CA2221416A1 - Bisphosphonate therapy for bone loss associated with rheumatoid arthritis - Google Patents
Bisphosphonate therapy for bone loss associated with rheumatoid arthritis Download PDFInfo
- Publication number
- CA2221416A1 CA2221416A1 CA002221416A CA2221416A CA2221416A1 CA 2221416 A1 CA2221416 A1 CA 2221416A1 CA 002221416 A CA002221416 A CA 002221416A CA 2221416 A CA2221416 A CA 2221416A CA 2221416 A1 CA2221416 A1 CA 2221416A1
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- Prior art keywords
- alendronate
- administered
- bone loss
- rheumatoid arthritis
- dose
- 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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- 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
-
- 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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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Bisphosphonates, and particularly alendronate, can prevent or treat bone loss associated with rheumatoid arthritis.
Description
TITLE OF THE INVENTION
BISPHOSPHONATE THERAPY FOR BONE LOSS ASSOCIATED
VVITH RHEUMATOID ARTHRITIS
SUMMARY OF THE INVENTION
This invention relates to the use of bisphosphonates, particularly alendronate, to prevent bone loss associated with rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Rheumatoid arthritis (RA) is a chronic, multisystemic disease of unknown cause. The characteristic feature of RA is persistent infl~mm~tory synovitis, usually involving peripheral joints. One h~llmzlrk of the disease is cartilage destruction and periarticular bone erosion caused by synovial infl~mm~tion, resulting in joint deformities.
The cell believed to be responsible for the erosive process in the osteoclast. In patients with RA, therapy often includes glucocorticoid ~lmini.~tration, immobilization of joints, cyclosporine or methotrexate, all of which may potentiate bone loss and deformity.
It would be desirable to prevent or treat generalized and periarticular bone loss associated with RA.
DETAILED DESCRIPTION OF THE INVENTION
It has been found in accordance with this invention that bisphosphonates can prevent and treat bone loss associtated with rheumatoid art_ritis when ~-lmini~tered in either a prophylactically or therapeutically effective amount.
In particular, alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) or a pharmaceutically effective salt thereof, can prevent and treat bone loss associated with rheumatoid arthritis when t ~lmini~tered either in a prophylactically or therapeutically effective amount.
A further aspect of this invention is a method of preventing or treating generalized and/or periarticular bone loss associated with rheumatoid arthritis comprising ~-lmini~tering an effective amount of a bisphosphonate selected from the group consisting of: alendronate, -etidronate (l-hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino- 1 -hydroxypropyildiene- 1,1 -diphosphanate), risedronate 5 (2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio-methylidene-bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpenty-lamino)-propylidene-bisphosphonic acid, and pharmaceutically acceptible salts of any of the foregoing, and mixtures 10 of any of the acids and any of the salts to a patient suffering from rheumatoid arthritis. All of the foregoing compounds are well kllown in the art.
Generally the patient undergoing treatment for rheumatoid arthritis will be receiving one or more of: an immunosuppressive drug, 15 cyclosporine, methotrexate, or glucocorticoids.
As used throughout the specification and claims, the following definitions apply:
"Prophylactically effective amount"--the amount of 20 alendronate needed to prevent or lessen the severity of bone loss associated with rheulnatoid arthritis.
"Therapeutically effective amount"--the amount of alendronate needed to treat bone loss associated with rheurnatoid arthritis.
In a preferred aspect of this invention, the patient will receive alendronate. Alendronate may be prepared according to any of the processes described in U.S. Patents 5,019,651, 4,992,007, and U.S.
Application Serial No. 08/286,151, filed August 4, 1994, each of which 30 is hereby incorporated by reference. The pharmaceutically acceptable salts of alendronate include salts of alkali metals (e.g., Na, K), ~lk~line earth metals (e.g. Ca), salts of inorganic acids, such as HCl and salts of organic acids such as citric acid and amino acids. Sodium salt forms are preferred, particularly the monosodium salt trihydrate form.
WO 96/39150 PCTtUS96tO8361 Many of the bisphosphonate compounds of the present J invention can be ~lmini~tered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, paste, tinctures, suspensions, syrups, emulsions, and zydis. Likewise they may be ~lmini~tered in an intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the bisphosphonate compound desired can be used as a an agent which treats or prevents bone loss associated with RA.
The dosage regime utilizing the claimed method is selected in accordance with a variety of factors including type, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of ~clminictration; the renal and hepatic function of the lS patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent and or treat bone loss.
