WO1996007418A1 - Phosphonates and parathyroid hormone for osteoporosis - Google Patents
Phosphonates and parathyroid hormone for osteoporosis Download PDFInfo
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- WO1996007418A1 WO1996007418A1 PCT/US1995/011336 US9511336W WO9607418A1 WO 1996007418 A1 WO1996007418 A1 WO 1996007418A1 US 9511336 W US9511336 W US 9511336W WO 9607418 A1 WO9607418 A1 WO 9607418A1
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- bisphosphonic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
Definitions
- This invention relates to methods of increasing bone mass in humans and other animals, i.e., for the treatment of osteoporosis and related bone metabolic disorders.
- this invention relates to such methods of treatment by the administration of an antireso ⁇ tive compound and parathyroid hormone.
- Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis” is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is "primary osteoporosis" Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
- Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
- Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone.
- This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called “basic multicellular units” or “BMUs".
- BMUs primarily consist of "osteoclasts", “osteoblasts”, and their cellular precursors.
- osteoclasts primarily consist of "osteoclasts", “osteoblasts”, and their cellular precursors.
- osteoclasts primarily consist of "osteoclasts”, "osteoblasts”, and their cellular precursors.
- This cavity is then filled with bone by osteoblasts.
- Parathyroid hormone has also been suggested as a therapy for osteoporosis. Treatments using parathyroid hormone are disclosed in the following references: Hefti, et al., "Increase of Whole-Body Calcium and Skeletal Mass in Normal and Osteoporotic Adult Rats Treated with Parathyroid Hormone", 62 Clin. Sci. 389-396 (1982); Hock, et al., "Resorption Is Not Essential for the Stimulation of Bone Growth by hPTH-(l-34) in Rats In Vivo", 4(3) Jnl. of Bone and Mineral Res. 449- 458 (1989); German Patent Publication DE 39 35 738, Forssman, published May 8, 1991; U.S.
- the methods of this invention provide effective methods of preventing and treating osteoporosis, with improved efficacy and reduced side effects compared to methods among those known in the art.
- the present invention provides methods of treating a human or other animal subject having a bone metabolism disorder, comprising the steps of:
- the methods of the present invention comprise the administration of an antireso ⁇ tive compound and parathyroid hormone compound to a human or other animal subject.
- Specific compounds and compositions to be used in these processes must, accordingly, be pharmaceutically-acceptable.
- a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
- Antireso ⁇ tive Compounds comprise administering one or more antireso ⁇ tive compounds.
- an "antireso ⁇ tive compound” is a compound that, when administered to a human or other animal subject, prevents bone loss by direct or indirect effect on the number of osteoclasts and/or their metabolism.
- Preferred antireso ⁇ tive compounds include those selected from the group consisting of bone-active phosphonates, estrogen compounds, antiestrogen compounds, calcitonin compounds, and mixtures thereof.
- Particularly preferred antireso ⁇ tive compounds include bisphosphonates, estrogen compounds, and antiestrogen compounds.
- Preferred antireso ⁇ tive compounds useful in the methods of this invention include bone-active phosphonates.
- a "bone-active phosphonate” includes one or more compounds of the general formula
- R is hydroxy (for bisphosphonates), or hydrogen or alkyl (for phosphonoalkylphosphinates).
- R is preferably unsubstituted alkyl, especially lower alkyl.
- preferred substituents include halogen, unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted amino, amino substituted with one or two lower alkyl groups, hydroxy, or carboxy. More preferred substituents are fluoro, phenyl, unsubstituted amino, and hydroxy; most preferred are fluoro (especially when present as trifluoromethyl) and phenyl.
- R moieties in the phosphonoalkylphosphinates are unsubstituted lower alkyl groups, especially unsubstituted, straight-chain, saturated lower alkyl groups.
- R moieties are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, and n-hexyl. More preferably, R is methyl, ethyl, n-propyl, or n-butyl. Most preferably, R is methyl.
