WO1994014455A1 - Therapie utilisant des bisphosphonates et des ×strogenes en vue de traiter et de prevenir la resorption osseuse - Google Patents

Therapie utilisant des bisphosphonates et des ×strogenes en vue de traiter et de prevenir la resorption osseuse Download PDF

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Publication number
WO1994014455A1
WO1994014455A1 PCT/US1993/012302 US9312302W WO9414455A1 WO 1994014455 A1 WO1994014455 A1 WO 1994014455A1 US 9312302 W US9312302 W US 9312302W WO 9414455 A1 WO9414455 A1 WO 9414455A1
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WO
WIPO (PCT)
Prior art keywords
bisphosphonate
estrogen
bone
bone loss
composition
Prior art date
Application number
PCT/US1993/012302
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English (en)
Inventor
Donna T. Whiteford
Original Assignee
Merck & Co., Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU59538/94A priority Critical patent/AU5953894A/en
Priority to JP6515312A priority patent/JPH08505142A/ja
Priority to EP94905419A priority patent/EP0675723A4/fr
Publication of WO1994014455A1 publication Critical patent/WO1994014455A1/fr
Priority to US08/880,735 priority patent/US6399592B1/en

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Classifications

    • 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
    • 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

Definitions

  • the instant invention relates generally to the combination of estrogen and bisphosphonates and their use in bone growth and maturation. Specifically, the invention relates to the use of estrogen and bisphosphonates to inhibit bone reso ⁇ tion and promote net bone formation. This therapeutic combination will result in a decreased rate of bone reso ⁇ tion with either an increase or stabilization of bone mass.
  • the normal bones are living tissues undergoing constant reso ⁇ tion and redeposition of calcium, with the net effect of maintenance of a constant mineral balance.
  • the dual process is commonly called "bone turnover".
  • the mineral deposition exceeds the mineral reso ⁇ tion
  • bone reso ⁇ tion exceeds bone deposition, for instance due to malignancy or primary hype ⁇ arathyroidism, or in osteoporosis.
  • the calcium deposition may take place in undesirable amounts and areas leading to e.g. heterotopic calcification, osteoarthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone reso ⁇ tion followed by an abnormal calcium deposition.
  • Bisphosphonates are also known in the art as bone reso ⁇ tion inhibitors.
  • Alendronate 4-amino- 1 -hydroxybutylidene- 1 ,1 - bisphosphonic acid monosodium trihydrate, is described as a composition, method of use and synthesis in US Patents 4,621 ,077 (Gentili); 4,922,007 and 5,019,651 (Merck).
  • Clodronate (dichloromethylene)bisphosphonic acid disodium salt (Proctor and Gamble, is described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 41 1 1 ( 1967) for its preparation.
  • Tiludronate ([(4-chlorophenyl)thiomethylene]- bisphosphonic acid) (Sanofi) is described in U.S. Patent 4,876,248 issued October 24, 1989.
  • YM 175 [(cycloheptylamino)methylene]bisphosphonic acid, disodium salt) by Yamanouchi is described in U.S. Patent 4,970,335 issued November 13, 1990.
  • a female patient is undergoing estrogen therapy for a menopausal or postmenopausal-related condition, (e.g., vasomotor symptoms, atrophy of the vaginal mucosa, increased cardiovascular risk, etc.) and is also discovered to be suffering from osteoporosis (i.e. rarefaction of bone) or to be at risk for developing osteoporosis.
  • a menopausal or postmenopausal-related condition e.g., vasomotor symptoms, atrophy of the vaginal mucosa, increased cardiovascular risk, etc.
  • osteoporosis i.e. rarefaction of bone
  • estrogens/hormone replacement therapy are known to help prevent the development of osteoporosis, there are instances, which are not at all uncommon, where HRT or a weak estrogen is prescribed at dosages which do not provide adequate protection against osteoporosis. There are also some women who continue to lose bone mass despite treatment with higher estrogen/HRT doses or who have established osteoporosis but fail to increase their bone mass on estrogen/HRT alone.
