl; hydroxy Or esters thereof derived from carboxylic acids of lower alkyl groups; thiols; Substituted amino or amides thereof derived from carboxylic acids of lower alkyl groups; Derived from an amino substituted with a lower alkyl group or a carboxylic acid of a lower alkyl group Derived amides; amino independently substituted with two lower alkyl groups; O_TwoH, its pharmaceutically acceptable salts, derived from lower alkyl alcohols Substituted with its ester, its unsubstituted amide or one or two lower alkyl groups. Amide.   To maintain the chemical stability of these compounds, the A and B moieties are preferably both Both are linked to a phosphonate moiety (ie, a carbon atom doubly substituted with a phosphorus atom). Heteroatoms (nitrogen, oxygen or sulfur) or heteroatoms and halogens And not. Therefore, oxygen and sulfur in which the A portion is bonded to the phosphorus-substituted methylene carbon , Nitrogen or a halogen atom, B represents hydrogen, unsubstituted or substituted lower alkyl. , Cycloalkyl, heterocycle (the carbon atom of the heterocycle is attached to the gem-carbon atom ) Or phenyl, -COOH, a pharmaceutically acceptable salt thereof, a lower alkyl group Its esters derived from alcohols, their unsubstituted amides, and one or two Selected from the amide substituted with a lower alkyl group.   Preferably, B is hydrogen, halogen, unsubstituted or substituted lower alkyl, unsubstituted or Substituted phenyl, unsubstituted or substituted benzyl, hydroxy or lower alkyl Ester, thiol, unsubstituted amino or lower alkyl derived from bonic acid Amide derived from the group carboxylic acid, substituted by one lower alkyl group Amides thereof derived from carboxylic acids of amino or lower alkyl groups, two lower Amino, -COOH independently substituted with an alkyl group, and pharmaceutically acceptable salts thereof , Its esters derived from alcohols of lower alkyl groups, their unsubstituted amides Or its amide substituted with one or two lower alkyl groups.   More preferably, B is hydrogen, chloro, methyl, ethyl, hydroxy, thiol , Unsubstituted amino, (N-methyl) amino, (N, N-dimethyl) amino, -CO OH or a pharmaceutically acceptable salt thereof, -COOCH_TwoOr -CONH_TwoIt is. More preferably, B is hydrogen, methyl, chloro, amino or hydroxy, more preferably Hydrogen, hydroxy, amino or thiol, more preferably hydroxy. You. Particularly preferred bone-active phosphonates are those wherein A is group (3) or (8) In the above, B may be hydroxy.   Particularly preferred bisphosphonates useful in the present invention are compounds of the formula: [In the above formula, n is an integer of 0 to 7 (preferably 0 to 3, and more preferably 1). R¹Is hydrogen, chloro, amino or hydroxy (preferably hydrogen or hydroxy X is -NH-, quaternary amine, oxygen, sulfur or a single bond (preferably- NH— or a single bond);^TwoIs a substituted or unsubstituted 5- to 7-membered carbocycle (preferably 6-7 members, more preferably benzyl or cycloheptyl), 1 to 3 hetero atoms Substituted or unsubstituted 5- to 7-membered heterocycle (preferably having one or two nitrogen atoms A 6-membered heterocyclic ring, wherein the ring nitrogen may be quaternized), -NH_Two, 1 Alkyl or two alkyl (preferably C₁-C_Five) Amino, quaternary amino or hydrogen forming a tertiary or tertiary amine; R^Two If is a substituted 5-7 membered carbocycle or heterocycle, the substituent is from 1 to about 6 carbon atoms. Substituted and unsubstituted, saturated and unsaturated alkyl, substituted and unsubstituted aryl , Substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy Si, nitro, amide, amino, substituted amino, carboxylate and combinations thereof One or more substituents selected from the group consisting of^Three Is independently hydrogen, or substituted or unsubstituted alkyl having 1 to about 4 carbon atoms ( Saturated or unsaturated)] and pharmaceutically acceptable salts and esters thereof.   As used herein, the term "pharmaceutically acceptable salts and esters" refers to Having the same general pharmacological properties as the acid form from which they are derived and pharmaceutically acceptable, Means hydrolysable esters and salts of bone-active phosphonates. Pharmaceutically acceptable Salts include, for example, alkali metals (eg, sodium and potassium), alkaline earths Metals (eg, calcium and magnesium), non-toxic heavy metals (eg, tin and ) With ammonium and low molecular weight substituted ammonium (eg, mono, di and Triethanolamine) salts. Preferred compounds are sodium, potassium and It is an ammonium salt. Pharmaceutically acceptable esters include unsubstituted and substituted alkyls. And aryl and phosphoryl esters. Exemption of pharmaceutically acceptable esters Limitations include, for example, isopropyl, tert-butyl, 2-chloroethyl, 2,2,2 -Trichloroethyl, 2,2,2-trifluoroethyl, p-toluenesulfoni Ruethyl, glycyl, sarkosyl, benzyl, phenyl, 1,2-hexanoyl Glyceryl, p-nitrophenyl, 2,2-dimethyl-1,3-dioxolene 4-methyl, isopentenyl, o-carbomethoxyphenyl, pyraroyloxy Methyl salicylyl, diethylamidophosphoryl, pivaloyloxymethyl, acyl Ruoxymethyl, propionyloxymethyl, isobutyryloxymethyl, dodeoxy There are sil, octadecyl and isopropyloxymethyl.   Specific examples and definitions of substituents useful in the compounds of formulas (1) to (6) are 198 European Patent Publication No. 298,553 issued to Ebetino on Jan. 11, 2009 (Incorporated herein by reference). In that application, the book Phosphonoalkylphosphinates useful in the process of the invention, wherein R is hydrogen or alkyl Yes) and methods for preparing such compounds are also described. Phosphonoal The process for producing the kill phosphinate is described in Ebetin published January 11, 1989. o, EP 298,555, which is incorporated herein by reference. Incorporated in the specification).   