MXPA01001699A - Compositions and methods for treating osteoporosis - Google Patents

Abstract

This invention relates to methods, pharmaceutical compositions and kits useful in promoting bone formation and/or preventing bone loss and/or treating atherosclerosis. The compositions are comprised of a polyphosphonate as a first active component and a statin as a second active component and a pharmaceutically acceptable vehicle, carrier or diluent.

Description

COMPOSITIONS AND PROCEDURES FOR TREATING OSTEOPOROSIS FIELD OF THE INVENTION This invention relates to pharmaceutical compositions containing combinations of polyphosphonates and statins, and to pharmaceutically acceptable salts thereof, to kits containing such combinations and to methods of using such combinations to prevent bone loss and / or promote bone formation and / or or treat atherosclerosis. The compositions and methods are useful for treating subjects suffering from osteoporosis, fracture or bone deficiency, primary or secondary hyperparathyroidism, periodontal disease, metastatic bone disease, osteolytic bone disease or who have undergone orthopedic or buccal surgery.

BACKGROUND OF THE INVENTION In humans and other mammals, a series of disorders are associated or associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, metastatic bone disease, hypercalcemia of metastasis, multiple myeloma, periodontal disease and loss of teeth. The most common of these disorders is osteoporosis, which is the most frequent manifestation that occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and microarchitectonic deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures. Because osteoporosis, as well as other disorders associated with bone loss, are chronic disorders, it is believed that an appropriate therapy will generally require chronic treatment. The multinucleated cells called osteoclasts are responsible for the cause of bone loss through a process known as bone resorption. Polyphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a series of generalized or localized disorders caused by or associated with abnormal bone resorption. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2 edition, Parthenon Publishing (1995). At present, there is a large number of preclinical and clinical data for the polyphosphonate alendronate. Evidence suggests that other polyphosphonates such as risedronate, tiludronate, ibandronate and zolendronate have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone resorption. An ancient polyphosphonate compound, etidronate, also inhibits bone resorption. However, unlike more potent polyphosphonates, etidronate imparts mineralization at clinically used doses and can lead to osteomalacia, a disorder that causes an undesirable decrease in bone mineralization (Boyce, BF, Fogelman, I., Ralston, S. et al., Lancet, 1984; 8381: 821-824, and Gibbs, CJ, Aaron, JE; Peacock, M., Br. Med. J .. 1986; 292: 1227-1229. Cholesterol level, statins have a bone-forming effect Statins inhibit the HMG-CoA reductase enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate at an early and limiting stage of the speed in the cholesterol biosynthetic pathway.It is believed that this effect is responsible for statins being considered as potent lipid lowering agents.The bone formation effect of statins may be due to their ability to increase speed bone formation, p ostensibly by stimulation of growth factors such as bone morphogenic protein-2 (BMP-2) (Mundy, G., et al., Science, 1999, 286: 1946-1949). Statins include compounds such as simvastatin, described in U.S. No. 4,444,784, pravastatin, described in U.S. 4,346,227, cerivastatin, described in U.S. 5,502,199, Mevastatin, described in U.S. 3,983,140, velostatin, described in U.S. 4,448,784 and U.S. 4,450,171, fluvastatin, described in U.S. 4,739,073, compactina, described in U.S. 4,804,770, lovastatin, described in U.S. 4,231,938, dalvastatin, described in European patent application n of publication 738510 A2, fluindostatin, described in European patent application n of publication 363934 A1, atorvastatin, described in US Pat. No. 4,681,893, hemicálcic salt of atorvastatin, described in U.S. Patent No. 5,273,995, dihydrocompactin, described in US Pat. 4,450,171, ZD-4522, described in U.S. Patent No. 5,224,440, bervastatin, described in U.S. Patent No. 5,082,859 and NK-104, described in U.S. Patent No. 5,102,888. Bone is a tissue that is subject to renewal. Osteoblasts that produce new bone and osteoclasts that destroy bone balance bone homeostasis. The activities of these cells are regulated by a large number of cytokines and growth factors, many of which have been identified and cloned. Mundy has described current knowledge regarding these factors (Mundy GR, Clin Orthop, 1996, 324: 24-28, Mundv GR, J. Bone Miner, Res. 1993. 8: S505-10. growth factors that stimulate bone formation, among which are transforming growth factor, heparin-binding growth factors (acid and basic fibroblast growth factor), insulin-like growth factors (growth factor-type), insulin I and insulin-like growth factor II) and a recently described family of proteins called bone morphogenetic proteins (BMP), all of these growth factors have effects on other cell types, in addition to on bone cells. new factors of the extended superfamily of transforming growth factor BMPs were identified by Wozney J. et al., Science 1988, 242: 1528-34, following previous descriptions that characterize bristling biological activity in demineralized bone extracts (Urist M., Science, 1965, 150: 893-99). Recombinant BMP2 and BMP4 can induce new bone formation when injected locally into the subcutaneous tissues of rats (Wozney J., Molec, Reprod Dev. 1992, 32: 160-67). These factors are expressed by normal osteoblasts when differentiated and have been shown to stimulate osteoblast differentiation and bone nodule formation in vitro, as well as bone formation in vivo (Harris S., et al., X Bone Miner. 1994, 9, 855-63). When osteoblasts differ from precursors as mature bone formation cells, they express and secrete a series of enzymes and structural proteins of the bone matrix, including type 1 collagen, osteocalcin, osteopontin and alkaline phosphatase (Stein G., et al. , Curr, Opin, Cell, Biol. 1990, 2: 1018-27, Harris S. et al., (1994), supra). They also synthesize a series of growth-regulating peptides, which are stored in the bone matrix and are presumably responsible for normal bone formation. These growth-regulating peptides include BMPs (Harris S., et al., (1994), supra). In studies of primary cultures of fetal rat calvarious osteoblasts, BMPs 1, 2, 3, 4 and 6 are expressed in cultured cells prior to the formation of mineralized bone nodes (Harris S., et al., (1994), supra). ).

Like alkaline phosphatase, osteocalcin and osteopontin, BMPs are expressed by cultured osteoblasts when they proliferate and differentiate.

