A method of treating osteoporosis, the composition for the treatment of osteoporosis, the use of active bone-phosphonate and estrogenic hormone for the treatment of osteoporosis

 

(57) Abstract:

A method of treating osteoporosis in humans or animals includes the introduction of actively acting on the bones of the phosphonate specified subject in the amount of at least about 0.1 and LED estrogenic hormone in an amount of from about 0.2 to about 0.8 LED a day for treatment. Active on the bones of the phosphonate is preferably a bisphosphonate or phosphonocrotonate. The invention allows to stop, slow down or stop the process of bone loss that occurs in osteoporosis. 3 C. and 16 h.p. f-crystals.

The invention relates to methods build bones in humans and animals, that is, to the treatment of osteoporosis and related diseases. In particular, the invention relates to such methods of treatment, which include the introduction of active bone-phosphonates and estrogen.

Most private metabolic bone disease is osteoporosis. Osteoporosis can in General terms be defined as the deterioration of bone or atrophy of the tissues of the skeleton. Generally there are two types of osteoporosis: primary and secondary. Secondary osteoporosis is a result of the identifiable disease process or dei is the zoom. Such primary osteoporosis includes osteoporosis associated with postmenopausal osteoporosis age (affecting mainly patients aged 70 to 80 years) and idiopathically osteoporosis affects middle-aged people and younger men and women.

Some patients with osteoporosis loss of bone tissue is so great that it causes mechanical destruction of bone structure. Frequent bone fractures, such as hip or spine in women suffering from postmenopausal osteoporosis. It may also be observed kyphosis (abnormal curvature of the spine).

Believe that the mechanism for the loss of bone tissue in osteoporosis associated with imbalance of the process of "remodeling of bone tissue". Reconstruction of bone occurs throughout life, updating the skeleton and maintaining bone strength. This reconstruction includes erosion and filling in areas on the surface of the bone through an organized group of cells called the "basic multicellular fragments" or "BMU". BMU consist mainly of osteoclasts, osteoblasts and their cell precursors. When the reconstruction of the bone recarbonate in a certain place, "activated" BMU due osteoclast the

Usually in adults cycle reconstruction leads to some deficiency of the bones as a result of incomplete filling resorcinol cavity. So, even in healthy adults, there is loss of bone with age. However, in osteoporosis, there is an increase in the number of BMU that are activated. This increase activation accelerates the reconstruction of the bones that leads to an abnormally large bone loss.

Although the etiology of osteoporosis is not fully understood, there are many risk factors that are perceived to be associated with osteoporosis. They include low body weight, poor absorption of calcium, lack of physical activity and estrogen deficiency.

Many compositions and methods of their use for the treatment of osteoporosis are described in the medical literature. Many of these compositions and methods are directed to attempt to either slow down the bone loss or increase the net weight of bone mass. (R. C. Haynes, Jr.et al., "Agents offecting Calerfication", The Phacmacological Basis of The rapentics, Jth Edition (A. G. Gilman, L. S. Goodman et al, Editors 1985); G. D. Whedon et al., "An Analysis of Current Concepts and Research Jnterest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoy et al., Editors., 1985); and W. A. Pick, et al., Physieian's Resanrel Manual on Osteoporosis (1987), published by the Notional Ostioporosis Fondation).

Among the methods of treatment osteoto phosphonates (Storm et al., "Effect of Intermittent Cyclical Etidronate Therapy on Rone Mineralization and Fracture Rate in Women with Post Menopausal Osteoporosis", 322 New England Journal of Medicine 1265 (1990); and Watts et al., "Intermittent Cyclical Etidronate Treatment of Post-Menapanial Osteoporosis", 323 New England Journal of Medicine 73 (1990).

Such methods of treatment using different bisphophonates described in U.S. patent N 4761406, 1988, 4812304, 1989, 4812311, 1989, 4822609, 1989. The use of such phosphonates for the treatment of osteoporosis and other diseases, including abnormal calcium and phosphate metabolism, also described in U.S. patent N 3683080, 1972, 4330537, 1980, 4267108, 1981, in European patent publication N 298553, 1989, and in the work of Francis et al. Chemical, biochemical and medical properties of diphosphonates. The role of phosphonates in living systems, 55, 1983.

Introduction estrogen is also used as a tool to prevent osteoporosis during postmenopause women. Such treatment usually includes a daily dose of from about 0.625 to about 1.25 mg of the conjugate of estrogen or equivalent amount of other estrogenic hormones. Estrogen can also be used for the treatment of osteoporosis (ie actual build bones in osteoporosis), although this was not generally accepted (Barzel, "Estrogens in the Preventroa and Treatment of Post-Menopanial Osteoporasis: a Review", 85 American Jornal of Medicine 847 (1988); Barzel, "Estrogen Therapy for Osteoporosis: Js it Effective?",. "The Minimum Effective Dose of. Estrojen for Prevention of Post-Menepausal Rone Loss", 63 Obstetrcs and Gynecology 759 (1984); and "Estrogen Drug Information 1765 (1990)).

In addition, the use of estrogen was associated with some side effects, such as uterine bleeding (Rudy. Hormone Replacement Nhe rapy (How to choose the best drug and mode), 88, Postgraduate Medicine, 157,1990).

Found that osteoporosis can be prevented or treated by taking active on the bone phosphonates low, ineffective in other cases, the doses of estrogen. Further, these are capable of allow you to use low, in other cases, ineffective or not effective doses of phosphonates. Accordingly, the methods of the invention are capable of effective prevention and treatment of osteoporosis with reduced side effects compared to methods known in the art.

In the invention methods of treating osteoporosis in humans or animals, including reception of actively acting on the bones of the phosphonate specified subject in the amount of at least about 0.1 LED to the introduction of the hormone estrogen specified subject in an amount of from about 0.2 to about 0.8 LED a day. Active bone-phosphonates are preferably bisphosphnonate and estrogenic hormone human or animal. Specific compounds and compositions to be used in these ways, must, of course, pharmaceutically acceptable. In the sense used here, the term "pharmaceutically acceptable" component, mean component, which is suitable for use with humans and/or animals without harmful unwanted effects (such as toxicity, irritation and allergic response) at the same time with a reasonable relation to the benefit/risk. In addition, the term "safe and effective amount" refers to that amount of a component which is sufficient to achieve the desired therapeutic effect without undesirable side effects (such as toxicity, irritation or allergic response), along with reasonable relation to the benefit/risk if it is used in the method of the invention. Specific "safe and effective amount" will, obviously, vary with such factors as the particular condition that must be treated, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if any), and specific compositions.