Bisphosphonates (R is hydroxy) useful in the method of the invention and such The methods for producing such compounds are described in the following patent documents, all of which are incorporated herein by reference. No .: Francis, U.S. Pat. US Patent No. 3,553,314; Francis U.S. Patent issued August 8, 1972. No. 3,683,080; Wollmann et al. Rice, issued November 5, 1974. National Patent No. 3,846,420; Schindle issued August 12, 1975 r et al., U.S. Patent No. 3,899,496; Pl issued March 2, 1976. Oger et al., U.S. Pat. No. 3,941,772; issued May 18, 1976. U.S. Pat. No. 3,957,160, issued to Jun. 8, 1976. Schmidt-Dunker, U.S. Pat. No. 3,962,432; Sep. 7, 1976 U.S. Pat. No. 3,979,385 issued to Wollmann et al., Oct. 1976. U.S. Pat. No. 3,988,443 issued to Proger et al. Blum et al., US Pat. No. 4,054,598, issued Oct. 18, 197; U.S. Pat. No. 4,113,861 to Fleisch et al., Issued Sep. 12, 8; U.S. Pat. No. 4,117,090 to Proger issued Sep. 26, 1978. Schmidt-Dunker, U.S. Pat. No. 4,134, issued Jan. 16, 1979; U.S. Pat. No. 4,26, issued May 12, 1981 to Blum et al. No. 7,108; Jary et al., US Pat. No. 4,3, issued Dec. 8, 1981. 04,734; Francis, U.S. Pat. No. 4, issued May 18, 1982. No., 330,537; Blum et al., US Pat. No. 4,407,761; Andrews US Patent issued Sep. 4, 1984. Fourth No. 469,686; Rosini U.S. Pat. No. 4, issued March 25, 1986. No. 5,578,376; Blum et al., U.S. Pat. No. 4,608,368; Rosini et al., US Pat. No. 4,621,077; Bosies et al.'S rice issued August 18, 1987. National Patent No. 4,687,767; Benedi issued October 18, 1987. U.S. Pat. No. 4,687,768 to C.t. et al., issued on Dec. 8, 1987. Stahl et al., U.S. Pat. No. 4,711,880; issued Jan. 12, 1988. U.S. Patent No. 4,719,203 to Bosies et al., Issued May 22, 1990. U.S. Pat. No. 4,927,814 issued to Gall et al., Issued on Feb. 5, 1991. Issued U.S. Pat. No. 4,990,503 to Isomura et al .; Aug. 17, 1972. Worms, German Patent Publication No. 2,104,476, issued April 4, 1975 No. 2,343,147 to Ploeger et al. German Patent Publication No. 2,360,7, Worms et al., Published June 26, 975. No. 98; Schmidt-Dunker's German patent published on October 7, 1976 No. 2,513,966; Doi of Eimers et al., Published March 24, 1977. Patent Publication No. 2,541,981; Blum published April 4, 1985 German Patent Publication No. 3,334,211; published on May 29, 1978 Suzuki et al., Japanese Patent Publication No. 78 / 59,674; Oct. 22, 1979 Published Suzuki et al., Japanese Patent Publication No. 79 / 135,724; July 1980. Suzuki et al., Japanese Patent Publication No. 80/98193, published on 25th; 1983. European Patent Publication No. 88,359, Blum et al., Published September 14, 1998; European Patent Publication No. 100,718 to Breliere et al. European Patent Publication No. 186,405 to Benedict et al., Published July 2, 986. Bosies et al., European Patent Publication No. 197,4, published Oct. 15, 1986; No. 78; European Patent Publication No. 23, Benedict et al., Published July 29, 1987. 0, No. 068; Ebetino et al., European Patent Publication No. 27, published Jul. 6, 1988. 3,514; European Patent Publication by Ebetino et al., Published on July 13, 1988. No. 274,158; Sakamoto et al., Published on September 14, 1988 Publication No. 282,309; Isomura et al., Published on September 14, 1988. European Patent Publication No. 282,320; Binder published June 18, 1987. PCT Patent Publication No. 87/03598 to Up et al., published Jan. 28, 1988. Gall et al., PCT Patent Publication No. 88/00590.   Preferred bone-active phosphonates useful in the method of the present invention include N- [2 '-( 3'-methyl) pyridinyl] aminomethanephosphonomethylphosphinic acid; N- [ 2 '-(5'-methyl) pyridinyl] aminomethanephosphonomethylphosphinic acid N- [2 '-(3'-methyl) piperidinylidene] aminomethanephosphonomethy; Ruphosphinic acid; N- [2 '-(5'-methyl) piperidinylidene] aminometa 2- (2'-pyridinyl) ethane-1-phosphonic acid 2--1-methylphosphinic acid; 2- (2'-piperidinyl) ethane-1-phospho No-1-methylphosphinic acid; 2- (p-aminophenyl) -1-hydroxyd Tan-1-phosphono-1-methylphosphinic acid; 2- (m-aminophenyl)- 1-hydroxyethane-1-phosphono-1-methylphosphinic acid; N- [1- ( 5-Amino-2-methyl-1-oxo) pentyl] aminomethanephosphonomethyl Phosphinic acid; N- [2 '-(3'-methyl) piperidinylidene] aminomethane Phosphonobutylphosphinic acid; S- (2'-pyridinyl) thiomethanephosphonome Tylphosphinic acid; 2- (2-pyridyl) -1-hydroxyethane-1-phospho No-1-methylphosphinic acid; 2- (3-pyridyl) -1-hydroxyethane- 1-phosphono-1-methylphosphinic acid; 2- (N-imidazoyl) -1-hydrido Roxyethane-1-phosphono-1-methylphosphinic acid; 3- (N-pentyl- N-methylamino) -1-hydroxypropane-1-phosphono-1-methylpho Sphinic acid; 4-amino-1-hydroxybutane-1-phosphono-1-methylpho Sphinic acid; 3- (N-pyrrolidino) -1-hydroxypropane-1-phosphono -1-methylphosphinic acid; N-cycloheptylaminomethanephosphonomethylphos Sphinic acid; S- (p-chlorophenyl) thiomethanephosphonomethylphosphine Acid; (7-dihydro-1-pyringin) methanephosphonomethylphosphinic acid; ( 7-dihydro-1-pyringin) hydroxymethanephosphonomethylphosphinic acid ; (6-dihydro-2-pyringin) hydroxymethanephosphonomethylphosphite Acid: 2- (6-pyrrolopyrindine) -1-hydroxyethane-1-phosphono- 1-methylphosphinic acid; 1-hydroxyethane-1,1-bisphosphonic acid; 1 -Hydroxypentane-1,1-bisphosphonic acid; methanebisphosphonic acid; Loromethane bisphosphonic acid; hydroxymethane bisphosphonic acid; 1-amino eta 1,1-bisphosphonic acid; 2-aminoethane-1,1-bisphosphonic acid; 3 -Aminopropane-1,1-bisphosphonic acid; 3-aminopropane-1-hydro Xyl-1,1-bisphosphonic acid; 3- (dimethylamino) -1-hydroxypro Pan-1,1-bisphosphonic acid; 3,3-dimethyl-3-amino-1-hydroxy Cypropane-1,1-bisphosphonic