SUMMARY OF THE INVENTION This invention relates to pharmaceutical compositions useful for stimulating bone formation and / or preventing bone loss and / or treating atherosclerosis. The compositions comprise a polyphosphonate that inhibits bone resorption and a statin and, optionally, a pharmaceutically acceptable carrier, vehicle or diluent. The compositions exert an effect that is additive or greater than the sum of the individual effects of polyphosphonates that inhibit bone resorption and statins when administered separately. A second aspect of the invention relates to methods of stimulating bone formation and / or prevention of bone loss and / or treatment of atherosclerosis. The methods comprise administering an effective amount of the pharmaceutical compositions comprising a polyphosphonate that inhibits bone resorption and a statin as described herein or the co-administration of a polyphosphonate and a statin. As a third aspect, the present invention provides kits for use by a consumer to stimulate bone formation and / or prevent bone loss and / or treat atherosclerosis. The kit comprises: a) a pharmaceutical composition comprising a polyphosphonate that inhibits bone resorption and a pharmaceutically acceptable carrier, vehicle or solvent, b) a pharmaceutical composition comprising a statin and a pharmaceutically acceptable carrier, vehicle or diluent, and optionally , c) instructions describing a method of using the pharmaceutical compositions to stimulate bone formation and / or prevent bone loss and / or treat atherosclerosis. The instructions may also indicate that the kit is for stimulating bone formation and / or preventing bone loss and / or treating atherosclerosis or another specific state related to these effects. The polyphosphonate that inhibits bone resorption and statin contained in the kit can optionally be combined in the same pharmaceutical composition. As a fourth aspect, the present invention provides the use of a polyphosphonate that inhibits bone resorption and statins for the manufacture of a medicament for stimulating bone formation and / or preventing bone loss and / or treating atherosclerosis. A fifth aspect of the invention is that the compositions and methods of the invention may further comprise a histamine H2 receptor blocker (ie, an antagonist) and / or a proton pump blocker.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions and methods for stimulating bone formation and / or preventing bone loss and / or treating atherosclerosis. Unless otherwise specified, the following terms have the meanings defined below: As used herein, "limitation", and "treatment" are interchangeable terms such as "limit" and "treat" and, as used in the present, include preventive treatment (for example prophylactic) and palliative treatment or the act of providing preventive or palliative treatment. The terms include a delay in the development of symptoms of bone deficit and / or a reduction in the severity of these symptoms that will develop or be expected to develop. The terms also include improving the symptoms of existing bone or cartilage deficits, preventing additional symptoms, improving or preventing the underlying metabolic causes of said symptoms, preventing or reversing bone resorption and / or stimulating bone growth. By "bone deficit" is meant an imbalance in the ratio of bone formation to bone resorption, so that, if unchanged, the subject will exhibit less bone than desirable, or the subject's bones will be less intact than desired . Bone deficit can also result from fracture, surgical intervention or dental or periodontal disease. By "cartilage deficit" is meant damaged cartilage, less cartilage than desired or cartilage that is less intact than desired. The terms limitation and treatment and limiting and treating also include the reduction of existing blood cholesterol levels and the prevention of elevated blood cholesterol levels and the symptoms and conditions caused or related to blood cholesterol levels, as atherosclerosis and hyperlipidemia, or increased cardiac risk and the inhibition of atherosclerotic plaque calcification or the stabilization of atherosclerotic plaques. Representative uses of the compositions and methods of the present invention include: repair of bone defects and deficiencies, such as those that appear in closed, open and non-union fractures, prophylactic use in the reduction of closed and open fractures, stimulation of healing of bone in plastic surgery, stimulation of the incarnation of the bone in non-cemented prosthetic joints and dental implants, elevation of the maximum bone mass in perimenopausal women, treatment of growth deficiencies, treatment of diseases and periodontal defects and other dental repair procedures, increase of bone formation during distraction osteogenesis and the treatment of other skeletal disorders, such as osteoporosis related to age, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis or osteoporosis due to disuse and arthritis, or any state that benefits from stimulation of bone formation. The compositions and methods of the present invention may also be useful in the repair of congenital, trauma-induced or surgical resection of bone (for example by treatment of cancer) and in cosmetic surgery. In addition, the compositions and methods of the present invention can be used to treat cartilage defects or disorders, and are useful for healing wounds or repairing tissues. In addition, the compositions and methods of the present invention can be used to treat atherosclerosis. Bony or cartilage deficiency or defect and atherosclerosis can be treated in vertebrate subjects by administration of the compositions of the invention. The compositions of the invention can be administered systemically or locally. For systemic use, the compounds herein are formulated for parenteral (e.g., intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal or transdermal) or enteral (e.g., oral or rectal) delivery, according to conventional procedures. Intravenous administration may be by a series of injections or by continuous infusion over an extended period. Administration by injection, or other administration routes discretely spaced, may be performed at weekly intervals of from one to three times a day or more. Alternatively, the compositions described herein may be administered in a cyclic fashion (administration of the described compound, followed by non-administration, followed by administration of the compositions described, and so on). The treatment will continue until the desired result is achieved. A "subject" is an animal, including a human, that needs the compositions, methods and kits of the present invention. The term "subject" or "subjects" is intended to refer to both the male and female gender, unless a specific gender is indicated.

