CN1158569A - Estrogens and prathyroid hormone for treating osteoporosis - Google Patents
Estrogens and prathyroid hormone for treating osteoporosis Download PDFInfo
- Publication number
- CN1158569A CN1158569A CN95195016A CN95195016A CN1158569A CN 1158569 A CN1158569 A CN 1158569A CN 95195016 A CN95195016 A CN 95195016A CN 95195016 A CN95195016 A CN 95195016A CN 1158569 A CN1158569 A CN 1158569A
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- Prior art keywords
- osteoporosis
- bone
- estrogen
- parathyroid hormone
- hormone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Physical Education & Sports Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention provides methods of treating a human or other animal subject having a bone metabolism disorder, consisting essentially of the steps of: (a) administering to said subject a safe and effective amount of an antiresorptive compound, 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.
Description
Background of invention
The present invention relates to increase the method for sclerotin in people and other animals, i.e. the treatment of osteoporosis and related bone metabolic disease.Particularly, the present invention relates to by using the method that bone active phosphonate and parathyroid hormone are treated.
The osteopathia of modal metabolic type is an osteoporosis.Osteoporosis can be defined as the minimizing of bone quantity usually, or the atrophy of osseous tissue.2 types osteoporosis is generally arranged: constitutional and Secondary cases." secondary osteoporosis " is by identifiable lysis or material and cause.Yet about 90% is " primary osteoporosis " in all osteoporosis.This primary osteoporosis comprises the osteoporosis after the amenorrhea, the osteoporosis (influence most of individualities that age surpass 70-80) relevant with the age and the essential osteoporosis that influences middle age and younger Men's and Women's.
For some osteoporosis individualities, the forfeiture of osseous tissue is enough serious, thereby causes the mechanicalness of bone structure to lose efficacy.For example in the women who suffers from post menopausal osteoporosis disease, buttocks and spinal column are fractured through being everlasting.Also can cause kyphosis (curvature anomalies of breast spinal column increases).
The mechanism that it is believed that bone forfeiture in osteoporosis relates to the unbalance of " bone remodeling " process.Bone remodeling is all taking place in life, thereby upgrades skeleton and keep bone strength.This reinventing relates to, and each site of bone surface is corroded and filled up by the one group of cell that is called " basic many cells unit " or " BMU ", and BMU mainly is made of " osteoclast ", " osteoblast " and precursor thereof.In remodeling process, bone is absorbed by osteoclast in " activated " BMU site, forms to absorb hole.This hole is filled up with sclerotin by osteoblast again then.
Generally, remodeling process can cause losing for a short time of bone in the adult and since the bone resorption hole fill up incomplete.Like this, even in the adult of health, the bone forfeiture relevant with the age takes place also.Yet, especially to suffer among the people of post menopausal osteoporosis disease many people, the number of the BMU that is activated can increase.Bone remodeling has been quickened in the activation of this increase, thereby causes unusual high bone forfeiture.
Although its cause of disease is not also understood fully, there are many risk factors to be considered to relevant with osteoporosis.These factors comprise that body weight is low, the calcium absorption is low, do not get enough athletic exercise and oestrogen deficiencies.
The compositions and the method for " treatment " osteoporosis of many being used for have been described in medical literature.Wherein many is the net increases of attempting slowing down bone forfeiture or generation sclerotin.Referring to for example R.C.Haynes, Jr. wait the people, " influence the material of calcification " (" Agents affecting Calcification "), the pharmacological basis (The Pharmacological Basis of Therapeutics) of treatment, 7 editions (A.G.Gilman, people such as L.S.Goodman chief editor, 1985); People such as G.D.Whedon, " analysis of present notion in osteoporosis and research interest " (＂ An Analysis of Current Concepts and Research Interest inOsteoporosis ＂), the present progress (Current Advances in Skeletogenesis) that skeleton forms people chief editors such as (, 1985) A.Ornoy; With people such as W.A.Peck, doctor's handbook of osteoporosis (Physician ' s Resource Manual on Osteoporosis) (1987) is published by state-run osteoporosis foundation (National Osteoporosis Foundation).