The methods of the invention include the introduction of actively influencing bone R>
and their pharmaceutically acceptable salts and esters, where A, B and R have the meanings indicated below.

In the formula (1) R is hidrocloruro (bisphosphonates), hydrogen or alkyl group (for phosphonocrotonate). In phosphonocrotonate R preferably represents an unsubstituted alkyl, especially lower alkyl. If R is a substituted alkyl, preferred substituents include halogen, substituted or unsubstituted phenyl, unsubstituted or substituted pyridinyl, an unsubstituted amino group, amino group, substituted by one or two lower alkyl groups, hydroxy - or carboxypropyl. More preferred substituents are fluorine, phenyl, unsubstituted amino and hydroxy-group, the most preferred is fluorine (especially when presented as trifluoromethyl and phenyl.

Particularly preferred R fragments in phosphonocrotonate are unsubstituted lower alkyl groups, especially unsubstituted, saturated lower alkyl group with an unbranched chain. Preferred R fragments are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-hexyl. More preferably, the l

In the formula (I) is hydrogen, halogen, a nitro-group, alkyl, heterocycle, aryl, heteroaryl, the unsubstituted amino group or its amidon derived from carboxylic acid replacement group, an amine, substituted one substituting group or its amidon derived from carboxylic acid replacement group, amino group, substituted independently with one alkyl group and one substituting group, a hydroxy-group, or a complex ester derived from a carboxylic acid replacement group, simple ether having the replacement group, a thiol or thiol complex ester derived from a carboxylic acid replacement group, tieferen, with the replacement group, or sulfoxides or sulfonic its derivatives, -SO3H, its pharmaceutically acceptable salts, its complex ester derived from an alcohol substitute group, it unsubstituted amidon or her amidon substituted by one or two alkyl groups, -CO2H, its pharmaceutically acceptable salts, its complex ester derived from an alcohol substitute group, it unsubstituted amidon or her amidon substituted by one or two alkyl groups, an aldehyde, a ketone, having the replacement group, a carbamate, unsubstituted or substituted Oli fragments A and B, covalently connected to form a ring containing 3 to 7 atoms, and 0 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, phosphorus and oxygen, the ring is not substituted or substituted by one or more of the substituents A, above; or fragments A and B replaced by unsubstituted or substituted alkyl fragment that is attached to genialnomu carbon (carbon is depicted in structure 1 above) a double bond.

Preferably A represents one of the following fragments:

1) hydrogen;

2) halogen (preferably fluorine or chlorine, more preferably fluorine):

3) substituted or substituted alkyl overall structure.

< / BR>
where

a) n=1-10, integer, preferably 1 to 5, more preferably 1 to 2, more preferably 1;

(b) each R1is independently hydrogen, halogen, lower alkyl, unsubstituted amino group or amide derived from a carboxylic acid lower alkyl group, amino group, substituted with one lower alkyl group or Amida derived from a carboxylic acid lower alkyl group, amino substituted independently with two lower alkyl groups, hydroxy-group or its ester derived from a carboxylic acid Nisse the and lower alkyl groups, or unsubstituted its amide or its amide, substituted by one or two lower alkyl groups, a simple ether having a lower alkyl group, -PO3H2or a pharmaceutically acceptable salt, or a nitro-group, or two R1one carbon atom is =0 or = NR9(where R9is lower alkyl or hydrogen, if another nitrogen atom attached to the same carbon atom, as =NR9fragment), or two R1on adjacent carbon atoms may be replaced by an additional bond between the carbon atoms; or R1the first carbon atom (on the right side of the structure (2)) and B (see structure (1) can be replaced by an additional bond; and

c) y is a halogen: the nitro-group; cyano; heterocycle; aryl; heteroaryl; unsubstituted amino group and amide derived from a carboxylic acid alkyl, heterocyclic, Alloway or heteroaryl group; amino substituted with one alkyl, heterocyclic, aryl or heteroaryl group and its amidon derived from carboxylic acid alkyl group; amino substituted independently with one alkyl group and one alkyl, heterocyclic, aryl or heteroaryl group; a hydroxy-group and the ester obtained from catheterizations aryl or heteroaryl group; thiol and thiol ester him, derived from carboxylic acids alkyl, heterocyclic, aryl or heteroaryl groups; simple thioether with alkyl, heterocyclic, aryl or heteroaryl group and sulfoxide and sulfonic its derivatives; -SO3H, pharmaceutically acceptable salts, its esters derived from alcohol alkyl groups, unsubstituted its amide and amide substituted by one or two alkyl groups; -CO2H, pharmaceutically acceptable salts, its esters derived from alcohol alkyl group, it unsubstituted amide and its amidon substituted by one or two alkyl groups; PO3H2, pharmaceutically acceptable salts, its esters derived from alcohol alkyl group, it unsubstituted amide and amide substituted by one or two alkyl groups(R8)PO2H (where R8is hydrogen or unsubstituted lower alkyl), its pharmaceutically acceptable salt, its esters derived from alcohol alkyl group, it unsubstituted amide and amide substituted by one or two alkyl groups; aldehyde; ketone having an alkyl group; carbamate, unsubstituted or substituted by one or two alkyl groups; ilename, having one or two nitrogen atom); an amino group; a substituted amino group. Particularly preferred Y fragments include pyridinyl, amino group and the amino group substituted by one or two lower alkyl groups. For phosphonocrotonate it is preferable that Y was represented by halogen (preferably fluorine); a trifluoromethyl; a simple ester with a lower alkyl group; an unsubstituted amino group and amide derived from a carboxylic acid lower alkyl group, amino substituted with one lower alkyl group and its amide derived from a carboxylic acid lower alkyl group; amino group independently is substituted by two lower alkyl groups; or peptidyl including from one to about six amino acid fragments;

4) cycloalkyl with 4 to 10 carbon atoms, preferably 5 or 6 atoms;

5) a heterocycle with 5 or 6 atoms in the ring; preferably one or two nitrogen atoms in the ring, more preferably one nitrogen atom in the ring. Especially preferred heterocycles are unsubstituted or substituted piperidinyl, pyrrolidinyl, piperazinil and morpholinyl;

6) unsubstituted or substituted phenyl and naphthyl;

7) unsubstituted or substituted heteroaryl what about pyridinyl;

8) aminecontaining fragment of the overall structure:

,

where

a) m = 0-10, integer, preferably 0-5, more preferably 0 or 1, more preferably 0;

b) R1and Y is represented as described above; and

c) R2is hydrogen, lower alkyl or acyl group derived from carboxylic acid lower alkyl;

9) oxygen-containing fragment having the General structure:

,

where

a) m = 0-10, integer, preferably 0-5, more preferably 0 or 1, more preferably 0 or 1, preferably 0; and

b) R1and Y is represented as described above;

10) structurai fragment of the overall structure:

,

where

a) m = 0-10, integer, preferably 0 to 5, more preferably 0 or 1, preferably 0; and

b) R1and Y is represented as described above.

