MXPA00012728A - Therapeutic combinations comprising a selective estrogen receptor modulator and parathyroid hormone - Google Patents

Abstract

This invention is directed to pharmaceutical combination compositions and methods comprising (-)-cis-6-phenyl-5-(4- (2-pyrrolidin-1-yl-ethoxy)- phenyl)-5,6,7,8- tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and parathyroid hormone or a biologically active fragment thereof, methods of using such compositions and kits containing such compositions. The compositions are useful for treating musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass and frailty.

Description

THERAPEUTIC COMBINATIONS THAT INCLUDE A SELECTIVE AND SELECTIVE ESTROGEN RECEIVER MODULATOR PARATHYROID HORMONE BACKGROUND OF THE INVENTION This invention relates to a pharmaceutical combination of a selective estrogen receptor modulator (SERM) and parathyroid hormone (PTH) or one of its biologically active fragments that stimulates bone formation, increases bone mass and enhances the restorative effects of bone of the PTH. The invention also relates to kits containing such combinations and to the use of such combinations to treat musculoskeletal fragility, including osteoporosis, osteoporotic fracture, reduced bone mass, frailty and similar conditions in mammals, including humans. In particular, this invention relates to a combination of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene -2-ol, or one of its pharmaceutically acceptable salts and parathyroid hormone, or one of its biologically active fragments, to kits containing said combination and to the use of said combination to treat musculoskeletal fragility, including osteoporosis, osteoporotic fracture, reduced bone mass , frailty and similar conditions in mammals, including humans.

Osteoporosis is a systemic skeletal disease, characterized by reduced bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures. In the United States, the disease affects more than 25 million people and causes more than 1.3 million fractures every year, including 500,000 spine fractures, 250,000 hip fractures and 240,000 wrist fractures each year. Hip fractures are the most serious, with 5-20% of patients dying within a one-year period and more than 50% of survivors being incapacitated. The elderly have a higher risk of osteoporosis and, therefore, it is expected that the problem will increase significantly with the aging of the population. The incidence of fractures worldwide is estimated to increase three times over the next 60 years and one study estimates that there will be 4.5 million hip fractures worldwide by the year 2050. Although both men and women are susceptible of musculoskeletal fragility, including osteoporosis, women have a higher risk of osteoporosis than men. Women experience a sudden acceleration of bone loss immediately after menopause. Other factors that increase bone loss that lead to osteoporosis include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.

Estrogens are the agents of choice in the prevention of osteoporosis or postmenopausal bone loss in women. In addition, Black et al., In EP 0605193A1, mention that estrogens, particularly when taken orally, lower plasma levels of LDL and increase those of high density lipoproteins (HDL), which are beneficial. However, long-term estrogen therapy has been linked to a number of disorders including an increased risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment or take medication only for a short period of time. Although it is believed that the risk of endometrial cancer is reduced by the concurrent use of progesterone, there is still the problem about the possible increased risk of breast cancer due to the use of estrogen. Recently suggested therapeutic regimens, which are intended to decrease the risk of cancer, such as the administration of combinations of progesterone and estrogen, cause the patient to suffer unacceptable bleeding. In addition, the combination of progesterone with estrogen seems to weaken the effects of lowering serum cholesterol of estrogen. The undesirable side effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable beneficial effect on serum LDL but do not cause undesirable side effects.

