WO1996007417A1 - Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone - Google Patents
Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone Download PDFInfo
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- WO1996007417A1 WO1996007417A1 PCT/US1995/011335 US9511335W WO9607417A1 WO 1996007417 A1 WO1996007417 A1 WO 1996007417A1 US 9511335 W US9511335 W US 9511335W WO 9607417 A1 WO9607417 A1 WO 9607417A1
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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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
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- 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
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- 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
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- 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
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- 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 a bone active phosphonate 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 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 In the remodeling cycle, bone is resorbed at the site of an "activated" BMU by an osteoclast, forming a reso ⁇ tion cavity. This cavity is then filled with bone by osteoblasts.
- osteoporosis Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
- compositions and methods are described in the medical literature for the "treatment” of osteoporosis. Many of these compositions and methods attempt to either slow the loss of bone or to produce a net gain in bone mass. See, for example, R. C. Haynes, Jr. et al., "Agents affecting Calcification", The Pharmacological Basis of Therapeutics. 7th Edition (A. G. Oilman, L. S. Goodman et al., Editors, 1985); G. D. Whedon et al., "An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoy et al., Editors, 1985); and W. A.
- estrogen is also used as a means to prevent osteoporosis in postmenopausal women. This therapy typically involves daily administration of from about 0.625 milligrams to about 1.25 milligrams of conjugated estrogens, or equivalent amounts of other estrogen hormones. Estrogen may also be used to treat osteoporosis (i.e., actual building of bone in osteoporotics), although this has not been fully established.
- 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., "Reso ⁇ tion 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 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 a bone active phosphonate and parathyroid hormone compound to a human or other animal subject.
- a bone active phosphonate and parathyroid hormone compound to be used in these processes must, accordingly, be pharmaceutically-acceptable.
- 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.
- the methods of this invention comprise administration of one or more 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
- 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
- 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 thiol ester thereof derived from a carboxylic acid of an alkyl, heterocycle, aryl or heteroaryl group; thioether having an alkyl, heterocycle, aryl or heteroaryl group, thi
- Y is preferably a heterocycle (preferably 5 to 7 membered heterocycles having one or two nitrogen atoms); amino; and substituted amino.
- Particularly preferred Y moieties include pyridyl, amino, and amino substituted with one or two lower alkyl groups.
- Y is halogen (preferably fluoro); trifluoromethyl; ether having a lower alkyl group; unsubstituted amino, and the amide thereof derived from a carboxylic acid of a lower alkyl group, amino substituted with one lower alkyl group and the amide thereof derived from carboxylic acid of a lower alkyl group; amino substituted independently with two lower alkyl groups; or peptidyl having from one to about six amino acid moieties.
- (4) cycloalkyl having from 4 to 10 carbon atoms, preferably 5 or 6 carbon atoms
- heterocycle having 5 or 6 atoms in the ring; more preferably one or two nitrogen atoms in the ring, more preferably having one nitrogen atom in the ring.
- Particularly preferred heterocycles are unsubstituted or substituted piperidinyl, pyrrolidinyl, piperazinyl, and mo ⁇ holinyl.
- (a) m is an integer from 0 to 10, preferably from 0 to 5, more preferably 0 or 1, more preferably 0;
- R2 is hydrogen, lower alkyl or acyl derived from a carboxylic acid of a lower alkyl
- (a) m is an integer from 0 to 10, preferably from 0 to 5, more preferably 0 or 1, more preferably 0;
- m is an integer from 0 to 10, preferably from 0 to 5, more preferably 0 or 1, more preferably 0; and (b) Rl and Y are as described hereinbefore
- "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 -
- 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); Rl 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); R ⁇ 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
- esters include unsubstituted and substituted alkyl, aryl and phosphoryl esters.