In the formula (1) B is hydrogen; halogen; unsubstituted or substituted lower alkyl; unsubstituted or substituted cycloalkyl with a ring consisting of 3 to 7 atoms; unsubstituted or substituted heterocycle ring containing 3 to 7 atoms; unsubstituted or substituted phenyl; hydroxy-group or a complex ester derived from a carboxylic acid lower alkyl group; diography, substituted with one lower alkyl group, or its amidon derived from a carboxylic acid lower alkyl group; amino substituted independently with two lower alkyl groups; or-CO2H, its pharmaceutically acceptable salts, its complex ester derived from an alcohol of a lower alkyl group, it unsubstituted amidon, or its amidon substituted by one or two lower alkyl groups.

To maintain the chemical stability of these compounds fragments A and B are both preferably do not contain heteroatoms (nitrogen, oxygen or sulfur) or heteroatoms or halogen attached to the phosphonate fragment (i.e., the carbon atom gemenele replaced by two atoms of phosphorus). Thus, when the fragment A contains an atom of oxygen, sulfur, nitrogen or halogen attached to phosphorothionate methylene carbon, then B is selected from a range of: hydrogen; unsubstituted or substituted lower alkyl, cycloalkyl, heterocycle (where the carbon atom of the heterocycle attached to genialny carbon atoms) or phenyl; -CO2H, or its pharmaceutically acceptable salts, its esters derived from alcohol lower alkyl group, it unsubstituted amide and amide substituted by one or two lower alkasim-alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, hydroxy-group or its ester derived from a carboxylic acid lower alkyl group, a thiol, it unsubstituted amino group or its amidon derived from a carboxylic acid lower alkyl group, amino substituted with one lower alkyl group or Amida derived from a carboxylic acid lower alkyl group, amino substituted independently with two lower alkyl groups or-CO2H, or its pharmaceutically acceptable salts and its complex ester derived from an alcohol of a lower alkyl group, and the unsubstituted amidon or her amidon substituted by one or two lower alkyl groups.

More preferably B is hydrogen, chlorine, methyl group, ethyl group, hydroxy-group, thiol, unsubstituted amino, (N-methyl)amino, (N,N-diethyl)amino groups, -CO2H, or its pharmaceutically acceptable salts, -CO2CH3or-CONH2. More preferably, B was a hydrogen, methyl group, chlorine, amino group or hydroxy-group; more preferably hydrogen, or hydroxy-group, or amino group, or thiol; more preferred is where a is the fragment groups (3) or (8), and B - hydroxy-group.

Especially preferred bisphosphonates used here are the bisphosphonates of the General formula:

,

where

n = 0-7, integer, preferably 0 to 2, more preferably 1); R1is hydrogen, chlorine, amino group or hydroxy-group, preferably hydrogen or a hydroxy-group); X is-NH-, oxygen or a simple link (preferably - NH - or a simple bond); R2- 5 - or 7-membered heterocycle having 1 to 3 heteroatoms (preferably 6-membered heterocycle having 1 or 2 nitrogen atom), amino group, amino group, substituted by one or two lower alkyl groups, or hydrogen; and their pharmaceutically acceptable salts and esters.

The term "pharmaceutically acceptable salts and esters" as used here, means hydrolyzable esters and salts, actively influencing bone phosphonates, which have the same General pharmacological properties as the acid form from which they are received, and which are pharmaceutically acceptable. Pharmaceutically acceptable salts include, for example, alkali metal salts (e.g. sodium and potassium), alkaline earth metals (e.g. calcium and magnesium), non-toxic heavy metals (n is anelmin). The preferred compounds are the salts of sodium, potassium, ammonium. Pharmaceutically acceptable esters include unsubstituted and substituted alkyl, aryl and phosphoryl esters. Non-limiting examples of pharmaceutically acceptable esters include, for example, isopropyl, tertiary butyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-triptorelin, n-toluensulfonate, glycyl, sarcosyl, benzyl, phenyl, 1,2-hexanolactam, p-nitrophenyl, 2,2-dimethyl-1,3-dioxolan-4-methyl, isopentenyl, o-carbomethoxybiphenyl, parallelogrammatical, Diethylaminoethanol, pivaloyloxymethyl, acyloxymethyl, propionylacetate, isobutyrylacetate, dodecyl, octadecyl and isopropylaminomethyl.

Specific examples and definitions for the substituents applicable to compounds of formula (1-6), described in European patent publication N 298553, Ebetino, 1989. This publication also describes phosphonocrotonate used in the methods of this discovery (where R is hydrogen or alkyl group), and methods of producing these compounds. Methods of obtaining phosphonocrotonate also described in European patent publication N 298555, Ebetino, 1989.