In the Therapeutic Method of the osteoporosis of Ti Chuing, the method for using diphosphate or other bone active phosphonates is arranged in the literature.Referring to people such as for example Storm, " intermittent, periodicity vitamin D
3Diphosphate treatment in suffering from post menopausal osteoporosis disease women to the influence of bone mineralising and fracture rates " (＂ Effect ofIntermittent Cyclical Etidronate Therapy on Bone Mineralization and Fracture Ratein Women with Post-Menopausal Osteoporosis ＂) 322 new BMJs (NewEngland Journal of Medicine) 1265 (1990); With people such as Watts, " intermittence of post menopausal osteoporosis disease, vitamin D periodically
3The diphosphate therapy " (＂ Intermittent Cyclical EtidronateTreatment of Post-Menopausal Osteoporosis ＂), 323 new BMJs (NewEngland Journal of Medicine) 73 (1990).This class uses the Therapeutic Method of various diphosphate to be described in United States Patent (USP) 4,761,406, people such as Flora, and on August 2nd, 1988 authorized; United States Patent (USP) 4,812,304, people such as Anderson, on March 14th, 1989 authorized; United States Patent (USP) 4,812,311, people such as Uchtman, on March 14th, 1989 authorized; With United States Patent (USP) 4,822,609, people such as Flora, on April 18th, 1989 authorized.This phosphonate is used for the treatment of osteoporosis and other relate to the purposes of abnormal calcium and the metabolic disease of phosphonate, also is disclosed in United States Patent (USP) 3,683,080, Francis, and on August 8th, 1972 authorized; United States Patent (USP) 4,330,537, Francis, on October 28th, 1980 authorized; United States Patent (USP) 4,267,108, people such as Blum, on May 12nd, 1981 authorized; European patent publication 298,553, Ebetino, on January 11st, 1989 published; With people's " chemistry of diphosphate, biochemistry and medical performance " (＂ Chemical such as Francis, Biochemical, and Medicinal Properties ofDiphosphonates ＂), the effect (The Role of Phosphonates in LivingSystem) of phosphonate in live body, the 4th chapter (1983).
Use estrogen and also be used as the means that prevent osteoporosis after the amenorrhea among the women.This Therapeutic Method is used other estrogen of about 0.625-1.25 milligram conjugated estrogen hormone or equivalent typically every day.Estrogen also is used to treat osteoporosis (being the actual formation of bone in the osteoporosis), although this is not confirmed as yet fully.Referring to for example Barzel, " estrogen in the prevention of post menopausal osteoporosis disease and treatment: look back " (＂ Estrogens in the Prevention and Treatment of Post-MenopausalOsteoporosis:a Review ＂), 85 JAMA (American Journal of Medicine) 847 (1988); Barzel, " estrin treatment of osteoporosis: effectively not? " (＂ Estrogen Therapyfor Osteoporosis:It is Effective? ＂), hospital puts into practice (Hospital Practice) 95 (1990); People such as Ettinger, " treatment with low dose estrogen and calcium has prevented the forfeiture of post menopausal osteoporosis disease bone " (＂ Post-Menopausal Bone Loss is Prevented by Treatment with Low-DosageEstrogen with Calcium ＂), 106 internal medicine annual reports (Annals in Internal Medicine) 40 (1987); People such as Lindsay, " be used to prevent the estrogen minimum effective dose of post menopausal osteoporosis disease bone forfeiture " (＂ The Minimum Effective Dose of Estrogen for Prevention of Post-MenopausalBone Loss ＂), 63 obstetrics and gynecology (Obstetrics and Gynecology) 759 (1984); " estrogen " (＂ Estrogen ＂), drug information (Drug Information) 1765 (1990); With world patent publication 92 14474, McOsker, JIUYUE was published on the 3rd in 1992.In addition, estrogenic use is relevant with some side effect, for example metrorrhagia.Referring to Rudy, " hormone replacement therapy-how to select optimal formulation and scheme " (＂ Hormone Replacement Therapy-How to Select the Best Preparation andRegimen ＂), 88 postgraduate's medical science (Postgraduate Medicine) 157 (1990).