  • the present invention discloses a combination method for treating and/or preventing bone loss in a subject by the combination therapy of pharmaceutically effective amounts of estrogen and of a bisphosphonate selected from: alendronate, clodronate, tiludronate, YM 175, BM 210995, or mixture thereof.
  • estradien as used herein is meant “17-beta estradiol” and includes those equivalent materials contained in the MERCK INDEX - Eleventh Edition (1989). Estrogens, e.g. estradiol and its steroidal and non-steroidal equivalents which can be used herein include (page numbers taken from the above indicated MERCK INDEX):
  • Estradiol 3653 Estradiol Benzoate, 3655 Estradiol 17 ⁇ -Cypionate, 3656 Estriol, 3659 Estrone, 3660 Ethinyl Estradiol, 3689 Mestranol, 5819 Moxestrol, 6203 Mytatrienediol, 6254 Progesterone, 7783 Quinestradiol, 8065 Quinestrol, 8066 and including estrogen/progestin combinations.
  • bisphosphonates as used herein is meant bisphosphonates of the structure:
  • Rl is OH or H and R2 is an C1 -C5 linear, branched or cyclic alkyl or alkylidene which can be substituted by an terminal amino, substituted amino, e.g. dimethylamino, methylamino, ethylamino, heterocyclic amino, and the like.
  • bisphosphonates are the bisphosphonates described above, and those in the US Patents 4,732,998; 4,870,063; 5,130,304 to Leo Pharmaceuticals. Excluded from this category is risedronate.
  • the method can be used to treat subjects in general, including sport, pet, and farm animals, and humans.
  • the term “inhibition of bone reso ⁇ tion” refers to prevention of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity.
  • the term “inhibitor of bone reso ⁇ tion” as used herein refers to agents that prevent bone loss by the direct or indirect alteration of osteoclast formation or activity.
  • osteoogenically effective means that amount which effects the turnover of mature bone. As used herein, an osteogenically effective dose is also “pharmaceutically effective.”
  • subject refers to a living vertebrate animal such as a mammal or bird in need of treatment, i.e., in need of bone repair or replacement. Such need arises locally in cases of bone fracture, non-union, defect, prosthesis implantation, and the like. Such need also arises in cases of systemic bone disease, as in osteoporosis, osteoarthritis, Paget's disease, osteomalacia, multiple myeloma and other forms of cancer, steroid therapy, and age-related loss of bone mass. Particularly preferred is a human female subject.
  • treatment shall mean (1 ) providing a subject with an amount of a substance sufficient to act prophylactically to prevent the development of a weakened and/or unhealthy state; and/or (2) providing a subject with a sufficient amount of a substance so as to alleviate or eliminate a disease state and/or the symptoms of a disease state, and a weakened and/or unhealthy state.
  • Drugs which prevent bone loss and/or add back lost bone may be evaluated in the ovariectomized rat.
  • This animal model is well established in the art (see, for example, Wronski, et al. (1985) Calcif. Tissue Int. 37:324-328; Kimmel, et al. (1990) Calcif. Tissue Int. 46:101-1 10; and Durbridge, et al. (1990) Calcif. Tissue Int 47:383-387; these references are hereby inco ⁇ orated in their entirety).
  • Wronski, et al. ((1985) Calcif. Tissue Int. 43: 179-183)) describe the association of bone loss and bone turnover in the ovariectomized rat.
  • compositions of the invention which include a bone growth factor and/or an inhibitor of bone reso ⁇ tion for administration will generally include an osteogenically effective amount of the bone growth factor to promote bone growth, in addition to a pharmaceutically acceptable excipient.