- Nonlimiting examples of pharmaceutically-acceptable esters include, for example, isopropyl, tertiarybutyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, p- toluenesulfonylethyl, glycyl, sarcosyl, benzyl, phenyl, 1,2-hexanoylglyceryl, p- nitrophenyl, 2,2 dimethyl-l,3-dioxolene-4-methyl, isopentenyl, o- carbomethoxyphenyl, piraloyloxymethylsalicylyl, diethylamidophosphoryl, pivaloyloxymethyl, acyloxymethyl, propionyloxymethyl, isobutyryloxymethyl, dodecyl, oc
- Preferred bone-active phosphonates useful in the methods of this invention include: N-(2'-(3'-methyl)-pyridinyl)arninomethane phosphonomethylphosphinic acid; N-(2'-(5'-methyl)-pyridinyl)amino methane phosphonomethylphosphinic acid; N-(2'-(3 '-methyl)-piperidinylidene)aminomethane phosphonomethylphosphinic acid; N-(2'-(5'-methyl)-piperidinylidene)aminomethane phosphonomethylphos ⁇ phinic acid; 2-(2'-pyridinyl)ethane-l -phosphono- 1 -methylphosphinic acid; 2-(2'- piperidinyl)ethane- 1 -phosphono- 1 -methylphosphinic acid; 2-(p-aminophenyl)- 1 - hydroxy-ethane- 1
- bone-active phosphonates useful in the methods of this invention include: 1 -hydroxyethane- 1,1 -bisphosphonic acid; dichloromethane bisphosphonic acid; 3 -amino- 1 -hydroxypropane- 1,1 -bisphosphonic acid; 6-amino- 1 -hydroxyhexane- 1 , 1 -bisphosphonic acid; 4-amino- 1 -hydroxybutane- 1, 1- bisphosphonic acid; 2-(3-pyridyl)-l -hydroxyethane- 1,1 -bisphosphonic acid; 2-(N- imidazoyl)- 1 -hydroxyethane- 1, 1 -bisphosphonic acid; 3-(N-pentyl-N-methylamino)- 1 -hydroxypropane- 1, 1 -bisphosphonic acid; 3-(N-pyrollidino)-l-hydroxypropane- 1, 1 -bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S-(p- chloroph)-
- Parathyroid Hormone The methods of this invention also comprise administration of a parathyroid hormone.
- parathyroid hormone refers to the naturally occurring human parathyroid hormone, synthetic analogs thereof, parathyroid hormone and parathyroid hormone fragments manufactured by recombinant DNA technology, and parathyroid hormone fragments and parathyroid hormone fragment analogs.
- Parathyroid hormone useful in the methods of this invention includes, for example hPTH (1-38), hPTH (1-34), hPTH (1-37), hPTH (2-34), and hPTH (2-38).
- Patent 4,105,602 Colescott, et al., issued August 8, 1978; U.S. Patent 4,698,328, Neer, et al., issued October 6, 1987; U.S. Patent 4,833,125, Neer, et al., issued May 23, 1987; DE 32 43 358, Hesch, publication date May 24, 1984; and DE 39 35 738, Forssmann, et al., publication date May 8, 1991.
- This invention provides methods for treating a human or other animal subject having a bone metabolism disorder, comprising the steps of: (a) administering to said subject a safe and effective amount of a bone active phosphonate, during a period of greater than about 6 months; (b) administering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to about 12 months.
- step (a) said bone active phosphonate is administered for greater than about 8 months.
- step (b) said parathyroid hormone is administered for from about 4 months to about 8 months, more preferably for about 6 months.
- steps (a) and (b) are repeated from 1 to 5 times (i.e, so the entire method comprises performance of each step, in sequence, 2 to 6 times).
- the bone active phosphonate is administered during the treatment period of step (b); i.e., the phosphonate is administered concurrently with the parathyroid hormone.
- the bone active phosphonate 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 amount and dosage regimen of a particular bone active phosphonate administered during the methods of this invention is a function of the potency of the compound, as well as other factors.
- the phosphonate is administered in amounts and in regimens recognized in the art of useful for treating osteoporosis in accordance with sound medical practice.
- Potency of a bone active phosphonate can be expressed in terms of its "LED” or "least effective dose", which is the minimum dose of compound that is effective, by itself, to cause a significant inhibition of bone reso ⁇ tion.
- the antireso ⁇ tive compound is administered at a level of at least about 0.8 LED of the compound, more preferably from about .8 LED to about 5 LED, more preferably from about .8 to about 3 LED.
- the specific LEDs of a given bone active phosphonate 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 phosphonates 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 phosphonates 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 11, 1989; all of which are inco ⁇ orated by reference herein.
- Another model is the "Schenk Model", which measures the effects of bone- active phosphonates on bone growth in young rats. This model is described in Schenk et al., 11 Calcif Tissue Res. 196 (1973); Shinoda et al., 35 Calcif. Tissue Int. 87 (1983); U.S. Patent 4,761,406, Flora et al., issued August 2, 1988; and European Patent Publication 298,553, Ebetino, published January 11, 1989; all of which are inco ⁇ orated by reference herein.
- Another model is the "ovariectomized” or "OVX" rat model, which measures the ability of bone-active phosphonates to prevent loss of bone in female rates induced by ovariectomy. This model is described in Wronski et al., 125 Endocrinology 810 (1989), inco ⁇ orated by reference herein.
- the LEDs for bone active phosphonates are conveniently expressed in "mgP/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:
- mg/kg compound administered ⁇ ⁇ 1 TM ⁇ X ( ⁇ ecular wtitfrt of compo ndN
- 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 mg 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)-l- hydroxyethane- 1, 1 -bisphosphonic acid; 0.0001 mg P/kg, for N-cycloheptyl- aminomethanebisphosphonic acid
- 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 bone active phosphonate can be administered daily, or in a cyclical fashion.