Parathyroid hormone also is suggested a kind of therapy as osteoporosis.Use the Therapeutic Method of parathyroid hormone to be disclosed in following document: people such as Hefti, " increase of whole body calcium and bone mass in the adult rat of normal and osteoporosis when handling " (＂ Increase of Whole-BodyCalcium and Skeletal Mass in Normal and Osteoporotic Adult Rats Treated withParathyroid Hormone ＂) with parathyroid hormone, 62 Clinical Sciences (Clin.Sci.) 389-396 (1982); People such as Hock, " the stimulation in rats osteogenesis is also nonessential in vivo for hPTH-(1-34) in absorption " (＂ Resorption Is NotEssential for the Stimulation of Bone Growth by hPTH-(1-34) in Rats In Vivo ＂), 4 (3). bone and mineral research magazine (Jnl of Bone and Mineral.Res.) 449-458 (1989); German patent publication thing DE 39 35 738, Forssman, on May 8th, 1991 published; United States Patent (USP) 4,698,328, people such as Neer, on April 18th, 1987 authorized; United States Patent (USP) 4,833,125, people such as Neer, on May 23rd, 1989 authorized; United States Patent (USP) 5,118,667, people such as Adams, on June 2nd, 1992 authorized; World patent publication 9311786, Geddes and Boyce published on June 24th, 1993; United States Patent (USP) 4,822,609, Flora, on April 18th, 1989 authorized; United States Patent (USP) 4,812,304, people such as Anderson, on March 14th, 1989 authorized; German patent publication thing DE 32 43 358, Hesch, on May 24th, 1984 published; People such as Hesch " with (1-38hPTH and diphosphate EHDP carry out the result of stimulation therapy to the low bone metabolism of osteoporosis " (" Results of a StimulatingTherapy of Low Bone Metabolism in Osteoporosis with (1-38hPTH andDiphosphonate EHDP ＂) 66 (19) Klin Wschr.976-984 (in October, 1988); German patent publication thing 32 43 358, Hesch, on May 24th, 1984 published; People such as Delling, " morphological research of osteoporosis pelvis ridge spongiosa in carry out ADFR treatment with parathyroid hormone and diphosphate " (＂ Morphologic Study of Pelvic Crest Spongiosa in Patients with OsteoporosisDuring ADFR Therapy with Parathyroid Hormone and Diphosphonates ＂), 128 (1) Z.Orthop.1-5 (1990) (hereinafter referred to as people such as " " Delling); With people such as Delmas, " when bone resorption is blocked by diphosphate in the body of hPTH-(1-34) anabolism effect by bluntization ", (＂ The In VivoAnabolic Effect of hPTH-(1-34) is Blunted when Bone Resorption Is Blocked by ABiphosphonate ＂) 6 (1) bones and mineral research (J.Bone Mineral Res.) S136 (#214) (in August, 1991).
The applicant is surprisingly found out that, uses parathyroid hormone can provide this area unrecognized benefit after using estrogen compound.Therefore, the inventive method provides the method for effective prevention and treatment osteoporosis, compares it with those methods as known in the art and renders a service higher and side effect is littler.
Summary of the invention
The invention provides the method that the human body of suffering from the bone disease of metabolism or other animal target are treated, consist essentially of the following step:
(a) about more than 6 months during in give the estrogens compounds of described object effective dose safe in utilization;
(b) give the parathyroid hormone of described object effective dose safe in utilization in during about 3-12 month.
Detailed Description Of The Invention
The inventive method comprises to human body or other animal target uses estrogen compound and parathyroid hormone chemical compound.Therefore, specific chemical compound that uses in these methods and compositions must be pharmaceutically acceptable.Here used " pharmaceutically acceptable " component is to be suitable for human body and/or animal body and not have bad side effect (as toxicity, zest and anaphylaxis), has simultaneously reasonably and is benefited/dangerous ratio.