Biophosphonate used in the methods of this discovery (where R t is received as a reference: U.S. patent N 3553314, Fronris, 1971; N 3683080, Francis, 1972; N 3846420, Wollman et. al, 1974; N 3899496, Schindler et al., 1975; N 3941772, Ploger et al., 1976; N 3957160, Ploger et al., 1976; N 3962432, Schmidt - Dunker, 1976; N 3979385, Wollmann et al., 1976; N 3988443, Ploger et al., 1976; N 4054598, Blum et al/ issued 1977; N 4113861, Fleisch et al. , 1978; N 4117090, Ploger, 1978; N 4134969, Schmidt-Dunker, 1979; N 4267108, Blum et al., 1981; N 4304734, Jary et al. , 1981; N 4330537, Francis, 1982; N 4407761, Blum et al., 1983; N 4469686, Andrews, 1984; N 4578376, Bosini, 1986; N 4608368, Blum et al., 1986; N 4621077, Rosini et al., 1986; N 4687767, Basies et al., 1987; N 4687768, Benedict et. al., 1987; N 4711880, Stahl et. al., 1987; N 4719203, Basies et. al. , 1988; N 4927814, Gall et al., 1990; N 4990503, Jsomura et al. , 1991; West German open patent calculations N 2104476, Worms, 1972; N 2343147, Ploger et. al., 1975; N 2360798, Worml et. al, 1975; N 2513966, Schmidt - DunKer, 1976; N 2541981, Ermers et. al, 1977; N 3334211, Blum, 1985; patent publication Japan N 78/59674, Suzuk; et. al, 1978; N 79/13524, Suzuk et. al, 1979; N 80/98193, Suzuki et. al, 1980; European patent publication N 88359, Blum et. al 1983; N 100718, Rceliere et. al, 1984; N 186405, Renedict et. al, 1986; N 197478, Rosies et al, 1986; N 230068, Benedict et. al, 1987; N 273514, Ebetino et. al, 1988; N 274158, Ebetino et. al, 1988; N 282309, Sakamoto et. al, 1988; N 282320, Jsomura et. al, 1988; PCT patent publication N 87/03598, Binderug et. al, 1987; N 88/00590, Gall et. al, 1988.

Preferred actively influencing bone phosphonates suitable for use in the method of the invention include: N-(2'-(3'-methyl)-pyridinyl)aminomethanesulfonic acid; N-(2'-(5'-methyl)-pyridinyl)-aminomethylenemalonate acid is somethinginteresting acid; 2-(2'-pyridinyl)ethane)-1-phosphono-1-methylphosphonous acid; 2-(2'-piperidinyl)ethane-1-phosphono-1-methylphosphonous acid; 2-(para-AMINOPHENYL)-1-hydroxy-ethane-1-phosphono-1-methylphosphonous acid; 2-(m-AMINOPHENYL)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid; N-(1-(5-amino-2-methyl-1-oxo)-pentyl)aminomethanesulfonic acid; N-(2'-(3'-methyl)-piperidinylidene)aminomethanesulfonic acid; S-(2'-pyridinyl)timeandestimation acid; 2-(2-pyridyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid; 2-(3-pyridyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid; 2(N - imidazolyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid; 3-(N-pentyl-N-methylamino)-1-hydroxypropan-1-phosphono-1-methylphosphonous acid; 4-amino-1-hydroxybutane-1-phosphono-1-methylphosphonous acid; 3-(N-pyrrolidino)-1-hydroxypropan-1-phosphono-1-methylphosphonous acid; N - cyclohexenyltrichlorosilane acid; S-(para-chlorophenyl)timeinvestment/phosphinic acid; (7 - dihydro-1-pyrindine)-metapopulations acid; (7-dihydro-1-pyrindine)hydroxymethylphosphonate acid; (6-dihydro-2-pyrindine)hydroxymethylphosphonate acid; 2-(6-pyrrolopyridine)-1-hydroxyethane-1-phosphono-1 is anifonova acid; dichloromethanesulfonyl acid; hydroxymethylphosphonate acid; 1-aminoethane-1,1-bisphosphonic acid; 2-aminoethane-1,1-bisphosphonic acid; 3-aminopropane-1,1-bisphosphonic acid; 3-aminopropan-1-hydroxy-1,1-bisphosphonic acid; 3-(dimethylamino)-1-hydroxypropane-1,1-bisphosphonic acid; 3,3-dimethyl-3-amino-1-hydroxypropane-1,1-bisphosphonic acid; phenylaminopyrimidine acid; N,N-dimethylaminomethylphenol acid; N-(2-hydroxyethyl)aminomethanesulfonic acid; 4-amino-1-hydroxybutane-1,1-bisphosphonic acid; 5-amino-1-hydroxypentanal-1,1-bisphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; indan-2,2-bisphosphonic acid; hexahedronal-2,2-bisphosphonic acid; 2-methylcyclobutane-1,1-bisphosphonic acid; 3-chloropentane-1,1-bisphosphonic acid; cyclohexane-1,1-bisphosphonic acid; 2-(2-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid; N-2-(5-amino)-pyridinemethanol acid; N-(2-(5-chloro) pyridyl)-aminomethylphosphonic acid; N-(2-/3-picolyl)-aminomethylphosphonic acid; N-(2-/4-picolyl)aminomethanesulfonic acid; N-(2-/5-picolyl)-aminomethylphosphonic acid; N-(2-/6-picolyl)-amine the new 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-bisphosphonic acid; 2-(2-/3-picolyl)oxetan-1,1-bisphosphonic acid; 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid; 2-(N-imidazolyl)-1-hydroxyethane-1,1-bisphosphonic acid; 3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-bisphosphonic acid; 3-(N-pyrrolidino)-1-hydroxypropane-1,1-bisphosphonic acid; N-cycloheptaamylose acid; S-(para-chlorophenyl)timeconsistency acid; (7-digidoc-1-pyridine)meanbitches acid; (7-dihydro-1-pyridine)hydroxymethylphosphonate acid; (6-dihydro-2-pyridine)hydroxymethylphosphonate acid; 2-(6-pyrrolopyridine)-1-hydroxyethane-1,1-bisphosphonic acid; and pharmaceutically acceptable salts and esters.

The most preferred actively influencing bone phosphonates suitable in the method of the invention include: 1-hydroxyethane-1,1-bisphosphonic acid; dichloromethanesulfonyl acid; 3-amino-1-hydroxypropane-1,1-bisphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; 4-amino-1-hydroxybutane-1,1-bisphosphonic acid; 2-(3-pyridyl)-1-hydroxyethane-oxypropane-1,1-bisphosphonic acid; 3-(N-pyrrolidino)-1-hydroxypropane-1,1-bisphosphonic acid; N-cyclopentylamine meanbitches acid; (7-dihydro-1-pyridine)meanbitches acid; (7-dihydro-1-pyridine)-hydroxymethylphosphonate acid; (6-dihydro-2-pyridine)-hydroxymethylphosphonate acid; 2-(6-pyrimidin)-1-hydroxyethane-1,1-bisphosphonic acid; and pharmaceutically-acceptable their salts and esters.

Estrogenic hormones.