- Such 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.
- 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. Of course, 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.
- Such optional agents include, for example, Vitamin D and calcium.
- administering refers to any method which, in sound medical practice, delivers the actives used in this invention to the subject to be treated in such a manner so as to be effective in the building of bone.
- the actives may be administered by any of a variety of known methods of administration, e.g., orally, dermatomucosally (for example, dermally, sublingually, intranasally, and rectally), parenterally (for example, by subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection), and by inhalation.
- specific modes of administration include, but are not limited to, for example, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal, subcutaneous administration, and topical application.
- 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.
- Suitable diagnostics for the detection of established osteoporosis are also well known in the art. Such methods include the measurement of the radiodensity of skeletal radiographs, quantitative computerized tomography, single energy photon abso ⁇ tiometry, dual-energy photon abso ⁇ tiometry, dual energy X-ray abso ⁇ tiometry, and quantitative digital radiography. Diagnostic techniques among those useful herein are described in W. A. Peck et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation (inco ⁇ orated by reference herein).
- the bone active phosphonate and parathyroid hormone may be administered in any of a variety of pharmaceutically-acceptable compositions.
- Such compositions may comprise an active and a pharmaceutically-acceptable carrier.
- Pharmaceutically-acceptable carriers include solid or liquid filler diluents or encapsulating substances, and mixtures thereof, that are suitable for administration to a human or lower animal.
- the term "compatible", as used herein, means that the components of the pharmaceutical composition are capable of being commingled with the actives, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations.
- Pharmaceutically- acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
- 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.
- 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.
- Preferred dose forms for parathyroid hormone include subcutaneous, nasal, trandsermal, rectal, sublingual, and oral.
- Preferred oral forms include, for example, liposomes, lipid emulsions, and proteinaceous cages.
- Kits This invention also provides kits for conveniently and effectively implementing the methods of this invention.
- kits comprise one or more unit doses of bone active phosphonate, one or more unit doses of parathyroid hormone, and a means for facilitating compliance with methods of this invention.
- kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner.
- the compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.
- Such compliance means includes instructions, packaging, and dispensing means, and combinations thereof Examples of packaging and dispensing means are well known in the art, including those described in U.S. Patents 4,761,406, Flora et al., issued August 2, 1988; and U.S. Patent 4,812,31 1, Uchtman, issued March 14, 1989 and U.S. 4,833,125, Neer et al., issued May 23, 1989, all inco ⁇ orated by reference herein.
- EXAMPLE 1 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 eight months, the patient is administered the bisphosphonate, 2-(3- pyridyl)- 1 -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).
- 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.
- 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%.
- EXAMPLE 2 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 the bisphosphonate 4-amino-l- hydroxy-butane- 1,1 -bisphosphonic acid for a period of one year. After the one year period, the bisphosphonate 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. 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
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95932426A EP0779812A4 (en) | 1994-09-09 | 1995-09-06 | Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone |
AU35475/95A AU686458B2 (en) | 1994-09-09 | 1995-09-06 | Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone |
KR1019970701532A KR970705400A (en) | 1994-09-09 | 1995-09-06 | METHODS FOR THE TREATMENT OF OSTEOPOROSIS USING BONE ACTIVE PHOSPHONATES AND PARATHYROID HORMONE USING BONE ACTIVE PHOSPONATE AND PARTHROPHONE HORMONE |
JP8509664A JPH10505090A (en) | 1994-09-09 | 1995-09-06 | Method for treating osteoporosis using bone-active phosphonate and parathyroid hormone |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US30392594A | 1994-09-09 | 1994-09-09 | |
US08/303,925 | 1994-09-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996007417A1 true WO1996007417A1 (en) | 1996-03-14 |
Family
ID=23174289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/011335 WO1996007417A1 (en) | 1994-09-09 | 1995-09-06 | Methods for the treatment of osteoporosis using bone active phosphonates and parathyroid hormone |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0779812A4 (en) |