Estrogen compound
The inventive method comprises the use estrogen compound, and " estrogen compound " here refers to the hormone of natural generation, synthetic steroid and non-steroids, their conjugate, and metabolism thing and its derivant, they all have estrogen activity.The estrogen compound of natural generation is the steroid that contains ring valeryl perhydrophenanthrene loop systems.The estrogen of the natural generation of this class is from the urine of conceived mare or with the synthetic preparation of this technical field known method, referring to " estrogen " (＂ Estrogen ＂), drug information (Drug Information) 1765 (1990); And Rudy, " hormone replacement therapy-how to select optimal formulation and scheme " (＂ HormoneReplacement Therapy-How to Select the Best Preparation and Regimen ＂), 88 postgraduate's medical science (Postgraduate Medicine) 157 (1990); With C.Christiansen etc., " estrogen, bone-loss and prevent " (" Estrogens, Bone Loss and Prevention ") osteoporosis research (Osteoporosis Int.) 7 (1990); Here list and be made for reference.
The estrogen compound that is applicable to the inventive method comprises: estradiol for example, estrone, estriol, 1,3,5,7-estratetraen-3-ol-17-one, equilenin, cypionate estradiol ester, estradiol valerate, ethinyl estradiol, the polyphosphonic acid estradiol ester, estropipate, diethylstilbestrol, dienestrol, chlorine trianisene and composition thereof.Be applicable to that estrogen preferably of the present invention is " conjugated estrogen hormone ", it is the mixture of the sodium salt of water solublity OES and 1,3,5,7-estratetraen-3-ol-17-one ester.This conjugated estrogen hormone also can contain other estrogen substance of finding in pregnant horse urine, as the 17-a-dihydroequilin, and 17-a-estradione, equilenin and 17-a-dihydro equilenin.
Useful in the present invention also have an estrogen antagonist chemical compound.In this article, " estrogen antagonist chemical compound " is a kind ofly to have the estrogen agonist activity that suppresses bone resorption but the chemical compound that other tissue (particularly breast and uterus) is had the estrogen antagonistic activity.Estrogen antagonist can be steroid or non-steroids.The antiestrogenic example of steroid has zitazonium and related compound.Have found that many other chemical compounds because the cause of other activity (as progesterone antagonist or antiandrogen) also is suitable for as the estrogen antagonist in the inventive method.The on-steroidal estrogen antagonist also comprises, for example raloxifene and the related compound thereof that discloses in the United States Patent (USP) of announcing November 29 nineteen eighty-three 4,418,068 (list in this draw be with reference to).
Parathyroid hormone
The inventive method also comprises the use parathyroid hormone.In this article, " parathyroid hormone " refers to natural human body parathyroid hormone, and synthetic analog is by parathyroid hormone and parathyroid hormone segment and the parathyroid hormone and the pulsating analog of parathyroid hormone of DNA recombinant technique manufacturing.The parathyroid hormone that is applicable to the inventive method comprises, for example hPTH (1-38), hPTH (1-34), hPTH (1-37), hPTH (2-34) and hPTH (2-38).The type of obtainable parathyroid hormone and the manufacture method of parathyroid hormone are described in detail in the following list of references, and all these documents are all listed in this and drawn and be reference: the United States Patent (USP) 4,105,602 of the Colescott that on August 8th, 1978 announced etc.; The United States Patent (USP) 4,698,328 of the Neer that on October 6th, 1987 announced etc.; The United States Patent (USP) 4,833,125 of the Neer that on May 23rd, 1987 announced etc.; The Deutsche Bundespatent 3935738 of the Forssmann that the Deutsche Bundespatent 3243358 that on May 24th, 1984 announced and on May 8th, 1991 announce etc.
Therapeutic Method
The invention provides the method that the human body of suffering from the bone disease of metabolism or other animal target are treated, consist essentially of the following step:
(a) give the anti-absorption compound of described object effective dose safe in utilization in during about 2 weeks were by about 6 months;
(b) give the parathyroid hormone of described object effective dose safe in utilization in during about 3-12 month.
Be preferably in step (a), the administration time of described anti-absorption compound was greater than about 8 months.Be preferably equally in step (b), the administration time of described parathyroid hormone better was about 6 months for about 4-8 month.Be preferably step (a) and (b) repetition 1 to 5 time (that is, entire method comprises in order to each step execution 2 to 6 times).