- A is hydrogen; halogen; nitro; alkyl; heterocycle; aryl; heteroaryl; unsubstituted amino, or the amide thereof derived from a caboxylic acid of a substituent group; amino substituted with one substituent group, or the amide thereof derived from a carboxylic acid of a substituent group; amino substituted independently with one alkyl group and one substituent group; hydroxy, or the ester thereof derived from a carboxylic acid of a substituent group; ether having a substituent group; thiol, or the thiol ester thereof derived from a carboxylic acid of a substituent group; thioether having a substituent group, or the sulfoxide and sulfone derivative thereof; -SO3H, the pharmaceutically-acceptable salts thereof, the ester thereof derived from an alcohol of a substituent group, the unsubstituted amide thereof, or the amide thereof substituted with one or two alkyl
- halogen preferably fluoro or chloro, more preferably fluoro
- n is an integer from 1 to 10, preferably from 1 to 5, more preferably 1 or 2, more preferably 1 ;
- Y is halogen; nitro; cyano; heterocycle; aryl; heteroaryl; unsubstituted amino, and the amide thereof derived from a carboxylic acid of an alkyl, heterocycle, aryl or heteroaryl group; amino substituted with one alkyl, heterocycle, aryl or heteroaryl group and the amide thereof derived from a carboxylic acid of an alkyl group; amino substituted independently with one alkyl group and one alkyl, heterocycle, aryl or heteroaryl group; hydroxy, and the ester thereof derived from a carboxylic acid of an alkyl, heterocycle, aryl or heteroaryl group; ether having an alkyl, heterocycle, aryl or heteroaryl group; thiol, and the *hiol ester thereof derived from a carboxylic acid of an alkyl, heterocycle, a.
- (a) m is an integer from 0 to 10, preferably from 0 to 5, more preferably 0 or 1, more preferably 0;
- B is hydrogen; halogen; unsubstituted or substituted lower alkyl; unsubstituted or substituted cycloalkyl having from 3 to 7 atoms in the ring; unsubstituted or substituted heterocycle having from 3 to 7 atoms in the ring; unsubstituted or substituted phenyl; hydroxy, or the ester thereof derived from a carboxylic acid of a lower alkyl group; thiol; unsubstituted amino, or the amide thereof derived from a carboxylic acid of a lower alkyl group; amino substituted with one lower alkyl group, or the amide thereof derived from a carboxylic acid of a lower alkyl group; amino substituted independently with two lower alkyl groups; or - CO2H, the pharmaceutically-acceptable salts thereof, the ester thereof derived from an alcohol of a lower alkyl group, the unsubstituted amide thereof, or the amide thereof substituted
- the A and B moieties preferably do not both have heteroatoms (nitrogen, oxygen or sulfur), or a heteroatom and a halogen, bonded to the phosphonate moiety (i.e., the carbon atom geminally substituted with the phosphorous atoms).
- B is selected from hydrogen; unsubstituted or substituted lower alkyl, cycloalkyl, heterocycle (where a carbon atom of the heterocycle is bonded to the geminal carbon atoms), or phenyl, -COOH, the pharmaceutically- acceptable salts thereof, the ester thereof derived from an alcohol of a lower alkyl group, the unsubstituted amide thereof, and the amide thereof substituted with one or two lower alkyl groups.
- B is hydrogen, halogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, hydroxy or the ester thereof derived from a carboxylic acid of a lower alkyl group, thiol, unsubstituted amino or the amide thereof derived from a carboxylic acid of a lower alkyl group, amino substituted with one lower alkyl group or the amide thereof derived from a carboxylic acid of a lower alkyl group, amino substituted independently with two lower alkyl groups, or -COOH or the pharmaceutically- acceptable salts thereof and the ester thereof derived from an alcohol of a lower alkyl group and the unsubstituted amide thereof or the amide thereof substituted with one or two lower alkyl groups.
- B is hydrogen, chloro, methyl, ethyl, hydroxy, thiol, unsubstituted amino, (N-methyl)amino, (N,N-dimethyl)amino, -COOH or the pharmaceutically-acceptable salts thereof, -COOCH2, or -CONH2. More preferably. B is hydrogen, methyl, chloro, amino, or hydroxy; more preferably hydrogen, or hydroxy, or amino, or thiol; more preferably hydroxy.
- Particularly preferred bone- active phosphonates include those wherein A is a moiety of groups (3) or (8) above, and B is hydroxy.