The term "postmenopausal women" is defined to include not only older women who have gone through menopause, but also women who have been hysterectomized, or who for some other reason have suppressed estrogen production, such as those who have experienced a long-term administration of corticosteroids, who suffer from Cushions syndrome or who have gonadal dysgenesis. "Co-administration" of a combination of a statin and a polyphosphonate means that these components can be administered together as a composition, or as part of the same unit dosage form. "Co-administration" also includes the administration of a statin and a polyphosphonate separately but as part of the same program or therapeutic treatment regimen. The components do not necessarily have to be administered essentially at the same time, although they can, if desired. Thus "co-administration" includes, for example, administering a statin and a polyphosphonate in dosages or separate dosage forms, but at the same time. "Co-administration" also includes administration separately at different times and in any order. For example, when appropriate, the patient may take one or more components of the treatment in the morning and one or more of the other components at night. When a polyphosphonate which inhibits bone resorption and a statin are coadministered as part of the same pharmaceutical composition or as separate pharmaceutical compositions, it is / are effective (ces) in the stimulation of bone formation and / or prevention of bone loss and / or to treat atherosclerosis. In producing these effects, the compositions and methods of the invention are suitable for treating a variety of conditions. These conditions include osteoporosis, including osteoporosis related to age and osteoporosis associated with postmenopausal hormonal status. Other conditions characterized by the need for bone growth include primary and secondary hyperparathyroidism, osteoporosis of disuse, osteoporosis related to diabetes and osteoporosis related to glucocorticoids. The results of the procedures for stimulating bone formation make the compositions and methods useful for bone repair and bone deficit states. Such states would include bone fracture, facial reconstruction surgery and segmental bone defects, periodontal disease, metastatic bone disease, osteolytic bone disease, and conditions in which connective tissue repair would be beneficial, such as in the healing or regeneration of cartilage defects or injuries. Said compositions and methods are also useful for treating atherosclerosis and hyperlipidemia and for preventing calcification of atherosclerotic plaques or stabilizing said plaques. "Polyphosphonate that inhibits bone resorption", as used herein, refers to a polyphosphonate such as the type described in United States Patent No. 3,683,080 or Formula I below. Preferred polyphosphonates are gemine diphosphonates (also referred to as bisphosphonates). The polyphosphonates can be administered in the form of an acid or of an alkali metal or soluble alkaline earth metal salt. The polyphosphonates of the present invention include those of chemical formula I: wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, CrC3o alkyl, substituted C -? - C30 alkyl, NH2 substituted with alkyl or C1-C10 dialkyl, C17 alkoxy C10, uncle substituted with alkyl C1-C10 or phenyl, phenyl substituted with C1-C10 alkyl, pyridyl, furanyl, pyrrolidinyl, imidazolinyl and benzyl. In the above chemical formula, the alkyl groups may be linear, branched or cyclic. The substituted C1-Q30 alkyl may include a wide range of substituents, non-limiting examples of which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, and NH2 substituted with alkyl or C1-C10 dialkyl, OH , SH and alkoxy C1-C-10. In the above chemical formula, A may include X and X may include A, so that the two remains can be part of the same cyclic structure.

The above chemical formula also is intended to include carbocyclic, aromatic and complex heteroatom structures for substituents A and / or X, non-limiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl and chlorophenylthio. Preferred structures are those in which A is selected from the group consisting of H, OH and halogen and X is selected from the group consisting of C -? - C3o alkyl, substituted C30 alkyl, halogen and uncle substituted with C1-C-alkyl 10 or phenyl. The most preferred structures are those in which A is selected from the group consisting of H, OH and Cl and X is selected from the group consisting of C 1 -C 3 alkyl, substituted CtC 30 alkyl, Cl and chlorophenylthio. It is most preferred when A is OH and X is a 3-aminopropyl residue, so that the resulting compound is a 4-amino-1-hydroxybutylidene-1,1-bisphosphonate, ie, alendronate. The pharmaceutically acceptable salts and derivatives of the polyphosphonates are also useful herein. Non-limiting examples of salts include those selected from the group consisting of those of alkali metals, alkaline earth metals, ammonium, and of mono-, di-, tri- or tetra- (substituted C 4 alkyl) ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts. Non-limiting examples of derivatives include those selected from the group consisting of esters, hydrates and amides.

