CA2151240A1 - Biophosphonate/estrogen therapy for treating and preventing bone loss - Google Patents
Biophosphonate/estrogen therapy for treating and preventing bone lossInfo
- Publication number
- CA2151240A1 CA2151240A1 CA002151240A CA2151240A CA2151240A1 CA 2151240 A1 CA2151240 A1 CA 2151240A1 CA 002151240 A CA002151240 A CA 002151240A CA 2151240 A CA2151240 A CA 2151240A CA 2151240 A1 CA2151240 A1 CA 2151240A1
- Authority
- CA
- Canada
- Prior art keywords
- estrogen
- bisphosphonate
- 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.)
- Abandoned
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
Abstract
Disclosed is a combination therapy for treating and for preventing bone loss by the use of estrogen and a bisphosphonate selected from: alendronate, clodronate, tiludronate, YM175, BM210995, or mixture thereof. Also described is a pharmaceutical composition of the above for carrying out the therapeutic method.
Description
2~12~
,,. TITLE OF THE INVENTION
BISPHOSPHONATE/ESTROGEN THERAPY FOR TREATING AND
PREVENTING BONE LOSS
The instant invention relates generally to the combination of estrogen and bi,sphosphonate.s and their use in bone growth and maturation. Specifically, the invention relates to the use of estrogen and bisphosphonates to inhibit bone resorption and promote net bone formation. Thi,s therapeutic combination will result in a decreased rate of bone resorption with either an increase or stabilization of bone mass.
BACKGROUND OF THE INVENTION
The normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of m~intenance of a constant mineral balance. The dual process is commonly called "bone turnover". In normal growing bones, the mineral deposition exceeds the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition, for instance due to malignancy or primary hyperparathyroidism, or in o.steoporosi.s. ln other pathological conditions the calcium deposition may take place in undesirable amounts and areas leading to e.g.
heterotopic calcification, osteoarthriti.s, kidney or bladder .stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens, act by reducing bone resorption in the osteoporotic patient. See the review article, British Medical Bulletin 46 (I ), p. 94-1 12 (1990).
Bisphosphonates are also known in the art as bone resorption inhibitors.
WO 94/14455 PCT/US93/12302 ~
21~ 2~Q
Alendronate, 4-amino- 1 -hydroxybutylidene- 1, I - ,, bispho,sphonic acid monosodium trihydrate, is described as ~
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, 4111 (1967) for it~ preparation.
Tiludronate, (1(4-chlorophenyl)thiomethylenel-bisphosphonic acid) (Sanofi) i~s described in U.S. Patent 4,~s76,24g issued October 24, 19~S9.
YM 175 ([(cycloheptylamino)methylenelbisphosphonic acid, disodium salt) by Yamanouchi is described in U.S. Patent 4,970,335 issued November 13, 1990.
BM 210995 (1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonate) by Boehringer-Mannheim - is described in U.S. Patent 4,927,~ 14 issued May 22, 1990.
A study by Proctor and Gamble (Norwich Eaton Pharmaceuticals) using risendronate, whose chemical name is sodium trihydrogen [l-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in combination with estrogen showed a positive effect on bone lo.ss in ovaricetomized rats (published in Abstracts 731 and 732 at the Fall 1992 ASBMR meeting in Minnesota.
The article, J. Clin. lnvest., Jan. 1992, ~9 (1), p. 74-7~ by J. Chow et al., describes the effect of estrogen on ovariectomized rats in which bone resorption was suppressed by parnidronate. They concluded that estrogen inhibits bone resorption and also stimulates bone formation.
The article, J. Bone Miner. Res. (USA) 1991, p. 3~7-394 by T.J. Wron.ski et al., describes studies in rats with estrogen and the bisphosphonates etidronate and risedronate. The studies showed that etidronate, (l-hydroxyethylidene)bisphosphonic acid, disodium salt, (Proctor and Gamble) has long term adver.se effects on bone mineralization.
~0 94/1445~ PCT/US93/12302 ~ ~5~2~0 - However, these studies did not sugge,st the use of other bispho,sphonate,s including alendronate.
There are situation,s where a female patient is undergoing estrogen therapy for a menopau,sal or postmenopau,sal-related condition, (e.g., vasomotor symptoms, atrophy of the vaginal mucosa, increased cardiovascular risk, etc.) and is also discovered to be suffering from osteoporosi,s (i.e. rarefaction of bone) or to be at ri,sk for developing osteoporosi,s.