- n is an integer from 0 to 7 (preferably from 0 to 3, more preferably 1); R' is hydrogen, chloro, amino, or hydroxy (preferably hydrogen or hydroxy); X is -NH-, quaternary amine, oxygen, sulfur, or a single bond (preferably -NH- or single bond); R2 and is a substituted or unsubstituted 5- to 7-membered carbocycle (preferably 6- to 7- membered, more preferably benzene or cycloheptyl), a substituted or unsubstituted 5- to 7-membered heterocycle having from 1 to 3 heteroatoms (preferably a 6-membered heterocycle having 1 or 2 nitrogen atoms, wherein a ring nitrogen may be quaternarized), -NH2, amino substituted with one alkyl or two alkyl (preferably C1-C5) groups to give a secondary or tertiary amine, respectively, quaternary amino, or hydrogen; wherein if R ⁇ is a substituted 5- to
- pharmaceutically-acceptable salts and esters means hydrolyzable esters and salts of the bone-active phosphonates which have the same general pharmacological properties as the acid form from which they are derived, and which are pharmaceutically acceptable.
- Pharmaceutically-acceptable salts include, for example, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium), non-toxic heavy metals (e.g., stannous and indium), and ammonium and low molecular weight substituted ammonium (e.g., mono-, di- and triethanolamine) salts.
- alkali metals e.g., sodium and potassium
- alkaline earth metals e.g., calcium and magnesium
- non-toxic heavy metals e.g., stannous and indium
- ammonium and low molecular weight substituted ammonium e.g., mono-, di- and triethanolamine
- Preferred bone-active phosphonates useful in the methods of this invention include N-(2 , -(3'-methyl)-pyridinyl)aminomethane phosphonomethylphosphinic acid; N-(2'-(5'-methyl)-pyridinyl)amino methane phosphonomethylphosphinic acid; N-(2'- (3'-methyl)-piperidinylidene)aminomethane phosphonomethylphosphinic acid, N-(2'- (5'-methyl)-piperidinyIidene)aminomethane phosphonomethylphosphinic acid, 2-(2'- pyridinyl)ethane- 1 -phosphono- 1 -methylphosphinic acid; 2-(2'-piperidinyl)ethane- 1 - phosphono- 1 -methylphosphinic acid; 2-(2'-piperidinyl)ethane- 1 - phosphono- 1
- bone-active phosphonates useful in the methods of this invention include 1 -hydroxyethane- 1 , 1 -bisphosphonic acid, dichloromethane bisphosphonic acid, 3-amino-l -hydroxypropane- 1,1 -bisphosphonic acid, 6-amino-l- hydroxyhexane- 1 , 1 -bisphosphonic acid, 4-amino- 1 -hydroxybutane- 1 , 1 -bisphosphonic acid, 2-(3-pyridyl)-l -hydroxyethane- 1, 1 -bisphosphonic acid, 2-(N-imidazoyl)-l- hydroxyethane- 1 , 1 -bisphosphonic acid, 3-(N-pentyl-N-methylamino)- 1 - hydroxypropane- 1 , 1 -bisphosphonic acid, 3 -(N-pyrollidino)- 1 -hydroxypropane- 1, 1- bisphosphonic acid, N-cycloheptylaminomethanebisphosphonic acid,
- an “estrogen compound” refers to naturally occurring hormones, synthetic steroidal compounds, and non-steroidal compounds, and conjugates, metabolites and derivatives thereof, which having estrogenic activity
- Naturally-occurring estrogen compounds are steroids v/hich contain a cyclopentanoperhydrophenathrene ring system
- Such naturally-occurring estrogen compounds are obtained from pregnant mares' urine or prepared synthetically, using methods well-known in the art. See: “Estrogens", Drug Information 1765 (1990); and Rudy, “Hormone Replacement Therapy - How to Select the Best Preparation and Regimen," 88 Postgraduate Medicine 157 (1990); and C. Christiansen et al., “Estrogens, Bone Loss and Prevention," 1 Osteoporosis Int. 7 (1990); all of which are inco ⁇ orated by reference herein.