The methods of the invention also include the introduction estrogenic hormones. As stated, the term "estrogenic hormone" refers to the natural hormones, the synthetic steroid compounds and non-steroidal compounds and their conjugates, metabolites and derivatives, which possess estrogenic activity. Natural estrogenic hormones are steroids that contain cyclopentanoperhydrophenanthrene ring system. Such natural estrogenic hormone derived from the urine of pregnant mares or synthetic means, using methods well known in the art ("Estrogens", Drug Information, 1765 (1990); Rudy, "Hormone Replacement Therapy-Howto Select the Best Preparation and Regimen", 88 Postgraduate Medicine, 157 (1990); C. Christiansen et. al, "Estrogenes, Rone Loss adn Prevention 1 Osteoporosis Int, 7 (1990).

Estrogenic hormones, natural for ispolzovat, estradiolvalerate, levonorgestrel, polyestradiol, estropipate, diethylstilbestrol, dienestrol, hlortrianizen and mixtures thereof. Preferred estrogenic hormone that is suitable for the method of the invention is conjugated estrogen, which is a mixture of sodium salts of water-soluble sulfate esters of estrone and equilin. Such conjugated estrogens may also contain other estrogenic substances found in the urine of pregnant mares, for example, a 17-dihydroequilin, 17 - estradiol, equilenin and 17-dihydroequilin.

Methods of treatment.

In the invention methods of treating osteoporosis in humans and animals, which include: the introduction of actively acting on the bones of the phosphonate specified subject in the amount of at least about 0.1 LED (EDR) per day during treatment and the introduction of a specified subject estrogenic hormone in an amount of from about 0.2 to about 0.8 LED (EDR) per day during the specified treatment. The preferred method includes the introduction of from about 0.1 to about 2 LED (EDR) is actively affecting the bones of the phosphonate. And the most preferred method includes the introduction of from about 0.1 to about 0.9 LED (EDR) phosphonate. Preferably the introduction from east effective dose", represents the minimum dose of the active substance that is effective in itself causes a marked inhibition of resorbtive bones (in the sense used here, the term "active substance" refers to either active on bone phosphonate or estrogennouu hormone, or both). As for pharmaceutically active materials, the specific LED (EDR) active compounds can vary depending on their chemical components and methods of their administration (e.g. oral or parenteral). However, the LED (EDR) for a specific active substances suitable for the purposes of the invention, can be identified using well known in the art methods.

In particular, LED (EDR) for active towards the bone tissue of the compounds may be determined using any known experts model in vivo. One such model is thyroparathyroidectomy (TRTH) model in rats. In this way compounds assessed by in vivo inhibiting bone resorption ability by determining their ability to increase levels of calcium in the blood due to the introduction of parathyroid hormone to rats, which were removed parathyroid glands. This model is described in Russel et al, b Calcified Tissue Rescarch 183 (1970)tino, 1989.

Another model is "model Shinka", which determine the action of the active relative to the bone tissue of phosphonate on bone growth in young rats. This model is described in Schenk et al, 11 Caleif. Tissul Res. 196 (1973); Slinoda et al, 35 Calcif. Tissne Int., 87 (1983), U.S. patent N 4761406, Flora et al, 1988 and European patent publication N 298553, Ebetino, 1989.

Another model is the model for "ovariectomized" or "OVX" rats, in which the ability is active with respect to the bones of phosphonates to prevent bone loss in female rats caused by removal of the ovaries (oophorectomy). This model is described with Vronsky al. Endocrinology 125 810 (1989).

LED (EDR) for parenteral doses preferred active in the bones of the phosphonates used in the invention is 1.0 mg P/kg for 1-hydroxyethane-1,1-bisphosphonate acid; 0.5 mg P/kg for dehloretilifosfamida acid; 0.03 mg/kg for 3-amino-1-hydroxypropane-1,1-bisphosphonate acid; 0.01 mg P/kg for 4-amino-1-hydroxybutane-1,1 bisphosphonates acid; 0.1 mg P/kg for 6-amino-1-hydroxyhexane-1,1-bisphosphonate acid; 0.01 mg P/kg for N-(2-pyridyl)aminomethane-1,1-bisphosphonate acid; 0.0003 mg P/kg for 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid; 0,0001 mg/kg for N-(cyclic acid; 0.01 mg P/kg for 3-(dimethylamino)-1-hydroxypropane-1,1-bisphosphonate acid; 0.01 mg P/kg for 3-(N-pyrrolidino)-1-hydroxypropane-1,1-bisphosphonate acid; 0.03 mg P/kg for N-cycloheptaamylose acid; 0.3 mg P/kg for S-(para-chlorophenyl)timeconsistency acid.

LED for oral administration must be above in connection with the adsorption of phosphonates. Typically, the adsorption in oral introduction is about 1 to 10%. Thus, the LED for oral administration are typically 10 to 100 times higher than for parenteral administration.

In the sense, as he used herein, the term "mg P/kg" means the number of connections, expressed in milligrams of phosphorus compound per kg of patient's weight. The expression of the number of connections in the unit content of phosphorus (mg P") is given, in order to standardize the number of phosphonates used in pharmaceutical compositions and methods of the invention. So, for example, 2-(2'-piperidinyl)-ethane-1-phosphono-1 - methylphosphonous acid has a molecular weight of 271 g/mol, which is 22.9% (62 g/mol) is due to two phosphorus atoms present in the molecule. Therefore, 1 mg of this compound, according to the calculations, contains 0,229 mg P (1 mg x 22,9%). Therefore, for the headlights is soedineniya; for a dose of 1.0 mg P/kg of this compound for a patient weighing 50 kg, the dose should be about 220 mg of the compound.

Similarly, LED estrogenic hormone represents the amount of the hormone, which in itself effectively to prevent loss of bone tissue in patients suffering from osteoporosis. This level is usually considered to be about 0.625 mg per day of conjugated estrogen or equivalent dose of other estrogenic hormones (e.g., 25 mg per day ethinyl-estradiol or 2 mg / day of 17-estradiol) (Barzil. Extrogen for the prevention or treatment of osteoporosis associated with postmenopause. Review, 85, American Journal of Meolieine 847 (1988); Lindsay ef al. The minimum effective dose of estrogen for prevention of loss of bone tissue due to age, 63, Obstetries anb Gynecology 759 (1984); Genantet. al. The influence of externaldata for bone loss due to age, 76, Dbstetries and Gynecology 529 (1990).