0 Although e,strogens/hormone replacement therapy (HRT) are known to help prevent the development of o,steoporosis, there are instances, which are not at all uncommon, where HRT or a weak estrogen is prescribed at dosage.s which do not provide adequate protection against osteoporosi,s. There are also some women who continue to lose bone mass despite treatment with higher estrogen/HRT
doses or who have established osteoporosi,s but fail to increase their bone mass on estrogen/HRT alone.
What is de,sired in these cases is a therapy to optimally treat both the menopausal and postmenopausal-related conditions and the development of osteoporosis or osteoporosis n,sk concurrently.
SUMMARY OF THE INVENTION
The present invention di,scloses 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.
Also described is a pharmaceutical composition containing the combination described above in a pharmaceutically acceptable 3 o Carrler.
2~12~ --DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
By the term "e.strogen" as u,sed herein is meant " 17-beta estradiol" and includes those equivalent material~ contained in the MERCK INDEX - Eleventh Edition (19~s9). E,strogens, e.g. estradiol and its steroidal and non-steroidal e~uivalent~ which can be used herein include (page numbers taken from the above indicated MERCK
INDEX):
ESTROGEN
Nonsteroidal Benzestrol, 10~2 Broparoestrol, 143~
Chlorotrianisene, 2173 Dienestrol, 3094 Diethylstilbe~strol, 311 g Diethylstilbestrol Dipropionate, 3119 Dimestrol, 319g Fosfestrol, 416~S
Hexestrol, 4621 Methallenestril, 5~56 Methestrol, 5~
Tamoxifen, 9019 Steroidal Colpormon, 24g5 Conjugated Estrogenic Horrnones, 2504 Equilenin, 35~1 Equilin, 35~2 Estradiol, 3653 Estradiol Benzoate, 3655 Estradiol 17~-Cypionate, 3656 Estriol, 3659 ~WO 94/14455 PCT/US93/12302 21~4~
Estrone, 3660 Ethinyl Estradiol, 36~9 Me.stranol, 5~19 Moxestrol, 6203 Mytatrienediol, 6254 Progesterone, 77~S3 Quinestradiol, ~065 Quinestrol, ~s066 and including estrogen/progestin combinations.
By the term "bisphosphonates" as used herein is meant bisphosphonates of the structure:
R2 - C (P03H)2 Rl irl which R 1 is OH or H and R2 is an C 1 -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. Also included within the term "bisphosphonates" are the bisphosphonates described above, and those in the US Patents 4,732,99~; 4,~70,063; 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 ~nim~l~, and humans.
The term "inhibition of bone resorption" 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, 30 through direct or indirect alteration of osteoclast formation or activity.
Thus, the term "inhibitor of bone resorption" as used herein refers to agents that prevent bone loss by the direct or indirect alteration of osteoclast formation or activity.
WO 94/14455 PCT/US93/12302 ~
2~ ~12~
The term "osteogenically effective" means that amount which effects the turnover of mature bone. As used herein, an osteogenically effective dose is al,so "pharmaceutically effective."
The term "subject" as used herein refer.s to a living vertebrate ~nim~l such as a m~mm~l or bird in need of treatment, i.e., in need of bone repair or replacement. Such need arises locally in c~ses of bone fracture, non-union, defect, prosthesi~i implantation, and the like. Such need also ari.ses in cases of systemic bone disease, as in osteoporosis, osteoarthritis, Paget's disea.se, o.steomalacia, multiple myeloma and other forms of cancer, steroid therapy, and age-related loss of bone mass. Particularly preferred is a human female subject.
The term "treatment" or "treating" as used herein 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 elimin~te a disease state and/or the ,symptoms of a disease state, and a weakened and/or unhealthy state.
METHOD OF USE
Drugs which prevent bone loss and/or add back lo,st bone may be evaluated in the ovariectomized rat. This ~nim~l model is well established in the art (see, for example, Wronski, et al. (19~5) Calcif.
Tissue Int. 37:324-32~; Kimmel, et al. (1990) Calcif. Tissue Int.
46:101-110; and Durbridge, et al. (1990) Calcif. Tissue Int 47:383-387;
these references are hereby incorporated in their entirety). Wronski, et al. ((19g5) Calcif. Tissue lnt. 43:179-183)) describe the association of bone loss and bone turnover in the ovariectomized rat.