acid; phenylaminomethanebisphosphonic acid; N, N-dimethylaminomethanebisphosphonic acid; N- (2-hydroxyethyl) Aminomethanebisphosphonic acid; 4-amino-1-hydroxybutane-1,1-bi Sphosphonic acid; 5-amino-1-hydroxypentane-1,1-bisphosphonic acid 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; indane 2,2-bisphosphonic acid; hexahydroindane-2,2-bisphosphonic acid; 2 -Methylcyclobutane-1,1-bisphosphonic acid; 3-chlorocyclopentane- 1,1-bisphosphonic acid; cyclohexane-1,1-bisphosphonic acid; 2- (2 -Pyridyl) -1-hydroxyethane-1,1-bisphosphonic acid; N- [2- ( 5-amino) pyridyl] aminomethanebisphosphonic acid; N- [2- (5-chloro ) Lysyl] aminomethanebisphosphonic acid; N- [2- (3-picolyl)] aminometh Tanbisphosphonic acid; N- [2- (4-picolyl)] aminomethanebisphosphone Acid; N- [2- (5-picolyl)] aminomethanebisphosphonic acid; N- [2- ( 6-picolyl)] aminomethanebisphosphonic acid; N- [2- (3,4-lutidine) )] Aminomethanebisphosphonic acid; N- (2-pyrimidyl) aminomethanebispho Sulfonic acid; N- (2-pyridyl) -2-aminoethane-1,1-bisphosphonic acid 2- (2-pyridyl) ethane-1,1-bisphosphonic acid; 2- (3-pyridyl) ) Ethane-1,1-bisphosphonic acid; 2- (4-pyridyl) ethane-1,1-bi Sphosphonic acid; 2- [2- (3-picolyl)] oxaethane-1,1-bisphos Fonic acid; 2- (3-pyridyl) -1-hydroxyethane-1,1-bisphosphone Acid; 2- (N-imidazoyl) -1-hydroxyethane-1,1-bisphosphone Acid; 3- (N-pentyl-N-methylamino) -1-hydroxypropane-1, 1-bisphosphonic acid; 3- (N-pyrrolidino) -1-hydroxypropane-1, 1-bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S- ( (p-chlorophenyl) thiomethanebisphosphonic acid; (7-dihydro-1-pyrine) Gin) methanebisphosphonic acid; (7-dihydro-1-pyringin) hydroxy Tanbisphosphonic acid; (6-dihydro-2-pyringin) hydroxymethanebis Phosphonic acid; 2- (6-pyrrolopyridine) -1-hydroxyethane-1,1-bi Sphosphonic acids; their pharmaceutically acceptable salts and esters.   Particularly preferred bone-active phosphonates useful in the method of the present invention include 1-hydro Xyethane-1,1-bisphosphonic acid; dichloromethane bisphosphonic acid; 3-A Mino-1-hydroxypropane-1,1-bisphosphonic acid; 6-amino-1-hi Droxyhexane-1,1-bisphosphonic acid; 4-amino-1-hydroxybuta 1,1-bisphosphonic acid; 2- (3-pyridyl) -1-hydroxyethane- 1,1-bisphosphonic acid; 2- (N-imidazoyl) -1-hydroxyethane- 1,1-bisphosphonic acid; 3- (N-pentyl-N-methylamino) -1-hydrido Roxypropane-1,1-bisphosphonic acid; 3- (N-pyrrolidino) -1-hydrido Roxypropane-1,1-bisphosphonic acid; N-cycloheptylaminomethanebi S-phosphonic acid; S- (p-chlorophenyl) thiomethanebisphosphonic acid; (7- (Dihydro-1-pyringin) methanebisphosphonic acid; (7-dihydro-1-pyridin) Carbamate) hydroxymethanebisphosphonic acid; (6-dihydro-2-pyringin) Hydroxymethanebisphosphonic acid; 2- (6-pyrrolopyridine) -1-hydroxy Cietan-1,1-bisphosphonic acid; pharmaceutically acceptable salts and esters thereof There is.Estrogen compounds   Among the anti-absorbing compounds useful in the present invention are estrogen compounds. In this specification The “estrogen compounds” referred to are naturally occurring forms having estrogenic activity. , Synthetic steroids, non-steroids and their conjugates (conjuga tes), metabolites and derivatives. The natural estrogen compound is cyclopentane A steroid containing the noperhydrophenathrene ring system. Such natural es The trogen compound is obtained from pregnant mare urine or using methods well known in the art. Synthesized. "Estrogens", Drug Information, 1765 (1990); Rudy, "Hormone Repla cement Therapy-How to Select the Best Preparation and Regimen ", 88, Postgr aduate Medicine, 157 (1990); C. Christiansen et al., "Estrogens, Bone Loss and Pre vention ", 1, Osteoporosis Int. 7 (1990); all of which are hereby incorporated by reference. Incorporated in the handbook.   Estrogen compounds useful in the method of the invention include, for example, estradiol , Estrone, estriol, equilin, equilenin, estradiol Onate, estradiol valerate, ethinyl estradiol, polyether phosphate Stradiol, estropipate, diethylstilbestrol, dienest B Chlorotrianisene, and mixtures thereof. Preferred useful in the present invention Estrogen hormones are "conjugated estrogens", which are estrone and estrogen. It is a mixture of sodium salts of water-soluble sulfate esters of giraffe. Such conjugation d Strogens include 17α-dihydroequilin, 17α-estradiol, Other ests found in pregnant mare urine such as Nin and 17.ALPHA.-dihydroequilenin A logogenic substance may also be included.Calcitonin compound   Among the anti-absorbing compounds useful in the present invention are calcitonin compounds. In this specification The calcitonin compound referred to is a calcium-regulating hormone and its essence Biological activity counteracts the bone and kidney effects of parathyroid hormone, i.e., Inhibiting urinary calcium excretion. Natural calcitonin is 32 amino acids secreted from thyroid follicle peripheral cells and avian and fish retrogill glands in mammals It is an acid polypeptide hormone. Linear amino acid sequences vary from species to species as well as ability. However, when various calcitonins are administered in the same international unit equivalent, All calcitonins show equal potency as anti-absorbing compounds.   Natural calcitonin is described in Behrens, Grirmans Ann. Rev. Biochem., 38, 83, 1969. By a procedure similar to that performed, from mammalian glands, i.e., pigs, cows, humans, etc., Alternatively, it can be isolated from salmon, eel and other sources. For isolation of the peptide from the gland In addition, any calcitonin sequence can be synthesized by solid phase synthesis (J. Hirt et al., Rec. Trav. Chim., 98, 1). 