EP0675723A1 - Bisphosphonate/estrogen therapy for treating and preventing bone loss - Google Patents
Bisphosphonate/estrogen therapy for treating and preventing bone lossInfo
- Publication number
- EP0675723A1 EP0675723A1 EP94905419A EP94905419A EP0675723A1 EP 0675723 A1 EP0675723 A1 EP 0675723A1 EP 94905419 A EP94905419 A EP 94905419A EP 94905419 A EP94905419 A EP 94905419A EP 0675723 A1 EP0675723 A1 EP 0675723A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- bisphosphonate
- estrogen
- bone
- bone loss
- composition
- 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.)
- Ceased
Links
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)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US99641892A | 1992-12-23 | 1992-12-23 | |
US996418 | 1992-12-23 | ||
PCT/US1993/012302 WO1994014455A1 (en) | 1992-12-23 | 1993-12-17 | Bisphosphonate/estrogen therapy for treating and preventing bone loss |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0675723A1 true EP0675723A1 (en) | 1995-10-11 |
EP0675723A4 EP0675723A4 (en) | 1998-08-05 |
Family
ID=25542895
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94905419A Ceased EP0675723A4 (en) | 1992-12-23 | 1993-12-17 | Bisphosphonate/estrogen therapy for treating and preventing bone loss. |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0675723A4 (en) |
JP (1) | JPH08505142A (en) |
AU (1) | AU5953894A (en) |
CA (1) | CA2151240A1 (en) |
WO (1) | WO1994014455A1 (en) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2065313T5 (en) * | 1993-05-15 | 2004-01-01 | Roche Diagnostics Gmbh | TABLET WITH IMPROVED BIODISPONIBILITY CONTAINING DICHLOROMETILENDIFOSFONICO ACID AS ACTIVE SUBSTANCE. |
US5646134A (en) * | 1994-04-21 | 1997-07-08 | Merck & Co., Inc. | Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices |
UA41909C2 (en) * | 1994-07-22 | 2001-10-15 | Елі Ліллі Енд Компані | Use A combination of compounds for the inhibition of osteoporosis, a pharmaceutical agent |
US5780455A (en) * | 1994-08-24 | 1998-07-14 | Merck & Co., Inc. | Intravenous alendronate formulations |
EP0824341A4 (en) * | 1995-05-12 | 1999-07-07 | Merck & Co Inc | Prevention of tooth loss by the administration of alendronate or its salts |
US5545635A (en) * | 1995-05-23 | 1996-08-13 | Eli Lilly And Company | Inhibiting bone loss with equilenin |
US5616571A (en) * | 1995-06-06 | 1997-04-01 | Merck & Co., Inc. | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
IL120265A0 (en) * | 1996-02-28 | 1997-06-10 | Pfizer | Combination therapy to treat osteoporosis - polyphosphonates or progestins and estrogen agonists |
IL120270A0 (en) * | 1996-02-28 | 1997-06-10 | Pfizer | Combination therapy to treat osteoporosis |
AU712710B2 (en) * | 1996-05-17 | 1999-11-11 | Merck Sharp & Dohme Corp. | Effervescent bisphosphonate formulation |
EP1378234A1 (en) * | 1996-05-17 | 2004-01-07 | MERCK & CO. INC. | Effervescent bisphosphonate formulation |
US5853759A (en) * | 1996-05-17 | 1998-12-29 | Merck & Co.. Inc. | Effervescent alendronate formulation |
JP2001507338A (en) * | 1996-11-25 | 2001-06-05 | メルク エンド カンパニー インコーポレーテッド | Androgenic and bisphosphonic acid co-administered to treat disease |
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 |
DE19719680A1 (en) | 1997-05-09 | 1998-11-19 | Boehringer Mannheim Gmbh | Use of diphosphonic acids for the preventive treatment of long-term consequences of bladder enlargement or replacement |
US6555529B1 (en) * | 1997-12-25 | 2003-04-29 | Toray Industries, Inc. | Remedies for intramedullary diseases |