The terms "polyphosphonate", "bisphosphonate" and "bisphosphonates", as used herein when referring to therapeutic agents of the present invention are intended to also include diphosphonates, bisphosphonic acids and diphosphonic acids, as well as salts and derivatives of these materials and are examples of polyphosphonates that inhibit bone resorption. The use of specific nomenclature in referring to the bisphosphonate or bisphosphonates is not intended to limit the scope of the present invention, unless otherwise indicated. Due to the mixed nomenclature currently in use by those skilled in the art, reference to a specific weight or percentage of a polyphosphonate compound in the present invention is on a weight basis of acidic active compound, unless indicated otherwise. mode. Non-limiting examples of polyphosphonates useful herein include the following: a) alendronic acid, 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid; b) alendronate (also known as alendronate sodium or monosodium trihydrate), monosodium trihydrate 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid; c) alendronic acid and alendronate, such as those described in U.S. Patent No. 4,922,007 to Kieczykowski et al., issued May 1, 1990, and U.S. Patent No. 5,019,651 to Kieczykowski, issued at May 28, 1991; d) cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), as described in U.S. Patent No. 4,970,335 to Isomura et al., issued November 13, 1990; e) 1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid) and the disodium salt (clodronate, Procter and Gamble), described in the Belgian patent 672,205 (1966) and J. Orq. Chem., 1967; 32: 4111; f) 1-hydroxy-3- (1-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid (EB-1053); g) 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid); h) 1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim (Bandronate), described in US Pat. 4,927,814, issued May 22, 1990; i) 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate); j) 3- (dimethylamino) -1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate); k) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate); I) [2- (2-pyridinyl) ethyl] in] -1, 1-bisphosphonic acid (pyridronate) as described in U.S. Patent No. 4,761,406; m) 1-hydroxy-2- (3-pyridinyl) -etlidene-1,1-bisphosphonic acid (risedronate); n) (4-chlorophenyl) thiomethane-1,1-disphosphonic acid (tiludronate) as described in U.S. Patent No. 4,876,248 to Breliere et al., October 24, 1989; and o) 1-hydroxy-2- (1 H-imidazol-1-yl) -ethylidene-1,1-bisphosphonic acid (zolendronate). Polyphosphonates selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, their pharmaceutically acceptable salts and mixtures thereof are preferred. The most preferred is alendronate, its pharmaceutically acceptable salts and mixtures thereof, with alendronate monosodium trihydrate being most preferred. The exact dose of polyphosphonate will vary with the dosage regimen, the oral potency of the particular polyphosphonate chosen, the age, corpulence, sex and condition of the mammal, the nature and severity of the disorder to be treated and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount can not be specified in advance and can be easily determined by the person in the care or the doctor. In general, an appropriate amount of polyphosphonate is chosen to obtain an effect of inhibiting bone resorption, ie, an amount of the polyphosphonate that inhibits bone resorption is administered. For humans, an effective oral dose of polyphosphonate typically ranges from about 1.5 to about 6000 g / kg of body weight and preferably from about 10 to about 2000 g / kg of body weight. • For oral compositions for humans comprising alendronate, one of its pharmaceutically acceptable salts or one of its pharmaceutically acceptable derivatives, a unit dose typically comprises from about 8.75 mg to about 140 mg of alendronate compound, taken in a base in weight of active alendronic acid. For a once-a-week dosing schedule, an oral unit dose comprises from about 17.5 mg to about 70 mg of alendronate compound, on a weight basis of active alendronic acid. Examples of weekly oral doses include a unit dose which is useful for the prevention of osteoporosis, comprising about 35 mg of alendronate compound and a unit dose which is useful for treating osteoporosis comprising about 70 mg of alendronate compound. For a dosing twice a week, an oral unit dose comprises from about 8.75 mg to about 35 mg of alendronate compound on a weight basis of active alendronic acid. Examples of twice-weekly oral doses include a unit dose which is useful for the prevention of osteoporosis, comprising approximately 17.5 mg of alendronate compound and a unit dose which is useful for treating osteoporosis comprising approximately 35 mg of alendronate compound. For a dosage every two weeks or twice a month, an oral unit dose comprises from about 35 mg to about 140 mg of alendronate compound on a weight basis of active alendronic acid. Examples of oral doses every two weeks or twice a month include a unit dose that is useful for the prevention of osteoporosis, comprising approximately 70 mg of alendronate compound and a unit dose which is useful for treating osteoporosis comprising approximately 140 mg of alendronate compound. In other embodiments, the methods and compositions of the present invention may also comprise a histamine H2 receptor blocker (ie, an antagonist) and / or a proton pump inhibitor. H2 receptor blockers of histamine and proton pump inhibitors are well-known therapeutic agents to increase gastric pH. See L. J. Híxson, et al., Current Trends in the Pharmacotherapy for Peptic Ulcer Disease, Arch. Intern. Med .. 1992, 152: 726-732. It has been found in the present invention that sequential oral administration of a H2 receptor blocker of histamine and / or a proton pump inhibitor, followed by a polyphosphonate can help minimize adverse gastrointestinal effects. In these embodiments, the H2 receptor blocker of the histamine and / or the proton pump inhibitor are administered from about 30 minutes to about 24 hours before administering the polyphosphonate. In the most preferred embodiments, the H2 receptor blocker of the histamine and / or the proton pump inhibitor are administered from about 30 minutes to about 12 hours before administering the polyphosphonate. The dose of the H2 receptor blocker of the histamine and / or the proton pump inhibitor will depend on the particular compound selected and factors associated with the mammal to be treated, i.e., size, state of health, etc. Non-limiting examples of H2 receptor blockers of histamine and / or proton pump inhibitors include those selected from the group consisting of cimetidine, famotldine, nizatidine, ranitidine, omeprazole and lansoprazole. The other active component of the combinations of this invention is a statin. The term "statin", when used in the description and appended claims, is synonymous with the terms "inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase" and "inhibitor of HMG-CoA reductase". These three terms are used interchangeably throughout the description and appended claims. As the synonym suggests, statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and as such are effective in reducing the level of cholesterol in blood plasma and in stimulating bone formation. Statins and pharmaceutically acceptable salts thereof are particularly useful in preventing bone loss and / or stimulating bone formation and in lowering low density lipoprotein (LDL-C) cholesterol levels in mammals and particularly in humans. Statins suitable for use herein include, but are not limited to, simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, and ZD-4522 and pharmaceutically acceptable salts thereof. The statins described herein are prepared by methods well known to those skilled in the art. Specifically, simvastatin can be prepared according to the procedure described in US 4,444,784. Pravastatin can be prepared according to the procedure described in US 4,346,227. Cerivastatin can be prepared according to the procedure described in US 5,502,199. Cerivastatin can alternatively be prepared according to the procedure described in European Patent Application No. EP617019. Mevastatin can be prepared according to the procedure described in US 3,983,140. Velostatin can be prepared according to the procedures described in US 4,448,784 and US 4,450,171. Fluvastatin can be prepared according to the procedure described in US 4,739,073. Compactin can be prepared according to the procedure described in US 4,804,770. Lovastatin can be prepared according to the procedure described in US 4,231,938. Dalvastatin can be prepared according to the procedure described in European Patent Application Publication Number EP738510. Fluvastatin can be prepared according to the procedure described in European Patent Application Publication Number EP363934. The dihydrocompactin can be prepared according to the procedure described in US 4,450,171. Atorvastatin can be prepared according to the procedures described in US 4,681,893 and US 5,273,995. The bervastatin, shown in formula II below, can be prepared according to the procedures described in U.S. Patent No. 5,082,859. The NK-104, shown in the following formula lll, can be prepared by the procedures described in U.S. Patent No. 5,102,888. ZD-4522, shown in formula IV below, can be prepared by the procedures described in U.S. Patent No. 5,260,440.