The dosage of estrogen compound and parathyroid hormone is " a safe and effective amount ", this is meant when using method of the present invention, the use amount of material is enough to obtain required therapeutic response and be free from side effects (as toxicity, zest or anaphylaxis), has reasonably to be benefited/risk-benefit risks.Specific " safe and effective amount " is obviously along with the factor such as the character of the concrete state of an illness of being treated, patient's body constitution, the persistent period of treatment, common therapy (if existence) and used particular formulations changes and changes.
In the methods of the invention, the consumption of concrete estrogen compound and dosage form are that chemical compound is renderd a service and function of other factors.Be preferably, give anti-absorption compound with consumption and the dosage form that is used for treating the osteoporosis approval according to good medical practice in the prior art.
The effectiveness of estrogen compound can be expressed as " LED " or " minimum effective dose ", and this is that chemical compound itself produces the minimum dose that obviously suppresses bone resorption.Be preferably, in the methods of the invention, the dosage of anti-absorption compound is at least about 0.8LED, is more preferably about 0.8 to 5LED, is preferably about 0.8-3LED.
Unique LED of given estrogen compound is according to its chemical composition and different change of medication (being oral or parenteral administration).LED is low more, and the effectiveness of chemical compound is big more.In general, need be with than low dosage and the short estrogen compound that uses higher effectiveness the course of treatment.Equally, LED is high more, and the effectiveness of chemical compound is poor more.Therefore, need be to use the higher dosage and the long course of treatment the low estrogen compound of rendeing a service.
Estrogenic LED is the hormonal readiness that hormone itself effectively prevents to suffer from osteoporosis object bone-loss.It is generally acknowledged that this level is about 0.625mg/ days bonded estrogen or other estrogenic equivalent dosage (as 25mg/ days ethinyl estradiols; Or 2mg/ days 17-b-estradiol).Bonded estrogen dosage preferably is about 0.3-1.25mg/ days, is about 0.63mg/ days preferably.Referring to Barzel, " preventing and treat estrogen in the postmenopausal osteoporosis: look back " (" Estrogens in the Prevention and Treatmentof Post-Menopausal Osteoporosis:a Review ") 85 JAMA (AmericanJournal ofmedicine) 847 (1988); Lindsay etc., " being used to prevent that the minimum effectively agent of estrogen of bone-loss is heavy after the menopause " (" The Minimum Effective Dose of Estrogen for Prevention ofPost-Menopausal Bone Loss ") 63 obstetrics and gynecology (Obstertrics and Gynecology) 759 (1984); Genant etc., " OES to menopause after the influence of bone-loss " 76 obstetrics and gynecology (Obstertrics and Gynecology) 529 (1990); Here list and be made for reference.
The unit of parathyroid hormone routine is iu (IU).In the methods of the invention, the about 100-700IU/ of the dosage of parathyroid hormone days, be preferably 200-600IU/ days, be more preferably about 400-500IU/ days.
During step (a) treatment, but estrogen compound administration every day or cycle administration.During step (b) treatment, gave 1 day at least in per 7 days that parathyroid hormone must be per 30 days.Be preferably, during step (b), parathyroid hormone uses about 50% natural law at least.
Method of the present invention comprises all stages for the treatment of disease.Because osteoporosis is the loss of carrying out property of sclerotin, rather than have each other begin or the disease of terminal point, so here " treatment " of indication by stop, slowing down or the osteoporosis of overturning in any method of process of the bone-loss that takes place constitute.
Better method of the present invention comprises to the object treatment osteoporosis that bone-loss (being called " osteoporosis of being made a definite diagnosis " here) is arranged.The method of the osteoporosis that the present invention treatment is made a definite diagnosis comprises uses active matter to be enough to make described object os purum matter to increase reaching certain hour.The sclerotin that increases can be at cortical bone, trabecular bone or two places.Be preferably, os purum matter is annual to be increased at least about 5%, and being more preferably increases about 10% every year at least.
The time that is enough to described object os purum matter is increased decides according to various factors.This class factor comprises, for example, used specific active matter, the use amount of active matter, the age of object and sex, the concrete disease of being treated, used common therapy (if existence), the health condition (comprising the existence of other disease) that object is total, the degree of individual bone-loss and individual nourishment.