Recently, a number of selective estrogen receptor modulators have been proposed for the treatment of osteoporosis. It has been described (Osteoporosis Conference Scrip No. 1812/13 April 16/20, 1993, p.29) that raloxifene, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl ] benzo [b] -thiophene, emulates the favorable action of estrogen on bone and lipids but, unlike estrogen, has a minimal effect of uterine stimulation. [Black, L. J. et al., Raloxifene (LY139481 HCl) Prevents Bone Loss and Reduces Cholesterol Serum Without Causing Uterine Hypertrophy in Ovariectomized Rats, J. Clin Invest. 1994, 93: 63-69 and Delmas, P. D. et al., Effects of Raloxifene on Bone Mineral Density, Cholesterol Concentration Serum, and Uterine Endometrium in Postmenopausal Women, New England Journal of Medicine, 1997, 337: 1641-1647]. Agents such as droloxifene, U.S. Patent No. 5,254,595, prevent bone loss and therefore reduce the risk of fracture without the side effects of estrogens. However, estrogens and estrogen agonists can only be expected to reduce the risk of fracture by approximately 50%, with approximately 50% of osteoporotic women still at risk of osteoporotic fracture. U.S. Patent No. 5,552,412, commonly assigned, which is incorporated herein by reference, discloses SERM compounds of formula wherein the variables are defined as described therein. (-) - Cis-6-phenyl-5- (4- (2-pyrroidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol is a very potent SERM, orally Active, which prevents bone loss, lowers total serum cholesterol and has no uterine-stimulating effects such as estrogens in OVX rats. Tang et al., Restorinq and Maintaininq Bone in Osteogenic Female Rat Skeleton: I. Chanqes in Bone Mass and Structure, J. Bone Mineral Research 7 (9), p1093-1 104, 1992 describe data for the concept of loss, restoration and Maintenance (LRM), a practical approach to reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the demonstrated ability to maintain bone mass, maintain the new bone (phase +/-). The study in rats used PGE2 and risendronate, a bisphosphonate, to show that most of the new spongy and cortical bone induced by PEG2 could be maintained by administering risedronate for at least 60 days after discontinuing PGE2.

PTH is known to stimulate bone formation and restore bone mass in the skeleton of the osteoporotic rat. Spongy bone mass and connectivity also increased with a combined treatment of PTH and estradiol, when compared to PTH alone in ovariectomized rats (OVX). (Shen et al., Effects of Reciprocal Treatment with Estrogen and Estrogen plus Parathyroid Hormone on Bone Structure and Strength in Ovariectomized Rats, J. Clinical Investigation, 1995, 96: 2331-2338). Shen et al. it also describes data for the combination and / or sequential use of antiresorptive agents and anabolic agents for the treatment of osteoporosis.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a pharmaceutical composition comprising: a. a first compound, said first compound being (-) - cis-6-phenyI-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene- 2-ol or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being parathyroid hormone or one of its biologically active fragments. This invention further relates to a pharmaceutical composition as cited in the immediately preceding paragraph further comprising a pharmaceutical carrier or diluent.

This invention also relates to a pharmaceutical composition as described in any of the first two paragraphs of this disclosure, wherein said first compound is (-) - cis-6-phenyl-5- (4- ( 2-pyrrolidin-1-yl-ethoxy) -phenyl) -5, 6,7,8-tetrahydronaphthalen-2-ol and said second compound is parathyroid hormone 1-34. This invention also relates to a pharmaceutical composition as described in any of the first two paragraphs of this disclosure, wherein said first compound is (-) - cis-6-phenyl-5- (4- ( 2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is parathyroid hormone 1-38. This invention further relates to a method, called method A, for treating a mammal suffering from musculoskeletal fragility, which comprises administering to said mammal a pharmaceutical composition as cited in any of the first four paragraphs of this disclosure. A preferred method within method A, called method B, is when said mammal suffers from osteoporosis. Another preferred method within procedure A, called procedure C, is when the mammal suffers osteotomy, idiopathic bone loss of childhood or bone loss associated with periodontitis.