Actively acting on the bone phosphonate and estrogenic hormone can be entered in parallel or sequentially. Preferably estrogenic hormone be taken daily at a daily dose of from about 0.2 to about 0.8 LED. The medroxyprogesterone (and/or equivalent hormone, such as progesterone) can be entered in parallel to the mind of the cycles. One such cycle includes receiving estrogen hormone for one or more days, followed by a "free" period of one or more days, during which the active connection is not accepted; however, the cycles are repeated. One such cyclic mode for receiving estrogen hormone is receiving estrogen hormone in 21 days, with subsequent free from reception interval of 7 days. Medroxyprogesteron can be taken during the free period. Another such cycle mode for receiving estrogen hormone is reduced to the receiving estrogen hormone for about 14 days, and then receiving estrogen hormone together with medroxiprogesterona for about 11 days. These modes are described in the article: Ruby. Hormone replacement therapy - How to choose the best drug and the mode, 88, Postgraduate Medicine 157 (1990).

The preferred route of administration is actively acting on the bones of the phosphonate - daily, subject to receiving at least about 0.1 LED active compounds. Another preferred route of administration is actively acting on the bones of the phosphonate - cycle mode, comprising the introduction of at least about 0.1 LED active compounds for one or more days, followed by about the static modes are described in U.S. patent N 4761406, Flora et. al, 1988; N 4812304, Anderson et. al, 1989; N 4822609, Flora, 1989. The preferred method of the invention disables cyclic introduction 1-hydroxyethane-1,1-bisphosphonate acid or its pharmaceutically acceptable salt and cycles include receiving phosphonate for about 14 days, followed by a free period of about 76 days. During this free period, you can take additional calcium in food.

The methods of the invention include treatment of osteoporosis at all stages of the disease. Because osteoporosis is a daily process of loss of bone tissue, not a disease with a specific beginning or end point, "treatment", as here shown, consists in any of the ways that stop, slow down or reverse the process of bone loss that occurs in osteoporosis. Accordingly, the preferred method of the invention is a method, which includes the treatment of women in the postmenopausal period before the patient experienced a significant loss of mass of the skeleton. These preferred methods are, essentially, ways to prevent osteoporosis. Preferably, such method involved the treatment of these patients in the postmenopausal period, starting neposrednih method of the invention also includes the treatment of osteoporosis in patients already lost skeletal mass (hereinafter, the term "established osteoporosis"). Such methods of the invention for the treatment of established osteoporosis preferably include the introduction of the active compounds over a period of time sufficient to achieve the increase in net skeletal mass specified patient. The weight gain may occur in articulares bone or trabecular bone, or both. Preferably, the net weight of the skeleton is increased by at least about 1% and more preferably at least about 5%.

A particular period of time sufficient to achieve an increase in the mass of the skeleton of the patient may depend on a number of factors. Such factors include, for example, specifically to the active compounds, the amount of the active compounds, the age and gender of the patient, the particular disease to be treated, concomitant therapy (if any), General physical condition of the patient (including the presence of other diseases), the rate of loss of bone tissue of the patient and the usual food of the patient.

The methods of the invention preferably continued for at least about 6 months, and FAV the AI known in medicine practice. It is preferable to treat the patient up until skeletal mass reaches a value at which clinically determine no danger of fractures in a patient (B. L. Riggs et. al. Jnvolntional Osteoporasis, 314, New England J. of Medicine (1986).

In the method of the invention, "introduction" refers to any method that is being used, which in medical practice ensures the supply of active compound in the patient's body to be treated in such a way that it was effective in building bone. The active compounds can be entered by known methods, for example orally, through the skin or mucous membranes (for example, through the skin, under the tongue, through the nose, rectal), parenteral (e.g., subcutaneous injections, intramuscular injections, intravenous injections) and through inhalation. Thus, a specific type of injection includes, for example, oral, through the skin, through the mucous membrane under the tongue, intramuscularly, intravenously, intraperitoneally, under the skin and superficial application.

The preferred method of treatment of osteoporosis includes an initial stage of diagnosis to determine the presence of the disease. Thus, a preferred method of the invention includes the diagnosis of the human body for the definition is in accordance with the methods of the invention. For such methods of treatment of patients in the stage of post-menopausal to marked bone loss specified initial diagnostic stage includes diagnostics to determine the menopause. Such methods are well known in the art and include the determination of bone mass and the degree of bone reconstruction. The speed of reconstruction of the bone can be determined by measuring biochemical markers Hui et. al. The contribution of bone loss in osteoporosis during menopause, 1, Osteoporosis Jnt, 30(1990).

Appropriate diagnostics to determine the established osteoporosis is also well known in the art. Such methods include the measurement of radioplanet radiograms of the skeleton, quantitative computed tomography, simple absorptometry energy protons and double absorptometry energy protons. Diagnostic techniques along with those described in W. A. PecK et al. Guide to physical methods for osteoporosis (1987), published by the National osteoporosis Foundation.

Active bone-phosphonates and estrogenic hormones can be entered in any pharmaceutically acceptable composition. Such compositions may contain the active compound and a pharmaceutically acceptable carrier Il for joint reception of both active compounds include:

a) at least about 0.1 LED active on the bones of the phosphonate;

C) from about 0.2 to about 0.8 LED estrogenic hormone;

C) a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include solid or liquid diluents or fillers or encapsulated substances, mixtures thereof, which are suitable for administration to a human or lower animal. The term "compatible" refers to the components of pharmaceutical compositions which can be mixed with the active compounds and to each other so that between them there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under normal conditions of use. Pharmaceutically acceptable carrier, of course, must be sufficiently high purity and sufficiently low toxicity to be taken by humans or lower animals.

Some examples of substances which can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose, such starches like corn and potato; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose oil, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of Theobroma; such polyole as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar, alginine acid, water, purified from pyrogens, isotonic saline solution; solutions of phosphate buffers, wetting agents and lubricants, as nutriceuticals, coloring agents, perfumes and flavoring agents, and preservatives. Other compatible pharmaceutical additives and active compounds can also be included in the pharmaceutical acceptable carriers for use in the compositions of the invention.

The choice of pharmaceutically acceptable carrier for use with an active compound is determined by the way in which you will enter the active connection. If the active compound is administered by injection, the preferred pharmaceutical carrier is sterile water, saline, or a mixture thereof. the pH of such compositions for parenteral administration preferably set to about 7.4. Suitable pharmaceutically acceptable carriers for surface coating include those that are known in the art for use Cesky acceptable carrier, used together with the active ingredients used in concentrations sufficient to provide a practical use and size, correlated with the dose. Pharmaceutically acceptable carriers can typically be about 0.1 to 99.9 wt.% the pharmaceutical compositions of the invention, preferably about 5 to 80%, and most preferably about 10 to 50%.