Therapeutic scheme with the inventive method continues preferably at least about 12 months.Certainly, therapeutic scheme can go down according to rational medical practice with not limiting continuously.Till being preferably object and being treated the doctor and think that having obtained danger that os purum matter increase fractures simultaneously also descends.
Also can use nutrient and other therapeutic agent with the auxiliary sclerotin that increases simultaneously to object.The optional preparation of this class comprises, as vitamin D and calcium.
In the method for the invention, " administration " refer to be used for active matter of the present invention to make up any method of bone effectively to the object of being treated according to rational medical practice (by veteran doctor).Active matter can be by various known medication administrations, as oral, through skin mucosa delivery (as transdermal administration, sublingual administration, intranasal administration and rectally), parenteral administration (as, subcutaneous injection, intramuscular injection, intra-arterial injection, intravenous injection) and inhalation.Like this, the AD HOC of administration includes, but not limited to for example oral, transdermal administration, mucosa delivery, sublingual administration, intramuscular injection, quiet notes, intraperitoneal administration, subcutaneous administration and topical.
The better method of treatment osteoporosis comprises that initial diagnosis algorithm is to determine existing of disease.Like this, the present invention's method preferably comprises human body is diagnosed with the monitoring osteoporosis, and has obtained male result from described diagnosis, and the method according to this invention is used active matter.Suffer from the female subject of menopause for treatment before obvious bone-loss, described initial diagnosis algorithm comprises the diagnosis of checking menopause.These class methods are that this technical field is known, comprise, as measuring the reconstruction speed of sclerotin and bone.The reconstruction speed of bone can be measured by the measurement of biochemical markers.Referring to " bone-loss are to the effect of facilitating of postmenopausal osteoporosis " such as Hui (" The Contribution of Bone Loss to PostmenopausalOsteoporosis ") osteoporosis research (Osteoporosis Int) 30 (1990), list for reference here.
The proper diagnosis that detects definite osteoporosis also is that this technical field is known, and these class methods comprise the measurement, tomographic, monoergic photonic absorption meter, dual energy photonic absorption meter, dual energy X-absorptiometer and the quantitative technique radiogram of quantitative Analysis of radiodensity of the radiograph of bone.These useful diagnostic techniquess are seen W.A.Peck etc., about doctor's handbook of osteoporosis (Physician ' sResource Manual on Osteoporosis) (1987), national osteoporosis fund (NationalOsteoporosis Foundation) is published.Here list and be made for reference.
Dosage form:
Estrogen compound and parathyroid hormone can various pharmaceutically acceptable compositions administrations.This based composition can comprise active matter and pharmaceutically acceptable carrier.Pharmaceutically the carrier of Jie Shouing comprises solid or liquid filler diluent or encapsulated material and their mixture, and they are fit to human body or rudimentary animals administer.Terminology used here " compatible " expression can with active matter and fusion mutually each other, the result does not have obviously to reduce the cross reaction of pharmaceutical composition drug effect under normal operating position.Certainly, pharmaceutically acceptable carrier must be enough pure, and toxicity is enough low to be fit to human body or the rudimentary animals administer to being treated.
The example that can be used as pharmaceutical carrier is: sugar, as lactose, dextrose plus saccharose; Starch is as corn starch and potato starch; Cellulose and its derivative are as carboxymethyl cellulose, ethyl cellulose, cellulose ethanoate; The tragacanthin of powdered; Fructus Hordei Germinatus; Gelatin; Pulvis Talci; Stearic acid; Magnesium stearate; Vegetable oil is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, Semen Maydis oil and cupu oil; Polyhydric alcohol is as propylene glycol, glycerol, sorbitol, mannitol and Polyethylene Glycol; Agar; Alginic acid; Pyrogen-free water; Isotonic saline solution; Phosphonate buffer solution; Wetting agent and lubricant are as sodium lauryl sulphate; Coloring agent; Flavoring agent and antiseptic.Pharmaceutically acceptable carrier in the present composition also comprises other compatible medicated premix and active matter.
The selection that is used for the pharmaceutically acceptable carrier that matches with active matter can be by the administering mode decision of active matter.If drug administration by injection, pharmaceutical carrier is sterilized water, normal saline or their mixture preferably.The pH of this class parenteral administration compositions is adjusted to about 7.4 preferably.The pharmaceutically acceptable carrier that is fit to topical comprises that this technical field becomes known for the carrier in cream, gel, band agent, unguentum and the similar local delivery mode.