43, 1979) or by recombinant methods (J.W. Jacob). s et al., J. Biol. Chem., 254, 10600, 1979). Calcitonin compound Include synthetic-natural hybrids, analogs, mixtures, pseudopeptides and natural calcium Other variants of the tonin molecule are also included.Anti-estrogens   Among the anti-absorbing compounds useful in the present invention are anti-estrogenic compounds. This specification "Antiestrogen compounds" are estrogen agonists that inhibit bone resorption Active but has estrogen antagonistic activity in other tissues, especially breast and uterus Compound. The antiestrogens may be steroids or non-steroids. S Teloid antiestrogens are exemplified by tamoxifen and related compounds. Anti Many of the other activities found for progesterone or other activities such as antiandrogens Compounds are also antiestrogens useful in the methods of the invention. Non-steroidal anti-S Trogen includes, for example, U.S. Pat. No. 4,4,4, issued November 29, 1983. No. 18,068, incorporated herein by reference. There are also xifene and related compounds.                             Parathyroid hormone   The method of the present invention also includes administration of parathyroid hormone. As referred to in this specification, "Thyroid hormone" means natural human parathyroid hormone, its synthetic analogs, recombinant Parathyroid hormone and parathyroid hormone fragments produced by DNA technology; It relates to thyroid hormone fragments and parathyroid hormone fragment analogs. The method of the present invention Parathyroid hormones useful in the above include, for example, hPTH (1-38), hPTH (1- 34), hPTH (1-37), hPTH (2-34) and hPTH (2-38) ). Available parathyroid hormone types and how to make parathyroid hormone Detailed descriptions of the method are disclosed in the following references, all of which are incorporated herein by reference. Incorporated: US Patent No. 4 to Colescott et al., Issued August 8, 1978. Neer et al., U.S. Pat. No. 6,105,602; issued Oct. 6, 1987. U.S. Pat. No. 4,698,328 issued to Neer et al. On May 23, 1987. No. 4,833,125; Hesch DE No. 4, published May 24, 1984. No. 3243358; Forssmann et al., DE No. 5, published May 8, 1991. 3935 738.                                 Method of treatment   The invention is:   (A) administering a safe and effective amount of an anti-absorbing compound to a subject for about 2 weeks to about 6 months; Give;   (B) Applying a safe and effective amount of parathyroid hormone to a subject for about 3 to about 12 months Administer; A method for treating a human or other animal subject having a bone metabolic disorder, comprising the steps of: provide. Preferably, in step (a), the anti-absorbent compound is administered for about 2 to about 6 months. Or administered. More preferably, in step (b), the parathyroid gland Lumon is administered for about 4 to about 8 months, more preferably for about 6 months. Preferred Alternatively, steps (a) and (b) are repeated 1 to 5 times (ie, the overall method is (Consisting of 2-6 runs of each step in succession). In a preferred method of the invention The anti-absorbent compound is administered during the treatment period of step (b); The absorbing compound is administered simultaneously with the parathyroid hormone.   A preferred method of the invention is:   (A) administering a safe and effective amount of an anti-absorbing compound to a subject for about 2 weeks to about 1 month; Give;   (B) receiving a safe and effective amount of a parathyroid hormone compound for about 3 to about 6 months Administered to the body;   (C) administering a safe and effective amount of the anti-absorbing compound to the subject over a period of about 3 to about 6 months. The   (D) treated with a safe and effective amount of a parathyroid hormone compound for about 3 to about 6 months Administered to the body; Consists of steps. Preferably, in step (c), the period during which the anti-absorbing compound is administered is about 2 to about 6 months. Moreover, preferably, step (b) and step (d) The period during which the parathyroid hormone is administered is preferably about 4 to about 8 months. About six months. Preferably steps (c) and (d) are repeated one to four times (Ie, the method performs steps (a) and (b) and then performs step ( Each of c) and (d) is performed 2-4 times in a row).   The anti-absorbent compound and parathyroid hormone are administered in “safely effective amounts” and are described herein. As mentioned, it has a reasonable benefit / danger when used in the method of the present invention. No excessive adverse side effects (eg toxicity, irritation or allergic reactions) in proportion The amount of the substance sufficient to produce a desired therapeutic response. Specific “safe effective dose” "Indicates the specific condition being treated, the patient's physical condition, the duration of the treatment, and any concomitant Apparently dependent on factors such as the nature of the therapy and the specific prescription used You.   The specific amount and dosage of the specific anti-absorbing compound to be administered in the method of the present invention are as follows. , A function of the potency of the compound and other factors. Preferably, an anti-absorbent compound Is art-recognized, useful in treating osteoporosis according to sound medical practice It is administered in an amount and manner.   The efficacy of anti-resorptive compounds is a compound that is effective alone in significantly inhibiting bone resorption Can be indicated by the term “LED”, ie the “minimum effective dose”. Preferably, in the method of the present invention, the anti-absorbing compound comprises at least about 0.8 LED, More preferably from about 0.8 to about 5 LEDs, more preferably from about 0.8 to about 3 LEDs. Administered at the compound level.   