It will be recognized that some of the polyphosphonates that inhibit bone resorption and prior statins contain a carboxylic acid or free amine group as part of the chemical structure. In addition, certain polyphosphonates and statins within the scope of this invention contain lactone moieties, which exist in equilibrium with the free carboxylic acid form. These lactones can be maintained as carboxylates by preparing pharmaceutically acceptable salts of the lactone. Thus, this invention includes pharmaceutically acceptable salts of these carboxylic acid or amine groups. The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. "Pharmaceutically acceptable salts" further includes the mutual salts formed between statins and polyphosphonates. The term "pharmaceutically acceptable cationic salts" is intended to define, but is not limited to, salts such as alkali metal salts, (eg, sodium and potassium), alkaline earth metal salts (eg calcium and magnesium), aluminum salts , ammonium salts and salts with organic amines such as benzathine (N, N'-dibenzylethylenediamine), choline, diethanolamine, ethylendlamine, meglumine (N-methyglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2) -hydroxomethyl-1,3-propanedilol) and procaine. The term "pharmaceutically acceptable acid addition salts" is intended to define, but is not limited to, salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, methanesulfonate (mesylate), and toluenesulfonate (tosylate). The pharmaceutically acceptable cationic salts of the statins and polyphosphonates containing free carboxylic acids can be easily prepared by reacting the free acid form of the statin and / or polyphosphonate with an appropriate base, usually one equivalent, in a common solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by addition of a non-solvent medium. In many cases, the salts are preferably prepared by mixing a solution of the acid with a solution of a salt other than the cation (sodium or potassium ethylhexanoate, magnesium oleate), using a solvent (for example ethyl acetate) which precipitates the desired cationic salt, or it can be isolated otherwise by concentration and / or addition of a non-solvent. In this way, mutual salts of statins with polyphosphonates can also be prepared. The pharmaceutically acceptable acid addition salts of statins and polyphosphonates containing free amine groups can be easily prepared by reacting the free base form of the statin and / or polyphosphonate with the appropriate acid. When the salt is a monobasic acid (for example the hydrochloride, hydrobromide, para-toluenesulfonate, acetate), the hydrogenated form of a dibasic acid (for example the hydrogen sulfate, succinate) or the dihydrogenated form of a tribasic acid (for example the dihydrogen phosphate, citrate), at least one molar equivalent and usually a molar excess of the acid is used. However, when salts such as sulfate, hemisuccinate, hydrogen phosphate or phosphate are desired, the appropriate and exact chemical equivalents of the acid will generally be used. The free base and the acid are usually combined in a common solvent in which the desired salt precipitates, or may be otherwise isolated by concentration and / or addition of a non-solvent. In the same way, mutual salts of statins and polyphosphonates can be prepared in this way. For example, the mutual salt of atorvatatin and alendronic acid.