The preferred route of administration of the active compounds - the oral intake in the form of a unit dose (i.e. the dose that contains such quantity of the active substance, which is suitable for receiving a single dose in accordance with known medical practice). Preferred unit dosage forms include tablets, capsules, suspensions and solutions containing a safe and effective amount of active compound. Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration, a well-known specialists. Their choice depends on such secondary factors as taste, cost, stability, which are not critical for the purposes and which can be accounted for easily by specialists. Preferably, the oral unit dose form active action who are also kits for convenient and efficient embodiments of methods of the invention. Such kits include one or more unit doses of the active bone phosphonate, one or more unit doses of oestrogen hormone and means for facilitating compliance with methods of the invention. These kits provide an effective means to ensure that the patient to be treated, took the active connection in the right dose and in the right way. Such kits are particularly preferred in the methods of the invention using circular modes for the introduction of each or both of the active compounds.

Matching funds of such kits include tools that facilitate the introduction of the active compounds according to the method of the invention. Such AIDS include instructions, packaging and distribution tools, and combinations thereof. Examples of packaging and distribution means well known in the art and include those described in U.S. patent N 4761496, Flora et. al, 1988, and N 4812311, Uchtmon, 1989.

The following examples illustrate the compositions and methods of use the invention, but not limit it.

Example 1. A woman weighing about 60 kg, suffering from osteoporosis due to menopause treated by the method according to the invention is IU, each cycle consists of oral tablets1containing 200 mg of phosphonate daily for 14 days, followed by a 76-day break (free time), during which the patient takes no active bone phosphonates;

2) enter the conjugated estrogen daily pills2containing 0.3 mg of active compound. In this mode, active on the bone phosphonate is administered in an amount of about 0.5 to LED, and estrogenic hormone is administered in an amount of about 0.5 to LED. The density of the spine of the patient determine the photon absorbtiometry with double energy, which indicates an increase in bone mass.

1. Sold Norvich Eaton Pharmacentical, Jnc. under the brand Didronel in tablets containing 200 mg of active compounds in medium-stearate, microcrystalline cellulose and starch.

2. Sold by Wyeth - Ayerst Laboratories under the trademark "Premarin" in the media - Tihonova the calcium phosphonate, anhydrous calcium sulfate, wax rarnanba, glycerylmonostearate, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, stearic acid, powder and titanium dioxide.

according to the invention. Specifically, within one year:

1) daily give 2-(3-piridin)-1-hydroxyethane-1,1-bisphosphonic acid in tablets containing 15 mg of the active compound;

2) daily yield of 17-estradiol in the form of a transdermal patch delivering 0.03 mg active compound per day.

In this mode, active on the bone phosphonate is administered in an amount of about 1.0 LED and estrogenic hormone is administered in an amount of about 0.5 to LED. The density of the tissues of the spine of the patient is measured using photon absorptiometry with renewed energy and receive a certificate of increasing bone mass. In this example, the following active on the bone phosphonates: dichlorocyclopentane acid, 3-amino-1-hydroxypropane-1,1-bisphosphonic acid, 4-amino-1-hydroxybutane-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; N-(2-pyridyl)aminomethane-1,1-bisphosphonic acid; -2-(2-pyridyl)-1-hydroxyethane-1-phosphono-1-methylphosphinico acid, 2-(3-pyridyl)-1-hydroxyethane-1-phosphono-1-methyl-phosphinic acid; 2-(N-imidazole)-1-hydroxyethane-1-phosphono-1-methylphosphinico acid; 3-(N-methylamino)-1-hydroxypropan-1-phosphono-1-methylphosphinico acid; 4-amino-1-hydroxybutane-1-phosphono-1-methylphosphinico acid; 3-(N-acid, S-(para-chlorophenyl)timeangelinaangelina acid, (7-dihydro-1-pyrindine)metanfetamina acid, (7-dihydro-1-pyrindine)hydroxymethylphosphonate acid, (6-dihydro-2-pyrindine)hydroxymethylphosphonate acid, 2-(6-pyrrolopyridine)-1-hydroxyethane-1-phosphono-1-methylphosphinico acid, 2-(3-pyridyl)-1-hydroxyethane-1; 1-bisphosphonic acid, 2-(N-imidazolyl)-1-hydroxyethane-1,1-bisphosphonic acid, 3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-bisphosphonic acid, 3-(N-pyrrolidino)-1-hydroxypropane-1,1-bisphosphonic acid, N-cycloheptaamylose acid, S-(para-chlorophenyl)timeconsistency acid, (7-dihydro-1-pyrindine)mechanistically acid, (7-dihydro-1-pyrindine)hydroxymethylphosphonate acid, (6-dihydro-1-pyrindine)hydroxymethylphosphonate acid and 2-(6-pyrrolopyridine)-1-hydroxyethane-1,1-bisphosphonic acid can be replacing 2-(2-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid in comparable quantities and with virtually the same results.

Example 3. A patient weighing about 60 kg inspected after approximately 6 months after spontaneous menopause and find that it has a low bone mass and an abnormally high speed is of Arosa. Specifically daily for 5 years, the patient takes the pill with the following content:

Component - mg tablet

2-(2'-Piperidinyl)-ethane-1-phosphono-methylphosphinico acid - 120

Conjugated estrogen - 0,5

Lactose - 80

Microcrystalline cellulose - 50

Matrikamantra - 7,5

Magnesium stearate and 1.5

Each tablet contains about 0.3 LED active on the bones of the phosphonate and about 0.8 LED estrogenic hormone. The density of the spine of the patient determine, and it turns out that there is a noticeable decrease in bone mass.

1. A method of treating osteoporosis in humans and animals, characterized in that it includes an introduction to the specified patient is actively acting on the bones of the phosphonate in the amount of at least about 0.1 LED a day and estrogenove hormone in an amount of from about 0.2 to about 0.8 LED a day during the course of treatment.

2. The method according to p. 1, wherein said phosphonate is administered in an amount of from about 0.2 to about 1.0 LED a day during the course of treatment.