The specific LED of a given anti-absorbing compound has its chemical composition and method of administration (ie, oral Or parenteral). The lower the LED, the stronger the potency of the compound Become. Usually, low-dose high-potency anti-absorption compounds over a small number of days of treatment. It is desirable to administer. Similarly, the higher the LED, the more potent the compound become weak. Therefore, in general, low-potency anti-absorption It is desirable to administer the compound in high doses.   In particular, bone-active phosphonate LEDs are among several industry-recognized in vivo models. It can be determined using the difference. One such model is parathyroidectomy ("TPT"). X ") is a rat model in which the compound is parathyroidectomy Serum Calcium Levels Induced by Parathyroid Hormone Administration in Aged Rats. By measuring their ability to inhibit bone resorption, Will be evaluated. This model is described in Russell et al., 6, Calcified Tissue Research, 183 (1 970); Muhlbauer et al., 5, Mineral Electrolite Metabolism, 296 (1981); 1988. Flora et al., U.S. Pat. No. 4,761,406, issued Aug. 2, 1980; European Patent Publication No. 298,553 issued to Ebetino on Jan. 11, 2009 And all of which are incorporated herein by reference.   Another model is the effect of bone-active phosphonate on bone growth in young rats. Is the “Schenk model” that measures This model is based on Schenk et al., 11, Calcif. Tissue Res. 196 (1973); Shinoda et al., 35, Calcif. Tissue Int. 87 (1983); August 1988. U.S. Pat. No. 4,761,406 issued to Flora et al. In Ebetino's European Patent Publication No. 298,553, published on 11th May. And all of which are incorporated herein by reference.   Another model prevents bone loss in female rats induced by ovariectomy "Ovariectomy" or "OVX" rat model to measure the ability of bone-active phosphonates It is. This model is described in Wronski et al., 125, End, hereby incorporated by reference. ocrinology, 810 (1989).   Bone active phosphonate LEDs are conveniently expressed in "mgP / kg" and are described herein. As mentioned, this is the amount of compound in the compound per kg of the subject to be treated. The amount of the compound expressed as mg. Bone-active phosphonates vary in molecular weight so There is a comparison between compounds of different potency by showing the dose in mgP / kg Can be performed. To determine the mgP / kg administered to a patient according to the method of the present invention, Transformations are used: For example, 2- (3-pyridinyl) -1-hydroxyethane-1,1-bisphospho The nate has a molecular weight of 350. The two phosphorus atoms have a molecular weight of 62. This Therefore, if a patient is dosed with 0.01 mg / kg of compound, about 0.002 mg P / kg Has been administered.   Preferred bone-active phosphonate parenteral LEDs useful in the present invention include: 1.0 mg P / kg for hydroxyethane-1,1-bisphosphonic acid; 0.5 mg P / kg in the case of tanbisphosphonic acid; 3-amino-1-hydroxypropa 0.03 mg P / kg in the case of 1,1-bisphosphonic acid; 4-amino-1-hydro 0.001 mg P / kg for xybutane-1,1-bisphosphonic acid; 6-amino- 0.1 mg P / kg for 1-hydroxyhexane-1,1-bisphosphonic acid; N- 0.01 mg P / k in the case of (2-pyridyl) aminomethane-1,1-bisphosphonic acid g; of 2- (3-pyridyl) -1-hydroxyethane-1,1-bisphosphonic acid 0.0003 mg P / kg; of N-cycloheptylaminomethanebisphosphonic acid 0.0001 mg P / kg; 3- (N-pentyl-N-methylamino) -1-H 0.0001 mg P / kg for droxypropane-1,1-bisphosphonic acid; 3- In the case of (dimethylamino) -1-hydroxypropane-1,1-bisphosphonic acid 0.01 mgP / kg; 3- (N-pyrrolidino) -1-hydroxypropane-1,1 0.01 mg P / kg for N-bisphosphonic acid; N-cycloheptylaminomethane 0.03 mg P / kg for bisphosphonic acid; S- (p-chlorophenyl) thiometa In the case of bisphosphonic acid, it is 0.3 mgP / kg. (LED for oral administration is phospho Higher due to reliance on systemic absorption of nate. Typically, by oral administration The absorption is from about 1 to about 10%. For this reason, oral LEDs are typically used in parenteral LEs. About 10 to 100 times higher than D. )   Similarly, estrogen hormone LEDs can cause bone loss in patients with osteoporosis. To prevent it is just an effective hormone level. The level is about 0. 625 mg / day conjugated estrogen or equivalent dose of other estrogen hormones (eg For example, 25 mg / day of ethinyl estradiol or 2 mg / day of 17β-S (Tradiol). About 0.3 to about conjugated estrogens May be administered at a level of 1.25 mg / day, preferably about 0.63 mg / day. preferable. Barzel, "Estrogens in the Prevention and Treatment of Post-Meno pausal Osteoporosis: a Review ", 85, American Journal of Medicine, 847 (1988) Lindsay et al., "The Minimum Effective Dose of Estrogen for Prevention of P ost-Menopausal Bone Loss ", 63, Obstetrics and Gynecology, 759 (1984); Genant Et al., "Effect of Estron Sulfate on Postmenopausal Bone Loss", 76, Obstetrics and Gynecology, 529 (1990); all of which are incorporated herein by reference. It is.   The calcitonin compound is recognized in the industry as preferably suitable for treating osteoporosis Is administered at a fixed level. The preferred dosage is 100 international for subcutaneous and intramuscular injection Unit (IU) / day, almost twice as much for nasal administration. 25 to 5 in the method of the present invention. The dose is reduced, such as 0 IU, and injections are given every 5 days, every 2 days, or on a cycle. May go.   Parathyroid hormone is routinely administered in International Units (IU). The present invention In the method, parathyroid hormone is preferably from about 100 to about 700 IU / day, furthermore Preferably about 200 to about 600 IU / day, more preferably about 400 to about 500 IU. It is administered at the U / day level.   