Oral dosages of the present invention when alendronate is the bisphosphonate will range from between 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day. Preferred oral dosages in hllm~n~ may range from daily total dosages of about 2.5-50 mg/day over the effective treatment period, and a preferred amount is S, 10 or 20 mg/day.
Alendronate may be ~lmini~tered in a single daily dose or in a divided dose. It is desirable for the dosage to be given in the absence of food, preferably from about 30 minlltes to 2 hours prior to a meal, such as breakfast to permit adequate absorption.
f In the methods of the present invention, the active ingredient is typically ~lmini~tered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier materials") suitably selected with respect to the intended form of ~1mini~tration, i.e. oral tablets, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical practices. For example, for oral ~lmini~tration in the form of a tablet or capsule, the active ingredient can be combined with an oral, non- ~v toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, S sorbitol, croscarmellose sodium and the like; for oral ~lmini~tration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of active ingredient(s) and inert carrier materials. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium sterate, sodium benzoate, sodium acetate, sodium chloride and the like.
A particularly preferred tablet formulation of alendronate is that described in U.S. Patent 5,358,941, which is hereby incorporated by reference.
The compounds used in the instant method may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran co-polymer, polyhydroxylpropyl-methacrylamide and the like.
Patients suffering from rheumatoid arthritis may be male or female of any age. Women may be pre-or post-menopausal.
The following non-limiting examples are presented to better illustrate the invention.
Alendronate for the treatment and prevention of bone loss in patient,s with rheumatoid arthritis S 220 men and women with active rheumatoid arthritis (as defined by the 1987 ARA Diagnostic Criteria), ages 18-80 are studied in a randomized double-blind clinical trial. Patients are randomized into 5 groups which receive either placebo, 2.5, 5, 10, or 20 mg/day alendronate orally each day for one year. In addition to standard RA
therapy, patients are also given 1000 mg calcium and 250 IU Vitamin D
daily.
After one year, the bone mineral density (BMD) of the spine, hip and total body are measured. In addition, the hand erosion score is assessed using standard techniques.
It is found that patients who receive daily oral alendronate at doses of S-20 mg/day increase spine and hip BMD relative to both their baseline scores and to patients receiving placebo. The increase is statistically significant. Also, in patients receiving alendronate, hand erosion scores are decreased relative to baseline and placebo.
BISPHOSPHONATE THERAPY FOR BONE LOSS ASSOCIATED
VVITH RHEUMATOID ARTHRITIS
SUMMARY OF THE INVENTION
This invention relates to the use of bisphosphonates, particularly alendronate, to prevent bone loss associated with rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Rheumatoid arthritis (RA) is a chronic, multisystemic disease of unknown cause. The characteristic feature of RA is persistent infl~mm~tory synovitis, usually involving peripheral joints. One h~llmzlrk of the disease is cartilage destruction and periarticular bone erosion caused by synovial infl~mm~tion, resulting in joint deformities.
The cell believed to be responsible for the erosive process in the osteoclast. In patients with RA, therapy often includes glucocorticoid ~lmini.~tration, immobilization of joints, cyclosporine or methotrexate, all of which may potentiate bone loss and deformity.
It would be desirable to prevent or treat generalized and periarticular bone loss associated with RA.
DETAILED DESCRIPTION OF THE INVENTION
It has been found in accordance with this invention that bisphosphonates can prevent and treat bone loss associtated with rheumatoid art_ritis when ~-lmini~tered in either a prophylactically or therapeutically effective amount.
In particular, alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) or a pharmaceutically effective salt thereof, can prevent and treat bone loss associated with rheumatoid arthritis when t ~lmini~tered either in a prophylactically or therapeutically effective amount.
A further aspect of this invention is a method of preventing or treating generalized and/or periarticular bone loss associated with rheumatoid arthritis comprising ~-lmini~tering an effective amount of a bisphosphonate selected from the group consisting of: alendronate, -etidronate (l-hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino- 1 -hydroxypropyildiene- 1,1 -diphosphanate), risedronate 5 (2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio-methylidene-bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpenty-lamino)-propylidene-bisphosphonic acid, and pharmaceutically acceptible salts of any of the foregoing, and mixtures 10 of any of the acids and any of the salts to a patient suffering from rheumatoid arthritis. All of the foregoing compounds are well kllown in the art.
Generally the patient undergoing treatment for rheumatoid arthritis will be receiving one or more of: an immunosuppressive drug, 15 cyclosporine, methotrexate, or glucocorticoids.