Pharmaceutical formulations of the invention which include a bone growth factor and/or an inhibitor of bone resorption for ~lmini~tration 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 ~ministration, including water, ,saline, Ringer's solution, Hank's solution, and solutions of glucose, lactose, ~WO 94/14455 ~CT/US93/12302 2 1 5 ~
r dextrose, ethanol, glycerol, albumin, and the like. These compo.sitions may optionally include .stabilizer~, antioxidants, antimicrobial~, preservatives, buffering agents, .surfactants, and other acce.ssory additives. The inhibitor of bone resorption may also be delivered in sustained release form from a suitable carrier.
A presently preferred vehicle comprises about 1 mg/ml serum albumin (species-specific) in phosphate-buffered saline (P~S) or isotonic citrate buffer. A thorough di.scussion of suitable vehicles for parenteral ~clministration may be found in E. W. Martin. "Remington'~
Pharmaceutical Science,s" (Mack Pub. Co., current edition section~
relating to the excipient vehicles and formulating being incorporated herein by reference to disclo.se such). Such formulations are generally known to those skilled in the art and are a-lministered systemically to provide systemic treatment.
The estrogen and bisphosphonate may be ~lmini.stered sequentially or concurrently in separate dosages or as a single composition to the subject. If administered sequentially, the period between the ~lmini~tration of the estrogen and bisphosphonate will typically be one week to one year, and optimally, one week to six months.
If the estrogen and bisphosphonate are ~lmini~tered a.s a single composition, 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. Furthermore, if ~mini~tered as a single composition the estrogen and bisphosphonate may be separate components of the composition, or they may be conjugated to each other. Methods for conjugating bone growth factor~
to other agents are described above.
The precise dosage necessary will vary with the age, size, sex and condition of the subject, the nature and severity of the disorder to be treated, and the like; thus, a precise effective amount cannot be specified in advance and will be determined by the caregiver. However, appropriate amounts may be determined by routine experimentation with ~nim~l models, as described below. In general terms, an effective WO 94/14455 PCT/US93/12302 ~
~ 21~112~
dose of estrogen for systemic treatment will range from about 0.001 !lg/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 !lg/kg of body weight and preferably about 10 ,ug/kg to about 200 g/kg of body weight.
Effective doses for local ~lministration would be about 0.001 ,ug to 1 mg per application site.
The methods and composition,s of the invention are useful o 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 lo,ss resulting from side effect,s of other medical treatment (such a,s steroids), and age-related los,s of bone 1 5 mass.
In accordance with one method of use the estrogen and bisphosphonate may be ~lmini.~tered systemically either orally and/or parenterally, including subcutaneous or intravenous injection.
Additionally, the estrogen and bisphosphonate make be delivered in .slow release form from a suitable carrier.
In accordance with another method of use, the estrogen may be ~lmini~tered locally to a specific area in need of bone growth or repair, with either the concomitant ~lmini~tration of the bi.sphosphonate at the site, or the ~lmini~tration of the bisphosphonate in a separate 2 vehicle, or the inhibitor of bone resorption may be provided locally with the ~lmini~tration of the estrogen in a separate vehicle. Thus, 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 carrier.s include hydrogels, controlled- or sustained-relea,se devices (e.g., an Alzet(~) minipump), f polylactic acid, and collagen matrice.s. Presently preferred carriers are formulations of atelopeptide collagen cont~ining particulate calcium phosphate mineral components, such combinations of homologous or xenographic fibrillar atelopeptide collagen (for example Zyderm(~
Collagen Implant, available from Collagen Corporation, Palo Alto, _WO 94/14455 PCT/US93/12302 -- ~ 21~2~
Calif.) with hydroxapatitetricalcium phosphate (HA-TCP, available from Zimmer, Inc., Warsaw, ln.). It is presently preferred to a(lminicter implant compositions cont~ining and/or an bi.sphosphonate in 5 a collagen/mineral mixture implant.
Estrogen and/or an bisphosphonate delivered in sustained-relea.se vehicles is also particularly useful for improving implant fixation, for example for improving in growth of new bone into a metal pro.sthesis in joint reconstruction and dental or orthopedic implants.
o Alternatively, 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. Alternatively, the estrogen can be used to 15 coat the implant, and the bisphosphonate can be ~mini~tered concomitantly or sequentially in a separate vehicle, and vice-versa.