  • Suitable excipients include most carriers approved for parenteral administration, including water, saline, Ringer's solution, Hank's solution, and solutions of glucose, lactose, dextrose, ethanol, glycerol, albumin, and the like.
  • These compositions may optionally include stabilizers, antioxidants, antimicrobials, preservatives, buffering agents, surfactants, and other accessory additives.
  • the inhibitor of bone reso ⁇ tion may also be delivered in a sustained release form from a suitable carrier.
  • a presently preferred vehicle comprises about 1 mg/ml serum albumin (species-specific) in phosphate-buffered saline (PBS) or isotonic citrate buffer.
  • PBS phosphate-buffered saline
  • isotonic citrate buffer phosphate-buffered saline
  • suitable vehicles for parenteral administration may be found in E. W. Martin. "Remington's Pharmaceutical Sciences” (Mack Pub. Co., current edition sections relating to the excipient vehicles and formulating being inco ⁇ orated herein by reference to disclose such).
  • Such formulations are generally known to those skilled in the art and are administered systemically to provide systemic treatment.
  • the estrogen and bisphosphonate may be administered sequentially or concurrently in separate dosages or as a single composition to the subject. If administered sequentially, the period between the administration of the estrogen and bisphosphonate will typically be one week to one year, and optimally, one week to six months.
  • the molar ratio of the estrogen and bisphosphonate will be about 50: 1 to 1 :50, preferably, 5:1 to 1 :5. The optimal ratio is expected to vary from compound to compound.
  • the estrogen and bisphosphonate may be separate components of the composition, or they may be conjugated to each other. Methods for conjugating bone growth factors to other agents are described above.
  • an effective dose of estrogen for systemic treatment will range from about 0.001 ⁇ g/kg to about 50 ⁇ g/kg of body weight and preferably about 30 ⁇ g/kg of body weight.
  • An effective dose for biphosphonate is about 1.5 to 3000 ⁇ g/kg of body weight and preferably about 10 ⁇ g/kg to about 200 ⁇ g/kg of body weight.
  • Effective doses for local administration would be about 0.001 ⁇ g to 1 mg per application site.
  • the methods and compositions of the invention are useful for treating bone fractures defects and disorders which result in weakened bones such as osteoporosis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia, bone loss resulting from multiple myeloma other forms of cancer, bone loss resulting from side effects of other medical treatment (such as steroids), and age-related loss of bone mass.
  • weakened bones such as osteoporosis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia
  • bone loss resulting from multiple myeloma other forms of cancer bone loss resulting from side effects of other medical treatment (such as steroids), and age-related loss of bone mass.
  • the estrogen and bisphosphonate may be administered systemically either orally and/or parenterally, including subcutaneous or intravenous injection. Additionally, the estrogen and bisphosphonate make be delivered in a slow release form from a suitable carrier.
  • the estrogen may be administered locally to a specific area in need of bone growth or repair, with either the concomitant administration of the bisphosphonate at the site, or the administration of the bisphosphonate in a separate vehicle, or the inhibitor of bone reso ⁇ tion may be provided locally with the administration of the estrogen in a separate vehicle.
  • the estrogen and/or bisphosphonate may be implanted directly at the site to be treated, for example, by injection or surgical implantation in a sustained-release carrier.
  • Suitable carriers include hydrogels, controlled- or sustained-release devices (e.g., an Alzet® minipump), polylactic acid, and collagen matrices.