As used throughout the specification and claims, the following definitions apply:
"Prophylactically effective amount"--the amount of 20 alendronate needed to prevent or lessen the severity of bone loss associated with rheulnatoid arthritis.
"Therapeutically effective amount"--the amount of alendronate needed to treat bone loss associated with rheurnatoid arthritis.
In a preferred aspect of this invention, the patient will receive alendronate. Alendronate may be prepared according to any of the processes described in U.S. Patents 5,019,651, 4,992,007, and U.S.
Application Serial No. 08/286,151, filed August 4, 1994, each of which 30 is hereby incorporated by reference. The pharmaceutically acceptable salts of alendronate include salts of alkali metals (e.g., Na, K), ~lk~line earth metals (e.g. Ca), salts of inorganic acids, such as HCl and salts of organic acids such as citric acid and amino acids. Sodium salt forms are preferred, particularly the monosodium salt trihydrate form.
WO 96/39150 PCTtUS96tO8361 Many of the bisphosphonate compounds of the present J invention can be ~lmini~tered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, paste, tinctures, suspensions, syrups, emulsions, and zydis. Likewise they may be ~lmini~tered in an intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the bisphosphonate compound desired can be used as a an agent which treats or prevents bone loss associated with RA.
The dosage regime utilizing the claimed method is selected in accordance with a variety of factors including type, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of ~clminictration; the renal and hepatic function of the lS patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent and or treat bone loss.
Oral dosages of the present invention when alendronate is the bisphosphonate will range from between 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day. Preferred oral dosages in hllm~n~ may range from daily total dosages of about 2.5-50 mg/day over the effective treatment period, and a preferred amount is S, 10 or 20 mg/day.
Alendronate may be ~lmini~tered in a single daily dose or in a divided dose. It is desirable for the dosage to be given in the absence of food, preferably from about 30 minlltes to 2 hours prior to a meal, such as breakfast to permit adequate absorption.
f In the methods of the present invention, the active ingredient is typically ~lmini~tered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier materials") suitably selected with respect to the intended form of ~1mini~tration, i.e. oral tablets, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical practices. For example, for oral ~lmini~tration in the form of a tablet or capsule, the active ingredient can be combined with an oral, non- ~v toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, S sorbitol, croscarmellose sodium and the like; for oral ~lmini~tration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of active ingredient(s) and inert carrier materials. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium sterate, sodium benzoate, sodium acetate, sodium chloride and the like.
A particularly preferred tablet formulation of alendronate is that described in U.S. Patent 5,358,941, which is hereby incorporated by reference.
The compounds used in the instant method may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran co-polymer, polyhydroxylpropyl-methacrylamide and the like.
Patients suffering from rheumatoid arthritis may be male or female of any age. Women may be pre-or post-menopausal.
The following non-limiting examples are presented to better illustrate the invention.
Alendronate for the treatment and prevention of bone loss in patient,s with rheumatoid arthritis S 220 men and women with active rheumatoid arthritis (as defined by the 1987 ARA Diagnostic Criteria), ages 18-80 are studied in a randomized double-blind clinical trial. Patients are randomized into 5 groups which receive either placebo, 2.5, 5, 10, or 20 mg/day alendronate orally each day for one year. In addition to standard RA
therapy, patients are also given 1000 mg calcium and 250 IU Vitamin D
daily.
After one year, the bone mineral density (BMD) of the spine, hip and total body are measured. In addition, the hand erosion score is assessed using standard techniques.
It is found that patients who receive daily oral alendronate at doses of S-20 mg/day increase spine and hip BMD relative to both their baseline scores and to patients receiving placebo. The increase is statistically significant. Also, in patients receiving alendronate, hand erosion scores are decreased relative to baseline and placebo.
Claims (16)
1. A method of preventing or treating generalized and/or periarticular bone loss associated with rheumatoid arthritis (RA) comprising administering an effective amount of a bisphosphonate selected from the group consisting of: alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid), etidronate (1-hydroxy-ethidene-bisphosphonic acid), pamidronate (3-amino-1-hydroxy-propyildiene-1,1-diphosphanate), risedronate (2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonic acid), clodronate (dichloromethylene-bisphosphonic acid), tiludronate (chloro-4-phenylthio-methylidene-bisphosphonic acid), ibandronic acid (1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid, and pharmaceutically acceptible salts of any of the foregoing, and mixtures of any of the acids and any of the salts to a patient suffering from RA.