This invention also relates to a method, called method A1, for treating a mammal suffering from musculoskeletal fragility, which comprises administering said mammal. to. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being parathyroid hormone or one of its biologically active fragments. This invention relates in particular to a process of process A1, wherein the first compound and the second compound are administered substantially at the same time. This invention relates particularly to a process of process A1, hereinafter referred to as method D, wherein the second compound is administered for a period of from about after months to about after years. This invention relates more particularly to a method of process D, followed by administration of the first compound for a period of about three months to about three years, without the administration of the second compound for the period of about three months to about three years. This invention also relates more particularly to a method of process D, followed by the administration of the first compound for a period greater than about three years, without the administration of the second compound during the period greater than about three years. This invention also relates to a method, hereinafter referred to as method E, for treating a mammal suffering from musculoskeletal fragility, comprising administering to said mammal a therapeutically effective amount of a composition as cited in any of the first three paragraphs of this invention. description. A procedure within procedure E is one in which bone healing is enhanced after a facial reconstruction, a maxillary reconstruction or mandibular reconstruction, spinal synostosis is induced, the extension of the long bones is enhanced, the healing speed is enhanced of a bone graft or a fracture of a long bone or prosthetic incarnation is enhanced. In all the methods of this invention, it is preferred that the animal be a human being or a companion animal. The term "companion animal" refers to a domestic pet or other domesticated animal such as, but not limited to, cows, sheep, ferrets, pigs, horses, birds, fish, rabbits, goats, dogs, cats and similar animals. Especially preferred pets are dogs and cats. In all the methods of this invention, it is particularly preferred that the mammal be a human being.

This invention also relates to a kit comprising a treatment for a mammal suffering from musculoskeletal fragility, comprising: a. in a first unit dose form, a therapeutically effective amount of (-) - cis-6-phenyl-5- (4- (2-pyrroiidin-1-yl-ethoxy) -phenyl) - 5,6,7,8 -tetrahydronaphthalen-2-ol or a salt of its pharmaceutically acceptable salts and a pharmaceutically acceptable diluent carrier; b. in a second unit dose form, parathyroid hormone or one of its biologically active fragments and a pharmaceutically acceptable carrier or diluent; and c. a container. This invention particularly relates to a kit as described in the immediately preceding paragraph, wherein said first unit dose form comprises D-tatrato of (-) - cis-6-phenyl-5- (4- (2- pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthaIen-2-ol and said second unit dosage form comprises parathyroid hormone 1-34. This invention particularly relates to a kit as described in the immediately preceding paragraph, wherein said first unit dose form comprises (-) - cis-6-phenyl-5- (4- (2-D-tartrate -pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second unit dosage form comprises parathyroid hormone 1-38.

In all of the compositions, methods and kits of this invention, it is particularly preferred that the salt of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy-D-tartrate) is used. ) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol. The term "disorder with reduced bone mass" refers to a condition in which the level of bone mass is below the specific normal for that age, as defined in the World Health Organization regulations. of the Risk of Fracture and its Application for the Detection of Postmenopausal Osteoporosis (1994), Report of a Study Group of the World Health Organization, World Health Organization, Technical Series 843. " Idiopathic childhood and primary osteoporosis are also included. In the treatment of osteoporosis, it includes the prevention or attenuation of long-term complications such as curvature of the spine, weight loss, prosthetic surgery and prevention of malfunction of the prostate. In addition, it includes the increase in the rate of healing of bone fractures and the enhancement of the success rate in bone grafts. Periodontal disease and alveolar bone loss are also included. The term "disorder with reduced bone mass" also refers to a mammal known to have a significantly higher than average chance of developing diseases such as those described above, including osteoporosis (e.g., postmenopausal women). , men older than 60 years and people who are being treated with drugs known to cause osteoporosis as a side effect (such as glucocorticoids)). Those skilled in the art will recognize that the term "bone mass" actually refers to bone mass per unit surface, which is sometimes (although not entirely correct) called bone mineral density. The term "biologically active fragment", when used herein and in the appended claims, refers to a portion of the parent protein that has activity in the assay described below in example one. The term "musculoskeletal fragility" refers to a disorder in which a subject has reduced bone mass and / or reduced muscle mass, and includes diseases, disorders and conditions such as, but not limited to, disorders that involve reduced bone mass, osteoporosis, disorders that involve reduced muscle mass, osteotomy, idiopathic bone loss in childhood, bone loss associated with periodontitis, bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction and bone fracture. In addition, musculoskeletal fragility includes disorders such as those in the contact zones between newly implanted prostheses and bone, which require bone incarnation.