One of ordinary skill in the art will recognize that certain polyphosphonates that inhibit bone resorption and statins of this invention will contain one or more atoms that may be in a stereochemical configuration., tautomérica or particular geometric, giving rise to stereoisomers, tautomers and conformational isomers. All such isomers and mixtures thereof are included in this invention. The hydrates and solvates of the compounds of this invention are also included. The present invention also includes polyphosphonates that inhibit bone resorption and isotopically-labeled statins, which are structurally identical to those described above, except for the fact that one or more atoms are replaced by an atom having an atomic mass or different mass number. the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36CI respectively. The compounds of the present invention, derivatives thereof and pharmaceutically acceptable salts of said compounds and said aforementioned isotope-containing derivatives and / or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H and 14C have been incorporated, are useful in drug and / or substrate tissue distribution assays. The isotopes of tritiated, ie, 3H, and carbon 14, i.e., 14C, are particularly preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, ie, 2H, may provide certain therapeutic advantages caused by increased metabolic stability, for example, a longer half-life in vivo or the need for lower doses and, therefore, may be preferred in some circumstances. In general, the isotopically-labeled compounds of this invention and their prodrugs can be prepared by carrying out the known or referenced procedures and substituting a reagent without an isotopic label for an easily available isotope-labeled reagent. Those of ordinary skill in the art will readily recognize that physiologically active compounds having accessible hydroxyl groups are frequently administered in the form of pharmaceutically acceptable esters. The compounds of this invention can be effectively administered in the form of an ester, formed on the hydroxyl groups, as an expert in pharmaceutical chemistry would expect. It is possible, as has been known for a long time in pharmaceutical chemistry, to adjust the speed or duration of action of the compound by the appropriate choice of the ester groups. Certain ester groups are preferred as constituents of the compounds of this invention. Statins and / or compounds of formula I, II, III or IV can contain ester groups in various positions, as defined hereinbefore, these groups being represented by -COOR9, where R9 is C C alkyl? , CrC3-chloroalkyl, CrC3-fluoroalkyl, C5-C7-cycloalkyl, phenyl or phenyl mono- or di-substituted with C1-C4-alkyl, C1-C4-alkoxy, hydroxy, nitro, chloro, fluoro or trl (chloro or fluoro) methyl. As used herein, the term "effective amount" means an amount of compound of the compositions, kits and methods of the present invention that is capable of treating the symptoms of the described conditions. The specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the condition in which the patient is located and the severity of the pathological state to be treated. The dose of a compound of this invention to be administered to a subject is widely variable and is subject to the judgment of the attending physician. It will be noted that it may be necessary to adjust the dose of a compound when administered as a salt, like laureate, whose salt-forming moiety has an appreciable molecular weight. The following dosage amounts and other dosage amounts set forth elsewhere in this description and in the appended claims are for an average human subject weighing about 65 kg to about 70 kg. The skilled practitioner will be able to easily determine the dosage amount required for a subject whose weight is outside the range of 65 to 70 kg, based on the medical history of the subject and in the presence of diseases, eg diabetes, in the subject . The calculation of the dosage amount for other forms of the free base such as salts or hydrates is easily achieved by making a simple proportion relative to the molecular weights of the species involved. In general, according to this invention, representative statins are administered in the following daily dosage amounts: simvastatin, generally from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 40 mg; pravastatin, generally from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 40 mg; cerivastatin, generally from about 25 g to about 5 mg and preferably from about 1 mg to about 3.2 mg; fluvastatin, generally from about 2.5 mg to about 160 mg and preferably from about 20 mg to about 80 mg; lovastatin, generally from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 80 mg; and atorvastatin, usually around 2.5 mg to about 160 mg and preferably from about 10 mg to about 80 mg. In general, the pharmaceutical compositions will include a polyphosphonate which inhibits bone resorption as the first active ingredient and a statin as the second active ingredient, in combination with a pharmaceutically acceptable carrier such as saline, buffered saline, 5% dextrose in water, saline. buffered with borate containing trace elements or the like. The formulations may also include one or more excipients, preservatives, solubilizers, buffering agents, lubricants, fillers, stabilizers, etc. Formulation processes are well known in the art and are described, for example, in Reminton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th edition (1995). The pharmaceutical compositions for use in the present invention may be in the form of non-pyrogenic sterile liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art. Oral compositions may also include a histamine H2 receptor blocker and / or a proton pump inhibitor. Local administration can be by injection at the site of the lesion or defect, or by insertion or adherence of a solid carrier to the site, or by direct topical administration of a viscous liquid, or the like. For local administration, the delivery vehicle preferably provides a matrix for the growing bone or cartilage, and more preferably is a vehicle that can be absorbed by the subject without adverse effects. It is known that the active ingredient compounds are absorbed in the alimentary tract and thus their oral administration is preferred for reasons of convenience. However, the compounds can be administered equally efficiently percutaneously, locally at the site of injury or as suppositories for absorption in the rectum or vagina, if desired in a particular case. All common types of compositions can be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions. The compositions are formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit which may be a single tablet or capsule or a convenient volume of liquid. The capsules are prepared by mixing the compound or compounds with a suitable diluent and filling the capsules with the appropriate amount of the mixture. Typical diluents include inert powdered substances such as starch of many different types, cellulose powder, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. The tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrants as well as the compound or compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidone and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders. A lubricant may be necessary in a tablet formulation to prevent the tablet and punches from sticking to the die. The lubricant is chosen from sliding solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wetted to break the tablet and release the compound or compounds. They include starches, clays, celluloses, algines and gums, more particularly corn starch and potato starch, methyl cellulose, agar, betonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, pulp can be used. citric acid and carboxymethylcellulose, as well as sodium lauryl sulphate. The tablets are often coated with sugar as a flavoring and sealant, or with film-forming protective agents to modify the dissolution properties of the tablet. The compounds can also be formulated as chewable tablets using relatively large amounts of pleasant tasting substances such as mannitol in the formulation, as is now well established in the art. When it is desired to administer a compound in the form of a suppository, typical bases can be used. Cocoa butter is a traditional suppository base that can be modified by the addition of waxes to increase its melting point slightly. Water-miscible suppository bases comprising, in particular, polyethylene glycols of various molecular weights, are widely used. The effect of the compounds can be delayed or prolonged by an appropriate formulation. For example, a slow dissolving granule of the compound can be prepared and incorporated into a tablet or capsule. The technique can be improved by preparing granules of various dissolution rates and filling the capsules with a mixture of granules. The tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-acting by dissolving or suspending the compound or compounds in oily or emulsified vehicles that allow slow dispersion in the serum. The combinations of this invention can be administered in a controlled release formulation, such as a slow release formulation or rapid release formulation. Said controlled release formulations of the combination of this invention can be prepared using procedures well known to those skilled in the art. The administration procedure will be determined by the attending physician or other person skilled in the art after an assessment of the subject's condition and needs. The term "prodrug" means compounds that are transformed in vivo to provide a compound of the present invention. The transformation can occur by various mechanisms, such as by hydrolysis in blood. A good discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," vol. 14 of the A.C.S. Symposium Seríes, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term "prodrug" also includes mutual prodrugs in which one or more statins are combined with one or more polyphosphonates in a single molecule that can undergo transformation to provide statins and polyphosphonates of the present invention. For example, if a compound of the present invention contains a carboxylic acid functional group, a prodrug may comprise an ester formed by the replacement of the hydrogen atom of the acid group by a group such as alkyl (C-i-Ca), (C2-C2) alkanoyloxymethyl, 1- (alkanoyloxy) etyl of 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl of 5 to 10 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms , 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl of 3 to 9 carbon atoms, 1- ( N- (alkoxycarbonyl) amino) ethyl of 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C 1 -C 2) alkyl aminoalkyl ( C2-C3) (as -dlmetllaminoethyl), carbamoylalkyl (C? -C2), N, N-di (alkyl (Cr C2) carbamoyl-alkyl (C? -C2) and piperidino-, pyrrolidino- or morpholinoalkyl (C2-C3) Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C 1 -C 6) alkanoyloxymethyl, 1- (alkanoyloxy) C? -C6) ethyl, 1-methyl-1 - (C? -C6 alkanoyloxy) and lime, alkoxy (Ci-C 1 Jcarbonyloxymethyl, N-alkoxy (C 1 -C 6) carbonyllaminomethyl, succinoyl, alkanoyl (Ci-Cß), -aminoalkanoyl (C 1 -C 4), arylalkyl and -aminoacyl or -aminoacyl--aminoacyl, Each aminoacyl group is selected independently of the naturally occurring L-amino acids, P (O) (OH) 2, -P (O) (O-alkylC? -Ce) 2 or glycosyl (the radical resulting from the elimination of a hydroxyl group of the hemiacetal form of a carbohydrate). If a compound of the present invention comprises an amino functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group by a group such as Rx-carbonyl, RxO-carbonyl, NRxRx, -carbonyl, where Rx and Rx 'each independently C1-C10 alkyl, C3-C7 cycloalkyl, benzyl or Rx-carbonyl is a natural -aminoacyl natural or -aminoacyl-aminoacyl natural, -C (OH) C (0) OYx, (where YxH, alkyl C C6 or benzyl), -C-yOY ^ Y * 1, (Y x C C4 alkyl being and YX 1 being C? -C6 alkyl, carboxyalkyl (Ci-C?), Aminoalkyl (C? -C) or mono-N- or di-N, N-alkylaminoalkyl (C? -C6)), -C (YX2) YX3f where Y ^ H or methyl and YX3 are mono-N- or di-NN-alkylamino (Ci-Cß), morpholin, piperidin-1 -yl or pyrrolidin-1-yl. Advantageously, the present invention also provides kits for use by a consumer to stimulate bone formation and / or prevent bone loss and / or treat atherosclerosis. The kit comprises a) a pharmaceutical composition comprising a polyphosphonate that inhibits bone resorption and a pharmaceutically acceptable carrier, vehicle or diluent, b) a pharmaceutical composition comprising a statin and a pharmaceutically acceptable carrier, vehicle or diluent and, optionally, ) instructions describing a method of using the pharmaceutical compositions to stimulate bone formation and / or prevent bone loss and / or treat atherosclerosis. The polyphosphonate and the statin contained in the kit can optionally be combined in the same pharmaceutical composition. A "case", as used in the present application, includes a package for containing pharmaceutical compositions such as a divided bottle or a divided sheet package. The package can be in any conventional configuration or form such as those known in the art to be manufactured with a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic jar or jar, a bag that can be sealed repeatedly. (for example to store a "refill" of tablets to be placed in a different container), or a blister pack with individual doses to be withdrawn from the container according to a therapeutic program. The container used may depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to maintain a liquid suspension. It is feasible that more than one package can be used together in a single package to market a simple dosage form. For example, the tablets can be contained in a bottle that is in turn contained in a box. An example of such a case is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging dosage unit dosage forms (tablets, capsules and the like). The blister packs are generally formed by a sheet of relatively rigid material covered with a thin sheet of a plastic material, preferably transparent. During the packaging process, alveoli are formed in the thin sheet of plastic. The alveoli have the size and shape of the tablets or capsules to be packaged or can have the size and shape to accommodate multiple tablets and / or capsules to be packaged. Next, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed to the thin sheet of plastic on the face of the sheet opposite the direction in which the alveoli have been formed. As a result, the tablets or capsules are individually or collectively, as desired, hermetically sealed in the sockets between the thin sheet of plastic and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying a manual pressure on the cells, by means of which an opening is made in the sheet in the position where the socket is located. The tablet or capsule can then be extracted through said opening. It may be desirable to provide a written reminder, the written reminder being the type containing information and / or instructions for the physician, pharmacist or subject, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the administration regime in which the specified tablets or capsules should be ingested, or a card containing the same type of information. Another example of such a reminder is a calendar printed on the card, for example, as follows: "First week, Monday, Tuesday, and so on, Second week, Monday, Tuesday, and so on". Other reminder variations will be evident. A "daily dose" may be a single tablet or capsule or several tablets or capsules to take on a given day. In addition, a daily dose of one or several components of the kit may consist of a tablet or capsule, while a daily dose of another or other components of the kit may consist of several tablets or capsules. Another specific embodiment of the invention is a dispenser designed to dispense daily doses at each time in the order of its intended use. Preferably, the dispenser is provided with a reminder, to facilitate compliance with the dosage regimen. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a reminder is a battery-operated microprocessor memory coupled to a liquid crystal display, or an audible recall signal that, for example, displays the date on which the last dose was taken and / or remembers when it should Take the next dose. Based on reading the present disclosure and claims, certain modifications of the compositions and methods described herein will be apparent to one of ordinary skill in the art. The claims appended thereto are intended to cover these modifications. All references and patents cited herein are incorporated by reference.