JP (1) | JPH10505090A (en) |
KR (1) | KR970705400A (en) |
CN (1) | CN1157565A (en) |
AU (1) | AU686458B2 (en) |
CA (1) | CA2199252A1 (en) |
IL (1) | IL115224A0 (en) |
WO (1) | WO1996007417A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6284730B1 (en) * | 1997-06-19 | 2001-09-04 | Nps Allelix Corp. | Methods useful in the treatment of bone resorption diseases |
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 |
US8399023B2 (en) | 2009-07-31 | 2013-03-19 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US9340565B2 (en) | 2010-11-24 | 2016-05-17 | Thar Pharmaceuticals, Inc. | Crystalline forms |
US10093691B2 (en) | 2009-07-31 | 2018-10-09 | Grunenthal Gmbh | Crystallization method and bioavailability |
US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
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US4812304A (en) * | 1984-12-21 | 1989-03-14 | The Procter & Gamble Company | Treatment of osteoporosis |
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 (4)
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ATE66608T1 (en) * | 1984-04-30 | 1991-09-15 | Procter & Gamble | EQUIPMENT FOR THE TREATMENT OF OSTEOPOROSIS. |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US4868164A (en) * | 1986-12-19 | 1989-09-19 | Norwich Eaton Pharmaceuticals, Inc. | Octahydro-pyridine diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
US5403824A (en) * | 1993-03-19 | 1995-04-04 | The Procter & Gamble Company | Methods for the treatment of osteoporosis |
-
1995
- 1995-09-06 EP EP95932426A patent/EP0779812A4/en not_active Ceased
- 1995-09-06 AU AU35475/95A patent/AU686458B2/en not_active Ceased
- 1995-09-06 KR KR1019970701532A patent/KR970705400A/en active IP Right Grant
- 1995-09-06 CA CA002199252A patent/CA2199252A1/en not_active Abandoned
- 1995-09-06 CN CN95195007A patent/CN1157565A/en active Pending
- 1995-09-06 JP JP8509664A patent/JPH10505090A/en active Pending
- 1995-09-06 WO PCT/US1995/011335 patent/WO1996007417A1/en not_active Application Discontinuation
- 1995-09-08 IL IL11522495A patent/IL115224A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4812304A (en) * | 1984-12-21 | 1989-03-14 | The Procter & Gamble Company | Treatment of osteoporosis |
WO1993011786A1 (en) * | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
Non-Patent Citations (1)
Title |
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See also references of EP0779812A4 * |
Cited By (22)
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US8765674B2 (en) | 1997-06-19 | 2014-07-01 | Nps Pharmaceuticals, Inc. | Methods useful in the treatment of bone resorption diseases |
JP2002504140A (en) * | 1997-06-19 | 2002-02-05 | アレリックス バイオファーマシューティカルズ インク. | Combined pharmaceutical preparation containing parathyroid hormone and bone resorption inhibitor |
EP1001802B1 (en) * | 1997-06-19 | 2004-09-08 | NPS Allelix Corp. | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
EP1473040A1 (en) * | 1997-06-19 | 2004-11-03 | NPS Allelix Corp. | Use of human parathyroid hormone |
US7018982B2 (en) | 1997-06-19 | 2006-03-28 | Nps Allelix Corp. | Methods useful in the treatment of bone resorption diseases |
US7507715B2 (en) | 1997-06-19 | 2009-03-24 | Nps Allelix Corp. | Methods useful in the treatment of bone resorption diseases |
US7749543B2 (en) | 1997-06-19 | 2010-07-06 | Nps Pharmaceuticals, Inc. | Methods useful in the treatment of bone resorption diseases |
US8153588B2 (en) | 1997-06-19 | 2012-04-10 | Nps Pharmaceuticals, Inc. | Methods useful in the treatment of bone resorption diseases |
US6284730B1 (en) * | 1997-06-19 | 2001-09-04 | Nps Allelix Corp. | Methods useful in the treatment of bone resorption diseases |
JP2014015479A (en) * | 1997-06-19 | 2014-01-30 | Nps Pharmaceuticals Inc | Combined pharmaceutical preparation comprising parathyroid hormone and bone resorption inhibitor |
US8052987B2 (en) | 2000-06-20 | 2011-11-08 | Novartis Pharmaceuticals Corporation | Method of administering bisphosphonates |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
US8399023B2 (en) | 2009-07-31 | 2013-03-19 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US8933057B2 (en) | 2009-07-31 | 2015-01-13 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US9334296B2 (en) | 2009-07-31 | 2016-05-10 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US10093691B2 (en) | 2009-07-31 | 2018-10-09 | Grunenthal Gmbh | Crystallization method and bioavailability |
US10323052B2 (en) | 2009-07-31 | 2019-06-18 | Grunenthal Gmbh | Crystallization method and bioavailability |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
US9340565B2 (en) | 2010-11-24 | 2016-05-17 | Thar Pharmaceuticals, Inc. | Crystalline forms |
US10519176B2 (en) | 2010-11-24 | 2019-12-31 | Thar Pharma, Llc | Crystalline forms |
US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
Also Published As
Publication number | Publication date |
---|---|
CA2199252A1 (en) | 1996-03-14 |
AU686458B2 (en) | 1998-02-05 |
AU3547595A (en) | 1996-03-27 |
EP0779812A4 (en) | 1997-09-10 |
EP0779812A1 (en) | 1997-06-25 |
IL115224A0 (en) | 1995-12-31 |
CN1157565A (en) | 1997-08-20 |
KR970705400A (en) | 1997-10-09 |
JPH10505090A (en) | 1998-05-19 |
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