3. The method according to p. 2, characterized in that it is done to women in the postmenopausal period before the patient will be significant loss of bone mass.

6. The method according to p. 1, wherein said phosphonate is bisphosphonates acid, or its pharmaceutically acceptable salt, or a complex ester.

7. The method according to p. 6, characterized in that the said bisphosphonic acid has a General formula

< / BR>
where n = 0-7 integer;

R1is hydrogen, chlorine, amino or hydroxy;

X - N4 - oxygen or a simple bond;

R2- 5-7-membered heterocycle containing 1-3 heteroatoms, amino, amine, substituted by one or two lower alkyl groups, or hydrogen,

and their pharmaceutically acceptable salts and esters.

8. The method according to p. 6, characterized in that the specified bisphosphonic acid selected from the group consisting of 1-hydroxyethane-1,1-bisphosphonate acid, dehloretilifosfamida acid, 3-amino-1-hydroxypropane-1,1-bisphosphonate acid, 6-amino-1-hydroxyhexane-1,1-bisphosphonate acid, 4-amino-1-hydroxybutane-1,1-bisphosphonate acid, 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid, 2-(N-imidazolyl)-1-hydroxyethane-1,1-bisphosphonate acid, 3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-bis the background acid, S-(para-chlorophenyl) timeconsistency acid, (7-dihydro-1 - pyrindine)metalliferous acid, (7-dihydro-1-pyrindine)-hydroxymethylphosphonate acid, (6-dihydro-2-pyrindine)-hydroxymethylphosphonate acid; 2-(6-pyrrolopyridine)-1-hydroxyethane-1,1-bisphosphonate acid, 2-(2-pyridil)-1-hydroxyethane-1,1-bisphosphonate acid, and their pharmaceutically acceptable salts and esters.

9. The method according to p. 8, wherein the bisphosphonic acid is 1-hydroxyethane-1,1-bisphosphonate acid, or its pharmaceutically acceptable salt, or a complex ester.

10. The method according to p. 8, wherein the bisphosphonic acid is 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid, or its pharmaceutically acceptable salt, or a complex ester.

11. A method of treatment of osteoporosis under item 1, characterized in that the active bone-phosphonate is phosphonocrotonate, or its pharmaceutically acceptable salt, or a complex ester.

12. The method according to p. 11, characterized in that phosphonocrotonate selected from the group consisting of N-(2'-(3'-methyl)-pyridinyl)aminomethanesulfonic acid, N-[2'-(5'-methyl)-pyridinyl] aminomethylenemalonate kiminotamenarashineru acid, 2-(2'-pyridinyl)-ethane-1-phosphono-1-methylphosphonous acid, 2-(2'-piperidinyl)-ethane-1-phosphono-1-methylphosphonous acid, 2-(2'-piperidinyl)-ethane-1-phosphono-1-methylphosphonous acid, 2-(paraaminophenol)-1-hydroxy-ethane-1-phosphono-1-methylphosphonous acid, 2-(etaminophen)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid, N-[1-(5-amino-2-methyl-1-oxo)-pentyl] aminomethanesulfonic acid, N-[2'-(3'-methyl)-piperidinylidene] -aminomethanesulfonic acid, S-(2'-pyridinyl)-timeinhomogeneous acid and 2 - (2-pyridinyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid, 2-(3-pyridyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid, 2-(N-imidazolyl)-1-hydroxyethane-1-phosphono-1-methylphosphonous acid, 3-(N-pentyl-N-methyl-amino)-1-hydroxypropan-1-phosphono-1-methylphosphonous acid, 4-amino-1-hydroxybutane-1-phosphono-1-methylphosphonous acid, 3-(N-pyrrolidino)-1-hydroxypropan-1-phosphono-1-methylphosphonous acid, N-cyclohexenyltrichlorosilane acid, S-(parachlorophenyl)timeinhomogeneous acid, (7-dihydro-1-pyridine)metapopulations acid, (7-dihydro-1-pyridine)hydroxymethylphosphonate acid, (6-dihydro-2-pyridine)hydroxymethylphosphonate is utilized salts and esters.

13. The method according to p. 1, characterized in that the estrogenic hormone selected from the group consisting of estradiol, estrone, estriol, equilin, equilenin, estradioltenuate, estradiolvalerate, ethinyl estradiol, polyestradiol, estropipate, diethylstilbestrol, dienestrol, chlorotrianisene and mixtures thereof.

14. The method according to p. 13, characterized in that the estrogen hormone is conjugated estrogen.

15. The method according to p. 14, wherein about 0.3 mg conjugated estrogen is administered per day during the course of treatment.

16. Composition for the treatment of osteoporosis, containing active bone-phosphonate and a pharmaceutically acceptable carrier, wherein optionally the composition is in the form of a unit dose contains estrogenic hormone in the following active ingredients: active bone-phosphonate in the amount of at least about 0.1 and LED estrogenic hormone in an amount of from about 0.2 to about 0.8 LED.

17. A method of treating osteoporosis in humans or animals, characterized in that it includes the introduction of a specified subject one single dose on p. 16 per day during the course of treatment.

18. The method according to p. 6, characterized tetanusbactroban acid, 3-amino-1-hydroxypropane-1,1-bisphosphonate acid, 6-amino-1-hydroxyhexane-1,1-bisphosphonate acid, 4-amino-1-hydroxybutane-1,1-bisphosphonate acid, 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid, 2-(N-imidazolyl)-1-hydroxyethane-1,1-bisphosphonate acid, 3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-bisphosphonate acid, 3-(N-pyrrolidino)-1-hydroxypropane-1,1-bisphosphonate acid, N-cycloheptaamylose acid, S-(parachlorophenyl)timeconsistency acid, (7-dihydro-1-pyridine)-metalliferous acid, (7-dihydro-1-pyridine)hydroxymethylphosphonate acid, (6-dihydro-2-pyrindine)hydroxymethylphosphonate acid, 2-(6-pyrrolopyridine)-1-hydroxyethane-1,1-bisphosphonate acid, 2-(2-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acid and its pharmaceutical salts and esters, preferably selected from the group consisting of 1-hydroxyethane-1,1-bisphosphonate acid, 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonate acids and their pharmaceutically acceptable salts and esters.

19. The composition according to p. 16, characterized in that it contains in the form of a unit dose of at least 0,1 LED active on the bones of the phosphonate and 0.2 to 0.8 LED estrogenic hormone.

 

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