2. A method according to Claim 1 wherein the bisphosphonate is alendronate.
3. A method according to Claim 2 wherein the alendronate is in the form of monosodium salt trihydrate.
4. A method according to Claim 3 wherein the alendronate is administered orally.
5. A method according to Claim 3 wherein the alendronate is administered in a dose of from 2.5 to 50 mg per day.
6. A method according to Claim 5 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.
7. A method of treating bone loss associated with rheumatoid arthritis (RA) comprising administering a therapeutically effective amount of alendronate or a pharmaceutically acceptable salt thereof to a patient suffering from RA.
8. A method according to Claim 7 wherein the alendronate is in the form of monosodium salt trihydrate.
9. A method according to Claim 8 wherein the alendronate is administered orally.
10. A method according to Claim 8 wherein the alendronate is administered in a dose of from 2.5 to 50 mg per day.
11. A method according to Claim 10 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.
12. A method of preventing bone loss associated with rheumatoid arthritis (RA) comprising administering a therapeutically effective amount of alendronate or a pharmaceutically acceptable salt thereof to a patient suffering from RA.
13. A method according to Claim 12 wherein the alendronate is in the form of monosodium salt trihydrate.
14. A method according to Claim 13 wherein the alendronate is administered orally.
15. A method according to Claim 13 wherein the alendronate is administered in a dose of from 2.5 to 50 mg Per day.
16. A method according to Claim 15 wherein the alendronate is administered in a dose of 5 mg, 10 mg, or 20 mg per day.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47146495A | 1995-06-06 | 1995-06-06 | |
| US471,464 | 1995-06-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2221416A1 true CA2221416A1 (en) | 1996-12-12 |
Family
ID=23871729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002221416A Abandoned CA2221416A1 (en) | 1995-06-06 | 1996-06-03 | Bisphosphonate therapy for bone loss associated with rheumatoid arthritis |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0831843A1 (en) |
| JP (1) | JPH11506750A (en) |
| AU (1) | AU703887B2 (en) |
| CA (1) | CA2221416A1 (en) |
| WO (1) | WO1996039150A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0998292B1 (en) * | 1997-07-22 | 2001-11-21 | Merck & Co., Inc. (a New Jersey corp.) | Method for inhibiting bone resorption |
| AU741818C (en) * | 1997-07-22 | 2003-01-09 | Merck Sharp & Dohme Corp. | Method for inhibiting bone resorption |
| EP0998934A4 (en) | 1997-12-25 | 2005-09-14 | Toray Industries | Remedies for intramedullary diseases |
| EP0998933A1 (en) * | 1998-10-09 | 2000-05-10 | Boehringer Mannheim Gmbh | Process for producing pharmaceutical compositions containing diphosphonates for oral administration |
| AU781068B2 (en) * | 1999-08-19 | 2005-05-05 | Sydney Children's Hospitals Network (Randwick and Westmead) (incorporating The Royal Alexandra Hospital for Children), The | Drug for treating fractures |
| AUPQ232599A0 (en) * | 1999-08-19 | 1999-09-09 | Royal Alexandra Hospital For Children, The | Drug for treating fractures |
| US7084126B1 (en) * | 2000-05-01 | 2006-08-01 | Healthpartners Research Foundation | Methods and compositions for enhancing cellular function through protection of tissue components |
| US6548042B2 (en) | 2000-08-07 | 2003-04-15 | Arstad Erik | Bis-phosphonate compounds |
| JP2010043119A (en) * | 2009-10-16 | 2010-02-25 | Gador Sa | Composition for preventing and/or treating bone metabolic disease, method of preparing the same and use thereof |
| WO2016054056A1 (en) * | 2014-10-01 | 2016-04-07 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Methods of treating pxe with tnap inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5462932A (en) * | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
-
1996
- 1996-06-03 JP JP9500987A patent/JPH11506750A/en active Pending
- 1996-06-03 CA CA002221416A patent/CA2221416A1/en not_active Abandoned
- 1996-06-03 EP EP96916971A patent/EP0831843A1/en not_active Withdrawn
- 1996-06-03 WO PCT/US1996/008361 patent/WO1996039150A1/en not_active Ceased
- 1996-06-03 AU AU59679/96A patent/AU703887B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU703887B2 (en) | 1999-04-01 |
| WO1996039150A1 (en) | 1996-12-12 |
| JPH11506750A (en) | 1999-06-15 |
| EP0831843A1 (en) | 1998-04-01 |
| AU5967996A (en) | 1996-12-24 |
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