EXAMPLES EXAMPLE 1 Effect of polyphosphonates that inhibit bone resorption and statins in the Ovariectomized Rat Model: a model of postmenopausal osteoporosis.

In women, estrogen deficiency during menopause results in increased bone turnover that leads to bone loss. Ovariectomy in rats produces estrogen deficiency and increased bone turnover leading to trabecular bone loss Similar to that seen in postmenopausal women (Kalu, DN, Bone and Mineral 1991, 15: 175, Frost, HM, Jee, WSS, Bone and Mineral 1992, 18: 227, Wronski, TJ, Yen, CF, Cells Materials 1991, (Suppl 1): 69). OVX rats are thus an appropriate model to evaluate compounds for the prevention and treatment of postmenopausal osteoporosis. The ability of polyphosphonates that inhibit bone resorption and statins, alone or in combination, to inhibit bone loss due to estrogen deficiency was evaluated in OVX rats, since ovariectomy causes significant bone loss in the lumbar vertebrae, proximal tibia and metaphysis Distal femoral (Ke, HZ, et al., Endocrin 1995, 136: 2435, Chen, HK, et al .. J. Bone Miner, Res. 1995. 10: 1256). Seventy-five day old female Sprague Dawley rats (weight range 225 to 275 g) are obtained from Charles River Laboratories (Portage, Mich.). They are housed in groups of 3 and have ad libitum access to food (calcium content of approximately 1%) and water. The temperature of the room is maintained at 22.2 V1, 7 C, with a minimum relative humidity of 40%. The lighting period in the room is 12 hours of light and 12 hours of darkness. One week after arrival, the rats undergo bilateral oophorectomy under anesthesia (44 mg / kg Ketamine ™ and 5 mg / kg Xylazine ™ (Butler, Indiapapolis, Ind.) Administered intramuscularly). The vehicle treatment or the test compositions are started on the day of surgery after recovery from anesthesia or 35 days after surgery. The rats are treated with vehicle containing a polyphosphonate that inhibits bone or statin resorption or a polyphosphonate that inhibits bone and statin resorption or only with vehicle. The oral dose is made by esophageal tube in 0.5 ml of 1% carboxymethylcellulose (CMC) with adjusted pH. Body weight is determined at the time of surgery and weekly during the study and the dose is adjusted for changes in body weight. Ovariectomized (OVX) rats treated with vehicle and non-ovariectomized (intact) rats are evaluated in parallel in each experimental group to serve as negative and positive controls. The rats are treated daily for 35 days (6 rats per treatment group) and sacrificed by decapitation on day 36. The time period of 35 days is sufficient to allow a maximum reduction in bone density, measured as described below. . At the time of sacrifice, the uteri are removed, they are dissected leaving them free of foreign tissue and the fluids are expelled before determining the wet weight in order to confirm the estrogen deficiency associated with complete ovariectomy. The uterine weight is usually reduced by 75% in response to ovariectomy. The uteri are then placed in 10% neutral buffered formalin for subsequent histological analysis. 10 mg / kg calcein is injected subcutaneously to all rats 12 and 2 days before autopsy as a fluorochrome bone marker to measure dynamic histomorphometric parameters. The effects of the polyphosphonate, the statin and the combination of polyphosphonate and statin are determined on the following final variables: (a) serum osteocalcin, a biochemical marker of bone turnover, (b) mineral density of the bone of the lumbar vertebrae and the distal femoral metaphysis; (c) bone histomorphometry of the fifth lumbar spine and the proximal tibial metaphysis. To measure the final variables, the concentration of serum osteocalcin is determined by radioimmunoassays known in the art and the bone mineral content (BMC) and bone mineral density (BMD) are measured by conventional procedures such as those described below. The first to sixth lumbar vertebrae of each rat are removed during autopsy. These ex vivo are explored using double beam x-ray absorptiometry. The scanned images are analyzed and the bone area, BMC and BMD of the lumbar vertebrae complete (WLV) and LV1 to LV6 are determined.