The terms "treat", "treatment" or "treatment" as used herein, include curative, preventive (eg, prophylactic) and palliative treatment. The positive or negative sign in parentheses used in the present nomenclature represents the direction in which the polarized light in the plane is rotated by the particular stereoisomer. The compositions of this invention may include hydrates of the compounds used therein. The pharmaceutical compositions and methods of this invention result in a faster and larger increase in bone mass than can be achieved with the same doses of (-) - cis-6-phenyl-5- (4- ( 2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol as described above, alone, or parathyroid hormone, or one of its biologically active fragments, as described before, alone. Thus, combinations of the compounds of this invention increase bone density and decrease fracture rates to a greater degree than would be achieved with the use of either agent alone. This invention makes an important contribution to the art by providing compositions and methods that increase and maintain bone mass, resulting in the prevention, delay and / or reversal of osteoporosis and related bone disorders. Other features and advantages will be apparent from the specification and the claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION The first compound of this invention is (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2- or one of its pharmaceutically acceptable salts, which has the structure of formula I. (-) - cis-6-phenyI-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5 > 6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts are prepared as described in commonly assigned U.S. patent 5,552,412, cited above. D - tartrate of (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - 5,6,7,8-tetrahydronaphthalen-2-ol is prepared as described in the immediately preceding paragraph or, alternatively, as described in the international patent application, publication number W O97 / 16434, which designates the United States and which is incorporated herein by reference.

The second compound of this invention is parathyroid hormone (Sigma Chemical Company, 3050 Spruce Street, St. Louis, Missouri, 63103, see catalog and references thereof) or one of its biologically active fragments such as those available from Sigma Chemical Company , 3050 Spruce Street, St. Louis, Missouri, 63103, see the catalog and references therein. A particularly preferred parathyroid hormone is parathyroid hormone 1-34, which can be obtained from Sigma Chemical Company, with the above address. Another particularly preferred parathyroid hormone is parathyroid hormone 1-38, which can be obtained from Sigma Chemical Company, with the above address. In addition, when the compounds and their pharmaceutically acceptable salts used in the compositions or methods of this invention form hydrates or solvates, they are also within the scope of the invention. The pharmaceutical conditions and methods of this invention are all adapted to therapeutic use as agents that activate bone turnover or that prevent bone resorption or increase bone formation in mammals, particularly in humans. Since these functions are closely related to the development of osteoporosis and bone-related disorders, these combinations, by virtue of their action on the bone, prevent, stop, delay or reverse osteoporosis.

The utility of the compositions and methods of the present invention as medical agents in the treatment of musculoskeletal fragility (e.g., disorders involving reduced bone mass or reduced muscle mass, including osteoporosis) in mammals (e.g., humans) is demonstrated by the activity of the compounds of this invention in conventional tests such as those described in U.S. Patent 5,552,412. Further evidence of the utility of the present combination is shown in example one, below. Such assays also provide a means by which the activities of the compounds of this invention, among themselves, and with the activities of other known compounds can be compared. The results of these comparisons are useful for determining, dosage levels in mammals, including humans, for the treatment of such diseases. The administration of the compounds of this invention can be carried out by any method that free a compound of the combination of this invention systemically and / or locally. These procedures include the oral, parenteral, introduodenal and the like. In general, the compounds of this invention are administered orally, although parenteral administration (eg, intravenous, intramuscular, transdermal, subcutaneous or intramedullary) can be used, for example, when oral administration is inappropriate for the particular object or when the patient is unable to ingest the drug. The two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition can be administered comprising a first compound as described above and a second compound as described above in a pharmaceutically acceptable carrier. In any case, the amount and pattern of administration of the administered compounds will, of course, depend on the subject being treated, the intensity of the condition, the manner of administration, and the opinion of the prescribing physician. Thus, due to the variability between patients, the doses indicated below are indicative and the doctor can increase or decrease the dose of the drug to achieve the activity (for example, increase in bone mass) that the doctor considers appropriate for each patient. Considering the desired degree of activity, the doctor should assess a number of factors such as the initial level of bone mass, age of the patient, presence of previously existing disease, as well as the presence of other diseases (for example, cardiovascular disease). For example, administration of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tet.ahidronaftalen-2 -ol can provide cardiovascular benefits, particularly for postmenopausal women. The following paragraphs provide preferred dosage ranges for the different components of this invention.