- calcitonin compounds are calcium regulating hormones whose essential biological activity is to oppose the bone and renal effects of parathyroid hormone, i.e., to inhibit bone reso ⁇ tion and reduce urinary calcium excretion.
- Natural calcitonin is a 32 amino acid polypeptide hormone secreted form the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. The linear amino acid sequence varies between species as does the potency but when the various calcitonins are administered at similar International Unit equivalents, all such calcitonins will provide equivalent efficacy as an antireso ⁇ tive compound.
- the antireso ⁇ tive compound and parathyroid hormone are administered in a "safe and effective amount", which, as referred to herein, is the quantity of a material which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit risk ratio when used in the manner of this invention.
- a safe and effective amount is the quantity of a material which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit risk ratio when used in the manner of this invention.
- the specific "safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
- the specific LEDs of a given antireso ⁇ tive compound will vary depending upon its chemical composition, and method of administration (i.e., oral or parenteral). The lower the LED, the more potent the compound. Generally, it is desirable to administer higher potency antireso ⁇ tive compounds in lower doses and on a fewer number of days in the period of treatment. Likewise, the higher the LED, the less potent the compound. Accordingly, then, in general, it is desirable to administer a lower potency antireso ⁇ tive compound in higher doses and on a greater number of days in the period of treatment.
- the LEDs for the bone-active phosphonates may be determined using any of several art-recognized in vivo models.
- One such model is the thyroparathyroidectomized ("TPTX") rat model.
- TPTX thyroparathyroidectomized
- compounds are evaluated for in vivo bone reso ⁇ tion inhibition potency, by measuring their ability to inhibit the increase of serum calcium levels caused by administration of parathyroid hormone in rats whose parathyroid gland has been removed.
- TPTX thyroparathyroidectomized
- This model is described in Russell et al., 6 Calcified Tissue Research 183 (1970); Muhlbauer et al., 5 Mineral Electrolite Metabolism 296 (1981); U.S. Patent 4,761,406, Flora et al., issued August 2, 1988; and European Patent Publication 298,553, Ebetino, published January 1 1, 1989; all of which are inco ⁇ orated by reference herein.
- the LEDs for bone active phosphonates are conveniently expressed in " gP kg", which, as referred to herein, is the amount of compound, expressed as milligrams phosphorus in the compound, per kilogram weight of the subject to be treated. Because the bone active phosphonates vary in molecular weight, expressing the amount administered in mg P/kg normalizes the comparison between compounds of varying potencies. In order to determine the mg P kg administered to a patient according to the methods of this invention, the following conversion formula is used:
- mgkg compound administered ft P to k
- 2-(3-pyridinyl)-l -hydroxyethane- 1,1-bisphosphonate has a molecular weight of 350.
- Two phosphorus atoms have a molecular weight of 62.
- the LEDs for parenteral dosing of preferred bone-active phosphonates useful herein are: 1.0 g P/kg, for 1 -hydroxyethane- 1, 1 -bisphosphonic acid; 0.5 mg P/kg, for dichloromethane bisphosphonic acid; 0.03 mg P/kg, for 3-amino-l- hydroxypropane- 1, 1 -bisphosphonic acid; 0.001 mg P/kg, for 4-amino-l- hydroxybutane- 1,1 -bisphosphonic acid; 0.1 mg P/kg, for 6-amino-l-hydroxyhexane- 1, 1 -bisphosphonic acid; 0.01 mg P/kg, for N-(2-pyridyl) aminomethane-1, 1- bisphosphonic acid; 0.0003 mg P/kg, for 2-(3 -pyridyl)- 1 -hydroxyethane- 1, 1- bisphosphonic acid; 0.0001 mg P/kg, for N-cycloheptyl-aminomethanebisphosphonic acid;
- the LEDs for oral dosing would be higher, depending upon the systemic abso ⁇ tion of the phosphonate. Typically, abso ⁇ tion from oral administration is from about 1% to about 10%. Thus, oral LEDs are typically about ten- to one hundred-fold higher than the parenteral LEDs.