Can be enough to provide relevant dose practical size with the working concentration of the pharmaceutically acceptable carrier of active matter compatibility.Comprising that pharmaceutically acceptable carrier is total accounts for the about 0.1%-99.9% of pharmaceutical composition of the present invention (weight), about preferably 5-80%, preferably about 10-50%.
Using the better method of diphosphate is oral (that is the dosage form that, contains the active matter that is suitable for the single dose administration amount according to rational medical practice) of carrying out unit dosage forms.For diphosphate preferably unit dosage forms comprise tablet, capsule, suspending agent and solution, they comprise the active matter of safe and effective amount.The pharmaceutically acceptable carrier that is fit to the preparation oral unit dosage form is known in this technical field.Their selection basis is decided as second Consideration of taste, cost, storage stability, and this is not the key of the object of the invention, can be judged without difficulty by these those skilled in the art.Be preferably, the oral unit dosage form of the activatory phosphonate of bone comprises the 1.0mgP/kg of the about 0.0005mgP/kg-of oral phosphonate every day.
Parathyroid hormone medication preferably is a subcutaneous injection by unit dosage forms.The unit dosage forms that is used to inject preferably of injection comprises the sterile solution of water, normal saline or their mixture.The pH of described solution should be adjusted to about 7.4.The unit dosage forms of parathyroid hormone comprises the about 15IU/kg of about 4-every day preferably.
The better dosage form of other of parathyroid hormone comprises intranasal administration, transdermal administration, rectally, sublingual administration and oral.Peroral dosage form comprises preferably, for example, and liposome, lipoid Emulsion and protein box.
Test kit
For convenience and implement method of the present invention effectively, the present invention also provides test kit.This class test kit comprise one or more unit dosage forms estrogen compound, one or more unit dosage forms parathyroid hormone and be convenient to implement to meet the device of the inventive method.This class test kit provides the means easily and effectively of guaranteeing to be absorbed in correct mode by treatment target the correct dose active matter.The enforcement means of this class test kit comprise any measure of the active matter of the method according to this invention use easily.The enforcement means of this class test kit comprise description, packaging bag and instrument (dispensing means) and their combination adjusted by prescription.The example of packaging bag and the instrument adjusted by prescription is that this technical field is known, comprises as United States Patent (USP) 4,761 406 (Flora etc., 1988,8,2 promulgations); United States Patent (USP) 4,812,311 (Uchtman, 1989,3,14 promulgations) and United States Patent (USP) 4,833,125 (Neer etc., 1989,5,23 promulgations) list being made for reference here.
Following indefiniteness embodiment has disclosed compositions of the present invention, method and purposes.
Embodiment 1
Treat an about 62kg of body weight, diagnosed the Asia women who suffers from postmenopausal osteoporosis with method of the present invention.Concrete is to use diphosphate to patient in 8 months, 2-(3-pyridine radicals)-1-hydroxyl ethane-1,1-diphosphonic acid.Give patient's every day oral a slice, every contains the 0.002mgP/kg diphosphate.Interrupt estrogenic treatment.Then, (after) used parathyroid hormone (synthetic fragment 1-34 or h PTH1-34) to patient in 6 months.In 6 months with 13IU/kg dosage by insulin syringe to thigh front side subcutaneous injection hormone, injected weekly 5 days.
Hip ridge bone is carried out biopsy, compare with the biopsy of (before the treatment) benchmark, its mean wall thickness of rebuilding unit (BMU) shows to be increased.The absorption degree of depth of activation frequency and the cavity on cancellus, cortex and cortex inner surface is not increased to more than the reference value significantly.Measure bone mineral density, showing has increased by 11%.
Embodiment 2
Treat an about 60kg of body weight, diagnosed Caucasia (white race) women who suffers from postmenopausal osteoporosis with method of the present invention.Concrete is to use conjugated estrogen hormone to reach 1 year to patient.Use estrogen by transdermal patch, discharge 0.625mg estrogen every day.After 1 year one month, interrupt estrogenic treatment.But use parathyroid hormone (synthetic fragment 1-34 or h PTH 1-34) to reach 6 months to patient then, every day, the intranasal spraying discharged 5IU/kg.