  • telopeptide collagen containing particulate calcium phosphate mineral components such combinations of homologous or xenographic fibrillar atelopeptide collagen (for example Zyderm® Collagen Implant, available from Collagen Co ⁇ oration, Palo Alto, Calif.) with hydroxapatitetricalcium phosphate (HA-TCP, available from Zimmer, Inc., Warsaw, In.). It is presently preferred to administer implant compositions containing and/or an bisphosphonate in a collagen/mineral mixture implant.
  • Estrogen and/or an bisphosphonate delivered in sustained- release vehicles is also particularly useful for improving implant fixation, for example for improving in growth of new bone into a metal prosthesis in joint reconstruction and dental or orthopedic implants.
  • the estrogen may be delivered in the implant, with the bisphosphonate delivered in a separate vehicle, and vice-versa.
  • Dental and orthopedic implants can be coated with estrogen in combination with an bisphosphonate to enhance attachment of the implant device to the bone.
  • the estrogen can be used to coat the implant, and the bisphosphonate can be administered concomitantly or sequentially in a separate vehicle, and vice-versa.
  • implant devices may be coated with a estrogen and/or an bisphosphonate as follows.
  • the estrogen and the bisphosphonate if desired is dissolved at a concentration in the range of 0.01 ⁇ g/ml to 200 mg/ml in phosphate-buffered saline (PBS) containing 2 mg/ml serum albumin.
  • PBS phosphate-buffered saline
  • the porous end of an implant is dipped in the solution and is airdried (or lyophilized) or implanted immediately into the bony site.
  • the viscosity of the coating solution is increased, if desired, by adding hyaluronate at a final concentration of 0.1 mg/ml to 100 mg/ml or by adding other pharmaceutically acceptable excipients.
  • the solution containing the estrogen (and the bisphosphonate, if desired) is mixed with collagen gel or human collagen (e.g. Zyderm® Collagen Implant, Collagen Co ⁇ ., Palo alto, Calif.) to a final collagen concentration of 2 mg/ml to 100 mg/ml to form a paste or gel, which is then used to coat the porous end of the implant device.
  • collagen gel or human collagen e.g. Zyderm® Collagen Implant, Collagen Co ⁇ ., Palo alto, Calif.
  • the coated implant device is placed into the bony site immediately or is airdried and rehydrate with PBS prior to implanting, with the objective of maximizing new bone formation into the implant while minimizing the ingrowth of soft tissue into the implant site.
  • compositions according to the present invention containing, e.g., both alendronate and estradiol, may be prepared for use in the form of capsules or tablets or in solution for oral administration or for systemic use.
  • the compositions are advantageously prepared together with inert carriers such as sugars (saccharose, glucose, lactose), starch and derivatives, cellulose and derivatives, gums, fatty acids and their salts, polyalcohols, talc, aromatic esters.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une thérapie combinée visant à traiter et à prévenir la résorption osseuse au moyen d'÷strogènes et d'un bisphosphonate sélectionné parmi: alendronate, clodronate, tiludronate, YM175, BM210995, ou d'un mélange de ceux-ci. L'invention concerne également une composition pharmaceutique comprenant les éléments mentionnés ci-dessus afin de réaliser ce procédé thérapeutique.
PCT/US1993/012302 1992-12-23 1993-12-17 Therapie utilisant des bisphosphonates et des ×strogenes en vue de traiter et de prevenir la resorption osseuse WO1994014455A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU59538/94A AU5953894A (en) 1992-12-23 1993-12-17 Bisphosphonate/estrogen therapy for treating and preventing bone loss
JP6515312A JPH08505142A (ja) 1992-12-23 1993-12-17 骨損失を治療及び予防するためのビスホスホネート／エストロゲン療法
EP94905419A EP0675723A4 (fr) 1992-12-23 1993-12-17 Therapie utilisant des bisphosphonates et des strogenes en vue de traiter et de prevenir la resorption osseuse.
US08/880,735 US6399592B1 (en) 1992-12-23 1997-06-23 Bishphosphonate/estrogen synergistic therapy for treating and preventing bone loss