An effective dose for (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol varies in the range of 0.0001 to 100 mg / kg / day, preferably 0.001 to 10 mg / kg / day. An effective dose of parathyroid hormone varies in the range of 0.0001 to 10 mg / kg / day, preferably 0.001 to 1.0 mg / kg / day. When the D-tartrate salt or other pharmaceutically acceptable salt of any of the above compounds is used in this invention, the skilled person will be able to calculate the effective dosage amounts by calculating the molecular weight of the salt form and performing simple stoichiometric ratios. When a fragment of biologically active parathyroid hormone is used in this invention, the skilled person will be able to determine the effective dose amounts by comparing the activities of the parathyroid hormone and its biologically active fragments in the assay described in example one of the present. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds, or their pharmaceutically acceptable salts, of this invention, together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds and their pharmaceutically acceptable salts of this invention can be administered separately or together in any conventional oral, parenteral or transdermal dosage form. When administered separately, the administration of the other compound, or its pharmaceutically acceptable salt, of the invention follows.

For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used, together with various disintegrants such as starch and preferably potato starch or tapioca and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are frequently useful for preparing tablets. Solid compositions of a similar type are also employed as fillers in soft or hard filled gelatin capsules; including the preferred materials in this sense also lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds, or their pharmaceutically acceptable salts, of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For the purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, can be used. Such aqueous solutions can be suitably buffered if necessary and the liquid diluent first made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for the purposes of intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used can all be obtained easily by conventional techniques well known to those skilled in the art. For the purposes of transdermal administration, for example (topical), diluted sterile aqueous or partially aqueous solutions are prepared (usually in a concentration of about 0.1% to 5%), otherwise similar to the parenteral solutions above. The procedures for preparing the different pharmaceutical compositions with a certain amount of each of the active ingredients are known or will be apparent in light of this description for those skilled in the art. In Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th edition (1990) examples can be found. The pharmaceutical compositions according to the invention may contain 0.1% -95% of a combination of the compounds, or their pharmaceutically acceptable salts, of this invention, preferably 1% -70%. In any case, the composition or formulation to be administered will contain an amount of the compounds, or their pharmaceutically acceptable salts, of the invention in an amount effective to treat the disease / disorder of the subject being treated. Since the present invention relates to treatment with a combination of the two active ingredients that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 ol or one of its pharmaceutically acceptable salts and parathyroid hormone or one of its biologically active fragments. The kit includes a package for containing the separate compositions, such as a divided bottle or a package of a thin divided sheet, however, the separate compositions may also be contained in a single package Not divided. Typically, the kit includes instructions for administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when the prescribing physician wishes to increase or decrease the doses of the drugs. individual components of the combination. 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 preferably transparent plastic material. 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. 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 hermetically sealed in the alveoli 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 which an opening is made in the sheet in the position of the socket. The tablet or capsule can then be extracted through said opening. It would be desirable to provide a memory aid means in an inserted card, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the administration schedule in which the tablets should be ingested or specified capsules. Another example of such means of memory aid 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 variations of memory aids will be apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules that must be taken on a given day. In addition, a daily dose of SERM may be in a tablet or capsule, while a daily dose of parathyroid hormone or one of its biologically active fragments may consist of several tablets or capsules. The means of memory aid should reflect this. In another specific embodiment of the invention, a dispenser is provided to dispense the daily doses at each time in the order of their intended use. Preferably, the dispenser is provided with a means of memory aid, to facilitate compliance with the dosing schedule. An example of said memory aid means is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of said memory aid means is a battery-operated microprocessor memory coupled to a liquid crystal display or an audible recall signal which, for example, displays the date on which the last dose was taken and / or remember when the next dose should be taken.