During the treatment period of step (a) and (optionally) during the treatment period of step (b) In this, the anti-absorbing compound can be administered daily or in a cyclic manner. Such a cycle The law is commonly assigned to Flora et al., US Pat. No. 4,761, issued August 2, 1988. No. 4,406, issued to Mar. 14, 1989, issued to Anderson et al. U.S. Pat. No. 4,812,304; Flora, issued Apr. 18, 1989. No. 822,609; Geddes and Boyce published June 29, 1993. International Patent Publication No. WO 93/11786; McOske published September 3, 1992. r, WO 92 11474, all of which are incorporated herein by reference. Is incorporated herein by reference. With the method using bisphosphonate, Sphosphonates must be administered at least once every 30 days during the treatment period Absent. Preferably, the bisphosphonate is used daily, every two days, every three days during the treatment period. It is administered every 4 days, every 5 days or every 6 days.   During the treatment period of step (b), parathyroid hormone is released every 7 days out of every 30 days. It must be administered for at least one day. Preferably, the parathyroid hormone is a step It is administered on at least about 50% of the days during (b).   The methods of the present invention treat osteoporosis at all stages of the disorder. Osteoporosis is independent Is a progressive process of bone loss rather than a disorder with a defined start or end point Therefore, “treatment” as referred to herein stops the process of bone loss that occurs in osteoporosis. It consists of any method of stopping, delaying or reversing.   A preferred method of the present invention is for osteoporosis in a subject already having lost skeletal mass. (Referred to herein as "established osteoporosis"). Established Such a method of the invention for treating osteoporosis preferably comprises treating the subject The active agent over a period of time sufficient to increase the net skeletal mass of Become. The increase in mass may be cortical bone, cancellous bone or both. Preferably positive The taste skeleton mass is increased by at least about 5% / year, preferably at least about 10% / year You.   Specific periods of time sufficient to increase the net skeletal mass of the treated Is dependent on Such factors include, for example, the specific activity used. Agent, amount of active agent administered, age and gender of the subject to be treated, the specific disorder to be treated, Combination therapy used (if any), general physical health of the subject (other (Including presence), the degree of bone loss in the individual and the nutritional habits of the individual.   Treatment using the method of the present invention may last for at least about 12 months. Is preferred. Of course, treatments may continue indefinitely according to sound medical practice. Like Alternatively, the subject may be at a reduced risk of fracture as judged by the patient's physician. Until a net net skeletal mass is obtained.   Moreover, preferably, the subject is provided with nutrition and other nutrients to help increase bone mass. Administer a therapeutic agent. Such optional agents include, for example, vitamin D and calcium. is there.   In the method of the present invention, “administration” means effective in building bone according to sound medical practice. As such, it relates to any method of delivering the active agent used in the present invention to a subject. You. The active agent can be administered by any of a variety of known methods of administration, for example, oral, mucocutaneous ( For example, skin, sublingual, intranasal and rectal), parenteral (eg, subcutaneous injection, intramuscular injection) , Intraarticular injection, intravenous injection) and inhalation. Thus, the concrete Administration modes include, for example, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal, subcutaneous There are, but are not limited to, administration and topical application.   A preferred method for treating osteoporosis is to use an early diagnostic step to check for the presence of the disorder. Including For this reason, the preferred method of the present invention uses a human patient to detect osteoporosis. The step of making a diagnosis by Administer the active agent according to the method. In postmenopausal female patients before significant bone loss In the case of a proper treatment method, a diagnosis for examining menopause is performed in the initial diagnosis step. Such methods are well known in the art and include, for example, measuring bone mass and bone remodeling rate. No. The rate of bone remodeling can be determined by measuring biochemical markers. This specification for reference Hui et al., "The Contribution of Bone Loss to Postmenopausal O steoporosis ", 1, Osteoporosis Int. 30 (1990).   