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US99641892A 1992-12-23 1992-12-23
US996,418 1992-12-23

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US49184695A Continuation-In-Part 1992-12-23 1995-06-22

Publications (1)

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WO1994014455A1 true WO1994014455A1 (fr) 1994-07-07

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EP (1) EP0675723A4 (fr)
JP (1) JPH08505142A (fr)
AU (1) AU5953894A (fr)
CA (1) CA2151240A1 (fr)
WO (1) WO1994014455A1 (fr)

Cited By (28)

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WO1995028936A1 (fr) * 1994-04-21 1995-11-02 Merck & Co., Inc. Emploi de biphosphonates inhibant la resorption osseuse consecutive a l'implantation d'une prothese orthopedique
EP0744176A2 (fr) * 1995-05-23 1996-11-27 Eli Lilly And Company Médicaments pour inhiber les pertes osseuses
EP0777484A1 (fr) * 1994-08-24 1997-06-11 Merck & Co. Inc. Formulations intraveineuses d'alendronate
EP0792645A1 (fr) * 1996-02-28 1997-09-03 Pfizer Inc. Thérapie combinée pour le traitement de l'ostéoporose
EP0792639A1 (fr) * 1996-02-28 1997-09-03 Pfizer Inc. Thérapie à base d'une combination pour le traitement de l'ostéoporose et des conditions de la masse osseuse diminuée
WO1997044017A1 (fr) * 1996-05-17 1997-11-27 Merck & Co., Inc. Formulation de bisphosphonate efferverscente
EP0824341A1 (fr) * 1995-05-12 1998-02-25 Merck & Co., Inc. Prevention des pertes de dnets par l'administration d'alendronate ou de ses sels
EP0831844A1 (fr) * 1995-06-06 1998-04-01 Merck & Co., Inc. Prevention de la deperdition osseuse par des bisphosphonates associes a une therapie d'immunodepression
WO1998051314A1 (fr) * 1997-05-09 1998-11-19 Roche Diagnostics Gmbh Utilisation d'acides diphosphoniques ou de leurs sels ou esters physiologiquement tolerables pour le traitement preventif des sequelles tardives en cas d'agrandissement vesical ou de remplacement vesical
US5853759A (en) * 1996-05-17 1998-12-29 Merck & Co.. Inc. Effervescent alendronate formulation
EP0949928A1 (fr) * 1996-11-25 1999-10-20 Merck & Co., Inc. Agents androgene et bisphosphonique coadministres pour traiter des maladies
EP0998934A1 (fr) * 1997-12-25 2000-05-10 Toray Industries, Inc. Remedes contre les maladies intramedullaires
WO2000033849A1 (fr) * 1998-12-04 2000-06-15 Roche Diagnostics Gmbh Utilisation d'ibandronate pour favoriser l'osseointegration des endoprotheses
WO2000064516A1 (fr) * 1999-04-22 2000-11-02 Hydromed Sciences A Division Of Gp Strategies Corporation Administration regulee de bisphosphonates
FR2803521A1 (fr) * 2000-01-12 2001-07-13 Ceva Sante Animale Utilisation de l'acide tiludronique et de ses derives chez la volaille pour la preparation d'un medicament destine a prevenir et a traiter l'osteoporose
CN1079671C (zh) * 1994-07-22 2002-02-27 伊莱利利公司 抑制骨损失的组合疗法
US6376477B2 (en) 1996-11-25 2002-04-23 Merck & Co., Inc. Combination of an agent that binds to the androgen receptor and a bisphosphonic acid in the prevention and/or treatment of diseases involving calcium or phosphate metabolism
EP1214079A1 (fr) * 1999-08-19 2002-06-19 The Royal Alexandra Hospital for Children Medicament pour traiter des fractures
WO2002098307A1 (fr) * 2001-06-07 2002-12-12 The Royal Alexandra Hospital For Children Dispositif permettant l'apport d'un medicament a un os fracture
EP1365769A1 (fr) * 2001-02-06 2003-12-03 The Royal Alexandra Hospital for Children Medicament destine au traitement de l'osteonecrose et a la gestion de patients etant predisposes a l'osteonecrose
EP1378234A1 (fr) * 1996-05-17 2004-01-07 MERCK & CO. INC. Formulation de bisphosphonate effervescente
EP1383509A1 (fr) * 2001-04-03 2004-01-28 The Royal Alexandra Hospital for Children Medicament a utiliser en matiere de greffe osseuse
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US7611722B2 (en) 2001-12-24 2009-11-03 Teva Pharmaceutical Industries Ltd. Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it
US7612052B2 (en) 2001-07-19 2009-11-03 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
US7964212B2 (en) 2002-03-06 2011-06-21 Christer Rosen Effervescent compositions comprising phosphonates and methods related thereto
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone

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Cited By (57)