PT1135140E (en) * | 1998-12-04 | 2005-10-31 | Roche Diagnostics Gmbh | UTILIZATION OF IBANDRONATO FOR THE PROMOTION OF ENDOPROTESES OSSEA INTEGRATION |
EP1210138A4 (en) * | 1999-04-22 | 2003-05-07 | Hydro Med Sciences Inc | Controlled delivery of bisphosphonates |
AUPQ232599A0 (en) * | 1999-08-19 | 1999-09-09 | Royal Alexandra Hospital For Children, The | Drug for treating fractures |
FR2803521B1 (en) * | 2000-01-12 | 2002-10-25 | Ceva Sante Animale | USE OF TILUDRONIC ACID AND ITS DERIVATIVES IN POULTRY FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR PREVENTING AND TREATING OSTEOPOROSIS |
US7425549B2 (en) * | 2001-02-06 | 2008-09-16 | The Royal Alexandra Hospital For Children | Drug for the treatment of osteonecrosis and for the management of patients at risk of developing osteonecrosis |
WO2002080933A1 (en) * | 2001-04-03 | 2002-10-17 | The Royal Alexandra Hospital For Children | A drug for use in bone grafting |
AUPR553701A0 (en) * | 2001-06-07 | 2001-07-12 | Royal Alexandra Hospital For Children, The | A device for the delivery of a drug to a fractured bone |
TWI315982B (en) | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
WO2003057136A2 (en) | 2001-12-24 | 2003-07-17 | 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 |
US7488496B2 (en) | 2002-03-06 | 2009-02-10 | Christer Rosen | Effervescent compositions comprising bisphosphonates and methods related thereto |
EP1508343B1 (en) * | 2003-08-21 | 2015-11-04 | AddBIO AB | Bisphosponate coated implant device and method therefor |
US8940320B2 (en) | 2005-10-27 | 2015-01-27 | Thommen Medical Ag | Dental implant and production method for said implant |
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 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992005187A1 (en) * | 1990-09-18 | 1992-04-02 | Boehringer Mannheim Gmbh | NEW 17-β-OESTRADIOL DERIVATIVES, A METHOD OF PREPARING THEM, AND DRUGS CONTAINING THEM |
EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
WO1992014474A1 (en) * | 1991-02-26 | 1992-09-03 | Norwich Eaton Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3623397A1 (en) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
-
1993
- 1993-12-17 CA CA002151240A patent/CA2151240A1/en not_active Abandoned
- 1993-12-17 AU AU59538/94A patent/AU5953894A/en not_active Abandoned
- 1993-12-17 EP EP94905419A patent/EP0675723A4/en not_active Ceased
- 1993-12-17 WO PCT/US1993/012302 patent/WO1994014455A1/en not_active Application Discontinuation
- 1993-12-17 JP JP6515312A patent/JPH08505142A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992005187A1 (en) * | 1990-09-18 | 1992-04-02 | Boehringer Mannheim Gmbh | NEW 17-β-OESTRADIOL DERIVATIVES, A METHOD OF PREPARING THEM, AND DRUGS CONTAINING THEM |
EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
WO1992014474A1 (en) * | 1991-02-26 | 1992-09-03 | Norwich Eaton Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis |
Non-Patent Citations (2)
Title |
---|
CIMINERA N. ET AL: "Studio Comparativo degli effeti di estrogeni e difosfonati sulla perdita ossea postmenopausale" ANN. OSTET. GINECOL. MED. PERINAT., vol. 113, no. 5, 1992, pages 232-237, XP002064831 * |
See also references of WO9414455A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2151240A1 (en) | 1994-07-07 |
WO1994014455A1 (en) | 1994-07-07 |
EP0675723A4 (en) | 1998-08-05 |
JPH08505142A (en) | 1996-06-04 |
AU5953894A (en) | 1994-07-19 |
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