Diagnostic methods suitable for detecting established osteoporosis are also well known in the art. like this Methods include measurement of radiation density on skeletal radiographs, quantitative computed tomography Imaging method, single energy photon absorption measurement method, dual energy photon absorption measurement method, double energy There are energy X-ray absorption measurement and quantitative digital radiography. In the present invention Peck et al., Physician's Resource Manual on Osteoporosis (198 7), published by the National Osteoporosis Foundation (incorporated herein for reference) ).Dosage form   Antiabsorbable compounds and parathyroid hormone are among the various pharmaceutically acceptable compositions Either may be administered. Such compositions comprise the active agent and a pharmaceutically acceptable carrier. May include rear. Pharmaceutically acceptable carriers include human or lower Solid or liquid filler diluents or encapsulating substances and their mixtures suitable for administration to animals. There is a compound. As used herein, the term "compatibility" refers to The pharmaceutical composition such that there is no interaction that substantially reduces the pharmaceutical efficacy of the pharmaceutical composition at Means that the components of the product can be mixed with the active agent and with each other. Pharmaceutically acceptable Carriers will, of course, allow them for administration to the human or lower animal being treated. It must be of sufficiently high purity and sufficiently low toxicity to be suitable.   Some examples of substances that serve as pharmaceutical carriers are lactose, glucose and glucose. Sugars such as clath; starches such as corn starch and potato starch; Cellulose and sodium carboxymethyl cellulose, ethyl cellulose, acetic acid Derivatives thereof such as cellulose; powder tragacanth; malt; gelatin; talc; Stearic acid; magnesium stearate; peanut oil, cottonseed oil, sesame oil, oil Vegetable oils such as oil, corn oil and theobroma oil; Portions such as lyserin, sorbitol, mannitol and polyethylene glycol Riols; agar; alginic acid; nonpyrogenic water; isotonic solution; phosphate buffer; Humectants and lubricants, such as sodium sulphate; coloring agents; flavoring agents; preservatives. Other compatible pharmaceutical excipients and active agents are also pharmaceutically acceptable for use in the compositions of the present invention. May be contained in the carrier.   The choice of a pharmaceutically acceptable carrier to be used in conjunction with the active agent depends on the agent to which the active agent is administered. Is determined by the method used. Preferred pharmaceutical carrier if the active agent is injected Is sterile water, physiological saline, or a mixture thereof. PH of such parenteral compositions Is preferably adjusted to about 7.4. Pharmaceutically acceptable key for topical application Carriers include creams, gels, tapes, patches, and similar means of topical delivery. In use there are those known in the art.   The pharmaceutically acceptable carrier used in combination with the active agent should be of a practical size Used at a concentration sufficient to achieve Pharmaceutically acceptable carriers are About 0.1 to about 99.9%, preferably about 5 to about 80%, by weight of the pharmaceutical composition of the invention; Most preferably from about 10 to about 50%.   The preferred method of administering bisphosphonates is in unit dosage form (ie, Orally in a dosage form containing an appropriate amount of active agent for administration in a single dose according to the . Preferred unit dosage forms for bisphosphonates include a safe and effective amount of the active agent. There are tablets, capsules, suspensions and solutions. Suitable for the manufacture of unit dosage forms for oral administration Pharmaceutically acceptable carriers are well-known in the art. These choices are for the purposes of the present invention. It relies on secondary considerations such as insignificant taste, cost and storage stability, Business Can be done without difficulty. Preferably, the oral unit dosage form of the bone-active phosphonate is about 0%. . 0005 to about 1.0 mg P / kg oral / day of phosphonate.   A preferred method of administering the calcitonin compound and parathyroid hormone is a unit dose By subcutaneous injection in the form. Preferred unit dosage forms for injection include water, saline and There is a sterile solution of the mixture. The pH of the solution should be adjusted to about 7.4 . Preferably, the unit dosage form of parathyroid hormone is from about 4 to about 15 IU / kg / day.   Other preferred dosage forms of parathyroid and calcitonin compounds include nasal, transdermal, rectal Sublingual and oral. Preferred oral dosage forms include, for example, liposomes, lipid emulsions There are John and protein cages.kit   The present invention also provides kits for conveniently and effectively performing the methods of the present invention. This Kits such as 1 unit dose of anti-absorbable compound, 1 unit dose of parathyroid gland It includes hormones and means to facilitate compliance with the method of the invention. Such kits ensure that the subject receives exactly the right active agent at the correct dose. It provides a convenient and effective means for taking. The means of accepting such a kit include: There are all means to facilitate administration of the active agent according to the method of the present invention. like this Acceptance means include instructions, packaging, dispensing means, and combinations thereof. Pa Examples of the packaging and dispensing means are all incorporated herein by reference. US Patent No. 4,761,406 to Flora et al. Issued August 2, 1988. Uchtman, U.S. Pat. No. 4,812,31, issued Mar. 14, 1989. No. 1 and Neer et al., US Pat. No. 4,833, issued May 23, 1989. These are well known in the art, including those described in US Pat.   The following non-limiting examples illustrate the compositions, processes and uses of the present invention. .                                   Example 1   An Asian male patient weighing about 65 kg diagnosed with idiopathic osteoporosis Treat by law. Specifically, patients were given bisphosphonates, 2- ( (3-Pyridyl) -1-hydroxyethane-1,1-diphosphonic acid is administered. Suffering One tablet daily orally, each tablet containing 0.002 mg P / kg / day of bisphosphone Contains Discontinue bisphosphonate treatment. Then for the next six months Over a period of time, patients received parathyroid hormone (human synthetic fragment 1-34 or hPTH1-3). 