Obtain blood sample, analyze the bone special sign, sclerotin element (osteocalcin) and come autophya and total alkaline phosphatase.With the treatment before compare, the sclerotin element has increased by 57%, sclerotin and total alkaline phosphate have increase slightly.Fundamentals of Measurement inorganic matter density, showing has increased by 10%.
Claims (4)
1. test kit that is used in the scheme that the human body of suffering from the bone disease of metabolism or other animal target are treated, this therapeutic scheme consists essentially of the following step:
(a) give the estrogen compound of described object effective dose safe in utilization in during greater than 6 months;
(b) give the parathyroid hormone of described object effective dose safe in utilization in during 3-12 month.
Described test kit is characterised in that it contains following component:
(i) the bone estrogen of at least 180 days dosage;
The (ii) parathyroid hormone of 1-365 days dosage.
2. test kit according to claim 1, wherein, in step (b), described parathyroid hormone used about 6 months.
3. test kit according to claim 1, wherein said step (a) and (b) repeat 1-6 time.
4. test kit according to claim 2, wherein said estrogen compound are bonded estrogen, and its consumption level is about 0.3-1.25mg/ days.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30392694A | 1994-09-09 | 1994-09-09 | |
| US08/303,926 | 1994-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1158569A true CN1158569A (en) | 1997-09-03 |
Family
ID=23174293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95195016A Pending CN1158569A (en) | 1994-09-09 | 1995-09-06 | Estrogens and prathyroid hormone for treating osteoporosis |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0804202A4 (en) |
| JP (1) | JP2001503728A (en) |
| KR (1) | KR970705397A (en) |
| CN (1) | CN1158569A (en) |
| AU (1) | AU3674895A (en) |
| CA (1) | CA2199250A1 (en) |
| IL (1) | IL115225A0 (en) |
| WO (1) | WO1996007416A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5545635A (en) * | 1995-05-23 | 1996-08-13 | Eli Lilly And Company | Inhibiting bone loss with equilenin |
| SE9702401D0 (en) | 1997-06-19 | 1997-06-19 | Astra Ab | Pharmaceutical use |
| US6855703B1 (en) | 2000-03-10 | 2005-02-15 | Endeavor Pharmaceuticals | Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds |
| EP1945245A2 (en) | 2005-11-10 | 2008-07-23 | The Board of Control of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| AU2009356227A1 (en) | 2009-12-07 | 2012-06-21 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| WO2015057836A2 (en) * | 2013-10-15 | 2015-04-23 | The Trustees Of Columbia University In The City Of New York | Bone anabolic parathyroid hormone and parathyroid hormone related-protein analogs |
Family Cites Families (2)
| 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 |
| TW303299B (en) * | 1993-07-22 | 1997-04-21 | Lilly Co Eli |
-
1995
- 1995-09-06 WO PCT/US1995/011386 patent/WO1996007416A1/en active IP Right Grant
- 1995-09-06 EP EP95934405A patent/EP0804202A4/en not_active Withdrawn
- 1995-09-06 JP JP50968396A patent/JP2001503728A/en active Pending
- 1995-09-06 AU AU36748/95A patent/AU3674895A/en not_active Abandoned
- 1995-09-06 CA CA002199250A patent/CA2199250A1/en not_active Abandoned
- 1995-09-06 CN CN95195016A patent/CN1158569A/en active Pending
- 1995-09-06 KR KR1019970701533A patent/KR970705397A/en active IP Right Grant
- 1995-09-08 IL IL11522595A patent/IL115225A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL115225A0 (en) | 1995-12-31 |
| JP2001503728A (en) | 2001-03-21 |
| WO1996007416A1 (en) | 1996-03-14 |
| CA2199250A1 (en) | 1996-03-14 |
| EP0804202A4 (en) | 1999-01-13 |
| KR970705397A (en) | 1997-10-09 |
| EP0804202A1 (en) | 1997-11-05 |
| AU3674895A (en) | 1996-03-27 |
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