EXAMPLE ONE Sham operated (n = 18) or ovariectomized (OVX) (n = 42) S-D female rats were operated at 6.5 months of age. Sixty days after surgery, nine sham-operated rats and seven OVX rats were sacrificed as pretreatment controls, while the rest of the OVX rats were treated with PTH (40 μg / kg / day by subcutaneous (sc) injection). a solution in bovine serum (BSA) at 0.1%), (-) - cis -d-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7, 8-tetrahydronaphthalen-2-ol (0.1 mg / kg / day by oral esophageal tube (so) in 5% ethanol / water) or with a combination of both (40 μg / kg / day by sc injection of PTH and 0.1 mg / kg / day per so of (-) - cis-6-phenyI-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2-ol for 60 days All rats received subcutaneous injections with 10 mg / kg calcein (Sigma Chemical Co. St. Louis, MO) on days 12 and 2 before autopsy, trabecular bone volume was determined in the proximal tibial metaphysis ( TBV,%), the percentage marking perimeter (L. Pm,%), the per cent osteoclast perimeter ( Oc. Pm,%), the number of osteoclasts per mm of bone surface (Oc. N) and the rate of bone formation / bone volume (BFR / BV,% / yr) by conventional static and dynamic histomorphometric techniques (Parfitt AM et al., Bone histomorphometry; Standardization of nomenclature, symbols, and units, J Bone Miner Res 2: 595-610, 1997). The initial maximum loading and stiffness of the distal femoral metaphyseal trabecular bone were determined by the notch test according to the known procedure. (Meng, X. W. et al., Temporary expression of the anabolic action of PTH cancellous bone of ovariectomized rats, J Bone Miner Res 1 1: 421-429, 1996).

Results of the study and discussion After 60 days, the OVX rats resulted in significant decreases in TBV (-61%), the initial peak load (-73%) and stiffness (-70%), and significant increases in L. Pm (+ 78%), Oc. P.m (+ 100%), Oc. N (+ 76%) and BFR / BV (+ 127%), when compared with the simulated operated controls. Treatment with PTH restored the TBV and the initial maximum load and rigidity to a level above the simulated controls, increasing bone formation and decreasing bone resorption. (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2-ol significantly decreased both the formation as bone resorption and increased non-significantly the TBV (+ 9%) and the initial maximum load (+ 82%) when compared with the OVX controls. The combined treatment of PTH and (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol increased significantly TBV (+ 24%) and maximum initial load (+ 86%) decreasing bone resorption more than bone formation, when compared to treatment with PTH alone. Both the TBV and the initial peak load increased significantly in the combined treatment group when compared to the sham operated controls. Total serum cholesterol decreased significantly in all rats treated with (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -pheni) -5,6,7, 8-tetrahydronaphthalen-2-ol, while no significant change was observed in the PTH group alone when compared to the OVX controls. These data show that the combined treatment of PTH with (-) - cs-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7, 8-tetrahydronaphthalen-2-ol restored both bone mass and bone strength in osteopenic OVX rats and added additional cancellous bone to the proximal tibia and distal femur of these rats. (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-oi potentiated the restorative effects of bone of PTH by a greater inhibition of bone resorption than of bone formation. These results clearly demonstrate synergistic effects of the combined treatment of anabolic agents such as PTH and (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5, 6,7,8-tetrahydronaphthalen-2-ol in the osteopenic skeleton of the animal model of postmenopausal bone loss. It will be understood that the invention is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit and scope of this new concept, as defined by the following claims.