- the LED of the estrogen hormone is that level of the hormone which, by itself, is effective to prevent bone loss in subjects having osteoporosis. That level is generally recognized to be about 0.625 mg per day of conjugated estrogen or an equivalent dose of other estrogen hormones (for example, 25 mg per day of ethinyl estradiol; or 2 mg per day of 17-b-estradiol). Conjugated estrogen is preferably administered at a level of from about 0.3 mg to about 1.25 mg per day, preferably about 0.63 mg per day.
- Calcitonin compounds are preferably dosed at levels recognized in the art as suitable for the treatment of osteoporosis.
- Preferred dosages include 100 International Units (I. U.) per day for the subcutaneous and intermoscular injections and approximately twice that for nasal administration.
- Regimens of this invention also include reduced dosages, such as 25-50 LU, and injections given for 5 days out of every week, every other day, or in cycles.
- Parathyroid hormone is routinely dosed in International Units (IU).
- parathyroid hormone is preferably administered at levels of from about 100 to about 700 IU per day, more preferably from about 200 to about 600 IU per day, more preferably from about 400 to about 500 IU per day.
- the antireso ⁇ tive compound can be administered daily, or in a cyclical fashion.
- cyclical regimens are generally described in U.S. Patents 4,761,406, Flora et al., issued August 2, 1988; U.S. Patent 4,812,304, Anderson et al., issued March 14, 1989; U.S. Patent 4,822,609, Flora, issued April 18, 1989; World Patent Publication 93 1 1786, Geddes and Boyce, published June 29, 1993; and World Patent Publication 92 1 1474, McOsker, published September 3, 1992; all of which are inco ⁇ orated by reference herein.
- the bisphosphonate must be given at least one day of every thirty(30)-days of said treatment period.
- the bisphosphonate may be given every day, every second day, every third day, every fourth day, every fifth day, or every sixth day, of said treatment period.
- the parathyroid hormone must be given at least one day every seven days of every thirty(30)-days.
- the parathyroid hormone is administered at least about 50% of the days during the period of step (b).
- the methods of this invention comprise treatment of osteoporosis at all stages of the disorder. Since osteoporosis is an ongoing process of bone loss, rather than a disorder having a discrete beginning- or end-point, "treatment", as referred to herein, consists of any method which stops, slows, or reverses the process of bone loss which occurs in osteoporosis.
- Preferred methods of this invention comprise treatment of osteoporosis in subjects who have already lost skeletal mass (herein referred to as "established osteoporosis").
- Such methods of this invention for the treatment of established osteoporosis preferably comprise administering the actives for a period of time sufficient to achieve an increase in the net skeletal mass of said subject.
- the increase in mass may be in cortical bone, trabecular bone, or both.
- the net skeletal mass is increased by at least about 5% per year, preferably by at least about 10% per year.
- the specific period of time sufficient to achieve an increase in the net skeletal mass of the subject may depend on a variety of factors. Such factors include, for example, the specific actives employed, the amount of actives administered, the age and sex of the subject, the specific disorder to be treated, concomitant therapies employed (if any), the general physical health of the subject (including the presence of other disorders), the extent of bone loss in the individual, and the nutritional habits of the individual.
- the therapeutic regimen utilizing the methods of this invention are preferably continued for at least about twelve months.
- a therapeutic regimen may be continued indefinitely, according to sound medical practice.
- the subject is treated until a net skeletal mass is obtained commensurate with reduced fracture risk as assessed by the patient's physician.
- the subject is administered nutritional and other therapeutic agents to aid in the increase of bone mass.
- nutritional and other therapeutic agents include, for example, Vitamin D and calcium.
- a preferred method for the treatment of osteoporosis includes an initial diagnostic step, to determine the presence of the disorder.
- a preferred method of this invention comprises the steps of performing a diagnostic on a human subject for the detection of osteoporosis and, upon obtaining a positive result from said diagnostic, administering the actives according to the methods of this invention.
- said initial diagnostic step comprises performing a diagnostic for determining menopause.
- Such methods are well known in the art, and include, for example, determination of the bone mass and rate of bone remodeling. The rate of bone remodeling can be determined by measurement of biochemical markers. See, Hui, et al., "The Contribution of Bone Loss to Postmenopausal Osteoporosis," 1 Osteoporosis Int. 30 (1990), inco ⁇ orated by reference herein.