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Publication number Priority date Publication date Assignee Title
EP1197213A2 (fr) * 1994-04-21 2002-04-17 MERCK & CO. INC. Utilisation de bisphosphonates pour inhiber la résorption osseuse consécutive à l'implantation d'une prothèse orthopédique
US5972913A (en) * 1994-04-21 1999-10-26 Merck & Co., Inc. Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices
EP1197213A3 (fr) * 1994-04-21 2002-09-25 MERCK & CO. INC. Utilisation de bisphosphonates pour inhiber la résorption osseuse consécutive à l'implantation d'une prothèse orthopédique
US5646134A (en) * 1994-04-21 1997-07-08 Merck & Co., Inc. Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices
US5891863A (en) * 1994-04-21 1999-04-06 Merck & Co., Inc. Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices
WO1995028936A1 (fr) * 1994-04-21 1995-11-02 Merck & Co., Inc. Emploi de biphosphonates inhibant la resorption osseuse consecutive a l'implantation d'une prothese orthopedique
CN1079671C (zh) * 1994-07-22 2002-02-27 伊莱利利公司 抑制骨损失的组合疗法
US5914323A (en) * 1994-08-24 1999-06-22 Merck & Co., Inc. Intravenous alendronate formulations
EP0777484A4 (fr) * 1994-08-24 1998-08-05 Merck & Co Inc Formulations intraveineuses d'alendronate
US5843924A (en) * 1994-08-24 1998-12-01 Merck & Co., Inc. Intravenous alendronate formulations
EP0777484A1 (fr) * 1994-08-24 1997-06-11 Merck & Co. Inc. Formulations intraveineuses d'alendronate
JP2004075690A (ja) * 1994-08-24 2004-03-11 Merck & Co Inc 静脈内注入用アレンドロナート組成物
EP0824341A1 (fr) * 1995-05-12 1998-02-25 Merck & Co., Inc. Prevention des pertes de dnets par l'administration d'alendronate ou de ses sels
EP0824341A4 (fr) * 1995-05-12 1999-07-07 Merck & Co Inc Prevention des pertes de dnets par l'administration d'alendronate ou de ses sels
EP0744176A2 (fr) * 1995-05-23 1996-11-27 Eli Lilly And Company Médicaments pour inhiber les pertes osseuses
EP0744176A3 (fr) * 1995-05-23 2002-05-15 Eli Lilly And Company Médicaments pour inhiber les pertes osseuses
EP0831844A1 (fr) * 1995-06-06 1998-04-01 Merck & Co., Inc. Prevention de la deperdition osseuse par des bisphosphonates associes a une therapie d'immunodepression
EP0831844A4 (fr) * 1995-06-06 1998-12-30 Merck & Co Inc Prevention de la deperdition osseuse par des bisphosphonates associes a une therapie d'immunodepression
EP0792639A1 (fr) * 1996-02-28 1997-09-03 Pfizer Inc. Thérapie à base d'une combination pour le traitement de l'ostéoporose et des conditions de la masse osseuse diminuée
EP0792645A1 (fr) * 1996-02-28 1997-09-03 Pfizer Inc. Thérapie combinée pour le traitement de l'ostéoporose
WO1997044017A1 (fr) * 1996-05-17 1997-11-27 Merck & Co., Inc. Formulation de bisphosphonate efferverscente
EP1378234A1 (fr) * 1996-05-17 2004-01-07 MERCK & CO. INC. Formulation de bisphosphonate effervescente
US5853759A (en) * 1996-05-17 1998-12-29 Merck & Co.. Inc. Effervescent alendronate formulation
JP2009167200A (ja) * 1996-05-17 2009-07-30 Merck & Co Inc 発泡性ビスホスホネート製剤
US6376477B2 (en) 1996-11-25 2002-04-23 Merck & Co., Inc. Combination of an agent that binds to the androgen receptor and a bisphosphonic acid in the prevention and/or treatment of diseases involving calcium or phosphate metabolism
EP0949928A1 (fr) * 1996-11-25 1999-10-20 Merck & Co., Inc. Agents androgene et bisphosphonique coadministres pour traiter des maladies
EP0949928A4 (fr) * 1996-11-25 2000-09-13 Merck & Co Inc Agents androgene et bisphosphonique coadministres pour traiter des maladies
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JPH08505142A (ja) 1996-06-04
AU5953894A (en) 1994-07-19
EP0675723A4 (fr) 1998-08-05
EP0675723A1 (fr) 1995-10-11

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