Using double-beam X-ray absorptiometry, the right femur of each ex vivo rat is scanned. The bone mineral density (BMD) of the distal femoral metaphysis (the second 0.5 cm from the distal end of the femur) and the proximal femur (the first 0.5 cm from the proximal end of the femur, which contains the head of the femur, the neck and the greater trochanter). In order to determine the effects of polyphosphonates and statins on the metaphysis of long bones, histomorphometric analyzes of the proximal tibias are carried out.

EXAMPLE 2 Reduction of cholesterol levels in New Zealand white rabbits fed 0.2% cholesterol.

White rabbits from New Zealand were fed (females, 3-4 months of age, weighing less than 3 kg), six in each group, with a 0.2% cholesterol control diet (100 g of rabbits' food daily) containing 0.2 g of cholesterol) or a 0.2% cholesterol diet and a pharmaceutical composition containing a polyphosphonate that inhibits bone resorption or a 0.2% cholesterol diet and a pharmaceutical composition containing a statin or a 0.2% cholesterol diet and a pharmaceutical composition containing a polyphosphonate that inhibits bone resorption and a statin at a dose equivalent to the doses of polyphosphonate and statin administered to groups receiving a diet containing only polyphosphonate and only statin After 56 days, blood is drawn from the rabbits and the cholesterol levels in plasma and / or serum are determined using the enzymatic method of Mao, et al., Clin. Chem. (1983) 29: 1890-1897. Having described the invention as above, the contents of the following are declared as property

Claims (21)

1. - A pharmaceutical composition comprising: (a) a polyphosphonate or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof; and (b) a statin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof.

2. A pharmaceutical composition according to claim 1, wherein said polyphosphonate is selected from the group consisting of alendronic acid, alendronate, cimadronate, clodronic acid, clodronate, 1-hydroxy-3- (1-pyrrolidinyl) - propylidene-1,1-bisphosphonic acid, etidronic acid, bandronate, neridronate, olpadronate, pamidronate, pyridronate, risedronate, tlludronate, zolendronate and their optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable non-toxic prodrugs thereof and combinations thereof.

3. A pharmaceutical composition according to claim 1, wherein said statin is selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK- 104, ZD-4522 and its optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable prodrugs thereof and combinations thereof.

4. - A pharmaceutical composition according to claim 1, wherein said polyphosphonate is alendronate or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof.

5. A pharmaceutical composition according to claim 1, wherein said statin is atorvastatin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof.

6. A pharmaceutical composition according to claim 1, wherein said polyphosphonate is alendronate sodium or one of its hydrates and said statin is the hemicálcic salt of atorvastatin or one of its hydrates.

7. A pharmaceutical composition according to claim 1, further comprising an H2 receptor antagonist of histamine or a proton pump inhibitor or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 8.- The use of a polyphosphonate or one of its optical or geometric isomers; or of a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof; and of a statin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof for the manufacture of a first and a second medication respectively to promote bone formation and / or prevent bone loss and / or treat atherosclerosis, in a subject, wherein the first medication and the second medication are administered separately. 9. The use as claimed in claim 8, wherein said polyphosphonate is selected from the group consisting of alendronic acid, alendronate, cimadronate, clodronic acid, clodronalo, 1-hydroxy-3- (1-pyrrolidinyl) - propylidene-1, 1-bisphosphonic acid, etidronic acid, ibandronate, neridronate, olpadronate, pamidronate, pyridronate, risedronate, tiludronate, zolendronate and their optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable prodrugs thereof and combinations thereof. 10. The use as claimed in claim 8, wherein said statin is selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin. , NK-104, ZD-4522 and its optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable prodrugs thereof and combinations thereof. 11. The use as claimed in claim 8, wherein said polyphosphonate is alendronate or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 12. The use as claimed in claim 8, wherein said statin is atorvastatin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 13. The use as claimed in claim 8, wherein said polyphosphonate is alendronate sodium or one of its hydrates and said statin is the hemicálcic salt of atorvastatin or one of its hydrates. 14. The use as claimed in claim 8, further comprising administering together an antagonist of the histamine H2 receptor or a proton pump inhibitor or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 15. A case for use by a consumer to promote bone formation and / or prevent bone loss and / or treat atherosclerosis, said case comprising: a) a polyphosphonate or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof; b) a statin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof; and optionally c) instructions describing a method for using the polyphosphonate and the statin to promote bone formation and / or prevent bone loss and / or treat atherosclerosis. 16. A kit according to claim 15, wherein said polyphosphonate is selected from the group consisting of alendronic acid, alendronate, cimadronate, clodronic acid, clodronate, 1-hydroxy-3- (1-pyrrolidinyl) -propylidene-1, 1-bisphosphonic acid, etidronic acid, ibandronate, neridronate, olpadronate, pamidronate, pyridronate, risedronate, tlludronate, zolendronate and their optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable prodrugs thereof and combinations thereof. 17. A kit according to claim 15, wherein said statin is selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatine, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104. , ZD-4522 and its optical or geometric isomers; and the salts, N-oxides, esters, quaternary ammonium salts and pharmaceutically acceptable prodrugs thereof and combinations thereof. 1

8. A kit according to claim 15, wherein said polyphosphonate is alendronate or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 1

9. A kit according to claim 15, wherein said statin is atorvastatin or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof. 20. A kit according to claim 15, wherein said polyphosphonate is alendronate sodium or one of its hydrates and said statin is the hemicálcic salt of atorvastatin or one of its hydrates. 21- A kit according to claim 15, further comprising an H2 receptor antagonist of histamine or a proton pump inhibitor or one of its optical or geometric isomers; or a salt, N-oxide, ester, quaternary ammonium salt or pharmaceutically acceptable prodrug thereof.