Claims (25)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprising: a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or one of its pharmaceutically acceptable salts, and b. a second compound, said second compound being parathyroid hormone or one of its biologically active fragments.

2. The pharmaceutical composition according to claim 1, further comprising a pharmaceutical vehicle or diluent.

3. The pharmaceutical composition according to claim 1, wherein said first compound is D-tartrate of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is parathyroid hormone 1-34.

4. The pharmaceutical composition according to claim 1, wherein said first compound is (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl ) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound of parathyroid hormone 1 -38.

5.- The use of a. a first compound, said first compound being (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -pheni) -5,6,7,8-tetrahydronaphthalene- 2-ol or one of its pharmaceutically acceptable salts; and b. a second compound, said second compound being parathyroid hormone or one of its biologically active fragments for the manufacture of a first and second medication respectively to treat a mammal suffering from musculoskeletal fragility.

6. The use as claimed in claim 5, wherein the first medicament and the second medicament are administered substantially at the same time.

7. The use as claimed in claim 5, wherein the second drug is administered for a period of about three months to about three years.

8. Use as claimed in claim 7, followed by administration of the first drug for a period of from about three months to about three years without the administration of the second drug for the period from about three months to about three years .

9. The use as claimed in claim 7, followed by the administration of the first medication for a period greater than about three years without the administration of the second medication for a period greater than about three years.

10. The use as claimed in claim 5, wherein said mammal suffers from osteoporosis.

11. The use as claimed in claim 10, wherein said mammal is a human being.

12. - The use as claimed in claim 5, wherein said mammal suffers osteotomy, idiopathic bone loss of childhood or loss associated with periodontitis.

13. The use as claimed in claim 5, in which a bone fracture, bone healing after facial reconstruction, maxillary reconstruction or mandibular reconstruction is treated, spinal synostosis is induced or the extension of the bone is enhanced. the long bones, the speed of healing of a bone graft is enhanced or the prosthetic incarnation is enhanced.

14. The use as claimed in claim 13, wherein bone fracture is treated in a human being.

15.- A case that includes: a. in a first unit dose form, (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalene-2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; b. in a second unit dose form, parathyroid hormone or one of its biologically active fragments and a pharmaceutically acceptable carrier or diluent, and c. a container.

16. The kit according to claim 15, wherein said first unit dose form comprises (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-) D-tartrate. ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second unit dosage form comprises parathyroid hormone 1-34.

17. The kit according to claim 15, wherein said first unit dose form comprises (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) D-tartrate) phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second unit dosage form comprises parathyroid hormone 1-38.

18. The use of a pharmaceutical composition according to claim 1, for preparing a medicament for treating a mammal suffering from musculoskeletal fragility.

19. The use according to claim 18, wherein said first compound is D-tartrate of (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is parathyroid hormone 1-34.

20. The use according to claim 18, wherein said first compound is (-) - cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -tartrate. -5,6,7,8-tetrahydronaphthalen-2-ol and said second compound is parathyroid hormone 1-38.

21. The use according to claim 18, wherein said mammal suffers from osteoporosis.

22. The use according to claim 18, wherein said mammal suffers osteotomy, idiopathic bone loss of childhood or bone loss associated with periodontitis.

23. The use according to claim 18, wherein a bone fracture, bone healing after a facial reconstruction, a maxillary reconstruction or a mandibular reconstruction is treated, vertebral synostosis is induced or the extension of the long bones is enhanced. the healing speed of a bone graft is enhanced or the prosthetic incarnation is enhanced.

24. The use according to claim 23, wherein a bone fracture is treated in a human being.

25. The use according to claim 21, wherein osteoporosis is treated in a human being.