- substances which can serve as pharmaceutical carriers are: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions; wetting agents and lubricants such as sodium lauryl sulfate; coloring agents; flavoring agents; and preservatives.
- Other compatible pharmaceutical additives and actives may be included in the pharmaceutically-acceptable carrier for use in
- a pharmaceutically-acceptable carrier to be used in conjunction with the active is determined by the way the active is to be administered. If the active is to be injected, the preferred pharmaceutical carrier is sterile water, physiological saline, or mixtures thereof. The pH of such parenteral composition is preferably adjusted to about 7.4. Suitable pharmaceutically-acceptable carriers for topical application include those known in the art for use in creams, gels, tapes, patches, and similar topical delivery means.
- the pharmaceutically-acceptable carrier employed in conjunction with the actives is used at a concentration sufficient to provide a practical size to dosage relationship.
- the pharmaceutically-acceptable carriers in total, may comprise from about 0.1% to about 99.9% by weight of the pharmaceutical compositions of the present invention, preferably from about 5% to about 80%, and most preferably from about 10% to about 50%.
- a preferred method of administering bisphosphonates is orally, in a unit- dosage form (i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice).
- Preferred unit dosage forms for bisphosphonate include tablets, capsules, suspensions, and solutions, comprising a safe and effective amount of active.
- Pharmaceutically- acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, which are not critical for the pu ⁇ oses of the present invention, and can be made without difficulty by a person skilled in the art.
- oral unit dosage forms of the bone-active phosphonate comprise from about 0.0005 mgP/kg oral per day to about 1.0 mgP/kg oral per day of the phosphonate.
- a preferred method of administering calcitonin compounds and parathyroid hormone is via subcutaneous injection in a unit dosage form.
- Preferred unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereof. The pH of said solutions should be adjusted to about 7.4.
- unit dosage forms of parathyroid hormone comprise from about 4 IU to about 15 IU per kg per day.
- An Asian male human patient weighing approximately 65 kg and diagnosed with idiopathic osteoporosis is treated by a method of this invention. Specifically, for a period of four months, the patient is administered the bisphosphonate, 2-(3- pyridyl)-l -hydroxyethane- 1,1 -bisphosphonic acid. The patient is orally administered one tablet per day, with each tablet containing 0.002 mgP/kg per day of the bisphosphonate. The bisphosphonate treatment is discontinued. Then, for the next six months, the patient is administered parathyroid hormone (human synthetic fragment 1-34, or h PTH 1-34). The hormone is subcutaneously administered at a dose of 13 IU/kg via insulin syringe to the anterior thigh for five days out of every week during the six-month period.
- parathyroid hormone human synthetic fragment 1-34, or h PTH 1-34
- a biopsy of iliac crest bone is taken and reveals an increase in mean wall thickness of the remodeling units (BMU) compared to her baseline biopsy.
- BMU remodeling units
- the activation frequency and depth of reso ⁇ tion cavities on cancellous, cortical and endocortical surfaces are not significantly increased above the values observed at baseline. Bone mineral density is measured, indicating an increase of 1 1%.
- a human Caucasian female patient weighing approximately 60 kg and diagnosed with postmenopausal osteoporosis is treated by a method of this invention. Specifically, the patient is administered conjugated estrogen for a period of four months. The estrogen is administered via a transdermal patch, delivering estrogen at a level of 0.625 mg per day. After the four month period, the estrogen administration is continued. However, the patient is then also administered parathyroid hormone (human synthetic fragment 1-34, or h PTH 1-34) for six months, as a daily nasal spray delivering 5 IU/kg.
- parathyroid hormone human synthetic fragment 1-34, or h PTH 1-34
- a blood sample is then obtained and analyzed for the bone specific marker, osteocalcin, and bone-derived and total alkaline phosphatase. Osteocalcin values are increased by 57% and both bone and total alkaline phosphatase are slightly elevated compared to pretreatment values. Base mineral density is measured, indicating an increase of 10%.
Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP95933745A EP0779813A4 (en) | 1994-09-09 | 1995-09-06 | Phosphonates and parathyroid hormone for osteoporosis |
JP8509665A JPH10505091A (en) | 1994-09-09 | 1995-09-06 | Phosphonates and parathyroid hormone for osteoporosis |
KR1019970701531A KR970705399A (en) | 1994-09-09 | 1995-09-06 | PHOSPHONATES AND PARATHYROID HORMONE FOR OSTEOPOROSIS FOR OSTEOPEROSIS |
AU36277/95A AU686019B2 (en) | 1994-09-09 | 1995-09-06 | Phosphonates and parathyroid hormone for osteoporosis |
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US30398194A | 1994-09-09 | 1994-09-09 | |
US08/303,981 | 1994-09-09 |
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WO1996007418A1 true WO1996007418A1 (en) | 1996-03-14 |
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EP (1) | EP0779813A4 (en) |
JP (1) | JPH10505091A (en) |
KR (1) | KR970705399A (en) |
CN (1) | CN1157566A (en) |
AU (1) | AU686019B2 (en) |
CA (1) | CA2199251A1 (en) |
IL (1) | IL115223A0 (en) |
PE (1) | PE48597A1 (en) |
WO (1) | WO1996007418A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0831844A1 (en) * | 1995-06-06 | 1998-04-01 | Merck & Co., Inc. | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
WO2002034269A1 (en) * | 2000-10-27 | 2002-05-02 | Schering Oy | Method for the preparation of a pharmaceutical composition, and its use |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
US8052987B2 (en) | 2000-06-20 | 2011-11-08 | Novartis Pharmaceuticals Corporation | Method of administering bisphosphonates |
EP1932543A3 (en) * | 1996-02-28 | 2012-01-04 | Pfizer Inc. | Combination therapy for osteoporosis consisting of an estrogen agonist/antagonist and a growth hormone secretagogue |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993011786A1 (en) * | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5118667A (en) * | 1991-05-03 | 1992-06-02 | Celtrix Pharmaceuticals, Inc. | Bone growth factors and inhibitors of bone resorption for promoting bone formation |
-
1995
- 1995-09-06 EP EP95933745A patent/EP0779813A4/en not_active Withdrawn
- 1995-09-06 AU AU36277/95A patent/AU686019B2/en not_active Ceased
- 1995-09-06 WO PCT/US1995/011336 patent/WO1996007418A1/en not_active Application Discontinuation
- 1995-09-06 CN CN95195087A patent/CN1157566A/en active Pending
- 1995-09-06 KR KR1019970701531A patent/KR970705399A/en not_active Application Discontinuation
- 1995-09-06 JP JP8509665A patent/JPH10505091A/en active Pending
- 1995-09-06 CA CA002199251A patent/CA2199251A1/en not_active Abandoned
- 1995-09-08 IL IL11522395A patent/IL115223A0/en unknown
-
1996
- 1996-03-12 PE PE1996000165A patent/PE48597A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993011786A1 (en) * | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0831844A1 (en) * | 1995-06-06 | 1998-04-01 | Merck & Co., Inc. | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
EP0831844A4 (en) * | 1995-06-06 | 1998-12-30 | Merck & Co Inc | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
EP1932543A3 (en) * | 1996-02-28 | 2012-01-04 | Pfizer Inc. | Combination therapy for osteoporosis consisting of an estrogen agonist/antagonist and a growth hormone secretagogue |
US8052987B2 (en) | 2000-06-20 | 2011-11-08 | Novartis Pharmaceuticals Corporation | Method of administering bisphosphonates |
WO2002034269A1 (en) * | 2000-10-27 | 2002-05-02 | Schering Oy | Method for the preparation of a pharmaceutical composition, and its use |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
Also Published As
Publication number | Publication date |
---|---|
CN1157566A (en) | 1997-08-20 |
EP0779813A1 (en) | 1997-06-25 |
KR970705399A (en) | 1997-10-09 |
CA2199251A1 (en) | 1996-03-14 |
AU3627795A (en) | 1996-03-27 |
AU686019B2 (en) | 1998-01-29 |
EP0779813A4 (en) | 1998-05-06 |
JPH10505091A (en) | 1998-05-19 |
PE48597A1 (en) | 1997-12-11 |
IL115223A0 (en) | 1995-12-31 |
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