4) is administered. Hormones are delivered to the front thigh for five days each week for six months. Administer subcutaneously at a dose of 13 IU / kg with a syringe.   Biopsy of the iliac crest compared to baseline biopsy The average wall thickness increase in retrofit units (BMU) is shown. On sponge, cortex and cortical inner surface The depth of the cavity and the frequency of activation are significantly greater than those observed at baseline. Has not increased. Measurement of bone mineral density shows an increase of 11%.                                   Example 2   The present invention relates to a caucasian female patient weighing about 60 kg diagnosed as having postmenopausal osteoporosis. Treat in the manner described above. Specifically, patients receive conjugated estrogens for 4 months I do. Estrogen is administered via a transdermal patch, at a level of 0.625 mg / day Give estrogen with. After 4 months, estrogen administration is discontinued. But The patient is then given a daily nasal spray delivering 5 IU / kg for 6 months Parathyroid hormone (human synthetic fragment 1-34 or hPTH1-34) Give.   A blood sample was then obtained and the bone-specific markers osteocalcin and bone-derived And total alkaline phosphatase. Osteocalcin increased 57% In addition, both bone and total alkaline phosphatase are slightly elevated compared to pretreatment values doing. Measurement of the base mineral density shows a 10% increase.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 45/00 A61K 37/30 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR , IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP ( KE, MW, SD, SZ, UG), AM, AU, BB, BG, BR, BY, CA, CN, CZ, EE, FI, GE, HU, IS, JP, KG, KP, KR, KZ, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, TT, UA, UZ, VN

Claims (1)

[Claims]   1. (A) Treatment with a safe and effective amount of an anti-absorbing compound for about 2 weeks to about 6 months Administered to the body;   (B) A safe and effective amount of parathyroid hormone is administered to the subject for about 3 to 12 months. Give; A method for treating a human or other animal subject having a bone metabolic disorder, comprising the steps of:   2. In step (b), parathyroid hormone is administered for about 6 months. The method for treating a human or other animal subject according to claim 1, wherein   3. The method according to claim 1, wherein steps (a) and (b) are repeated 1 to 6 times. A method for treating a human or other animal subject.   4. 4. The method according to claim 3, further comprising administering an anti-absorbing compound in step (b). The method for treating a human or other animal subject as described above.   5. In step (a), the anti-absorbent compound is administered for about 2 to about 6 months 5. The method for treating a human or other animal subject according to claim 4, wherein the treatment is performed.   6. 6. The human or claim 5, wherein the anti-absorbent compound is an estrogen compound. A method for treating another animal subject.   7. The estrogen compound is a conjugated estrogen and has a concentration of about 0.3 to about 1.25. The human or other animal subject of claim 6, which is administered at a level of mg / day. Method of treatment.   8. The human or the human of claim 5, wherein the anti-absorption compound is a calcitonin compound. A method for treating another animal subject.   9. 6. The human or claim 5, wherein the anti-absorbent compound is a phosphonate compound. A method for treating another animal subject.   10. The phosphonate compound is oxyethane-1,1-bisphosphonic acid; Loromethanebisphosphonic acid; 3-amino-1-hydroxypropane-1,1-bi Sphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid 4-amino-1-hydroxybutane-1,1-bisphosphonic acid; 2- (3-pi Lysyl) -1-hydroxyethane-1,1-bisphosphonic acid; 2- (N-imida Zoyl) -1-hydroxyethane-1,1-bisphosphonic acid; 3- (N-pentyne Ru-N-methylamino) -1-hydroxypropane-1,1-bisphosphonic acid; 3- (N-pyrrolidino) -1-hydroxypropane-1,1-bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S- (p-chlorophenyl) Thiomethanebisphosphonic acid; (7-dihydro-1-pyringin) methanebisphos Fonic acid; (7-dihydro-1-pyringin) hydroxymethanebisphosphonic acid; (6-dihydro-2-pyringin) hydroxymethanebisphosphonic acid; 2- (6 -Pyrropyridine) -1-hydroxyethane-1,1-bisphosphonic acid; Bisphosphonates selected from the group consisting of pharmaceutically acceptable salts and esters of The method for treating a human or other animal subject according to claim 9, which is:   11. Bisphosphonate is 2- (3-pyridyl) -1-hydroxyethane- The human or other animal subject according to claim 10, which is 1,1-bisphosphonic acid. Treatment method.   12. (A) Receiving a safe and effective amount of an anti-absorbing compound for about 2 weeks to about 1 month Administered to the patient;   (B) receiving a safe and effective amount of a parathyroid hormone compound for about 3 to about 6 months Administered to the body;   (C) administering a safe and effective amount of the anti-absorbing compound to the subject over a period of about 3 to about 6 months. The   (D) treated with a safe and effective amount of a parathyroid hormone compound for about 3 to about 6 months Administered to the body; A method for treating a human or other animal subject having a bone metabolic disorder, comprising the steps of:   13. 13. The method of claim 12, wherein steps (c) and (d) are repeated one to five times. The method for treating a human or other animal subject as described above.