In general, irnplant 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 20 0.01 ~lg/ml to 200 mg/ml in phosphate-buffered saline (PBS) con~ining 2 mg/ml serum albumin. The porous end of an implant is dipped in the solution and is airdried (or Iyophilized) or implanted imrnediately into the bony site. The viscosity of the coating solution is increased, if desired, by ~ ling hyaluronate at a final concentration of 0.1 mg/ml to 25 100 mg/ml or by ~ ling other pharmaceutically acceptable excipients.
Alternatively, the solution cont~ining the estrogen (and the bisphosphonate, if desired) is mixed with collagen gel or hllm~n collagen (e.g. Zyderm~) Collagen Implant, Collagen Corp., Palo alto, Calif.) to a final collagen concentration of 2 mg/ml to 100 mg/ml to 30 form a paste or gel, which is then used to coat the porous end of the implant device. 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 maximi7ing new bone formation into the implant while minimi7.ing the ingrowth of soft tissue into the implant site.
W O 94/14455 PCTrUS93/12302 ~
2 1 3 1 2 ~ ~
The pharmaceutical composition,s 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 ~lmini~tration or for sy.stemic use. The compo.sition.s are advantageously prepared together with inert carriers such as sugars (saccharose, glucose, lactose), starch and derivatives, cellulose and derivatives, gums, fatty acid.s and their salts, polyalcohols, talc, aromatic esters.
Some typical pharmaceutical formulations cont~ining 4-amino-l-hydroxybutane-l,l-diphosphonic acid monosodium salt trihydrate are shown here below:
TABLE
OPERCOLATE~ (~APSULES
,,. TITLE OF THE INVENTION
BISPHOSPHONATE/ESTROGEN THERAPY FOR TREATING AND
PREVENTING BONE LOSS
The instant invention relates generally to the combination of estrogen and bi,sphosphonate.s and their use in bone growth and maturation. Specifically, the invention relates to the use of estrogen and bisphosphonates to inhibit bone resorption and promote net bone formation. Thi,s therapeutic combination will result in a decreased rate of bone resorption with either an increase or stabilization of bone mass.
BACKGROUND OF THE INVENTION
The normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of m~intenance of a constant mineral balance. The dual process is commonly called "bone turnover". In normal growing bones, the mineral deposition exceeds the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition, for instance due to malignancy or primary hyperparathyroidism, or in o.steoporosi.s. ln other pathological conditions the calcium deposition may take place in undesirable amounts and areas leading to e.g.
heterotopic calcification, osteoarthriti.s, kidney or bladder .stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens, act by reducing bone resorption in the osteoporotic patient. See the review article, British Medical Bulletin 46 (I ), p. 94-1 12 (1990).
Bisphosphonates are also known in the art as bone resorption inhibitors.
WO 94/14455 PCT/US93/12302 ~
21~ 2~Q
Alendronate, 4-amino- 1 -hydroxybutylidene- 1, I - ,, bispho,sphonic acid monosodium trihydrate, is described as ~
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, 4111 (1967) for it~ preparation.
Tiludronate, (1(4-chlorophenyl)thiomethylenel-bisphosphonic acid) (Sanofi) i~s described in U.S. Patent 4,~s76,24g issued October 24, 19~S9.
YM 175 ([(cycloheptylamino)methylenelbisphosphonic acid, disodium salt) by Yamanouchi is described in U.S. Patent 4,970,335 issued November 13, 1990.
BM 210995 (1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonate) by Boehringer-Mannheim - is described in U.S. Patent 4,927,~ 14 issued May 22, 1990.
A study by Proctor and Gamble (Norwich Eaton Pharmaceuticals) using risendronate, whose chemical name is sodium trihydrogen [l-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in combination with estrogen showed a positive effect on bone lo.ss in ovaricetomized rats (published in Abstracts 731 and 732 at the Fall 1992 ASBMR meeting in Minnesota.
The article, J. Clin. lnvest., Jan. 1992, ~9 (1), p. 74-7~ by J. Chow et al., describes the effect of estrogen on ovariectomized rats in which bone resorption was suppressed by parnidronate. They concluded that estrogen inhibits bone resorption and also stimulates bone formation.
The article, J. Bone Miner. Res. (USA) 1991, p. 3~7-394 by T.J. Wron.ski et al., describes studies in rats with estrogen and the bisphosphonates etidronate and risedronate. The studies showed that etidronate, (l-hydroxyethylidene)bisphosphonic acid, disodium salt, (Proctor and Gamble) has long term adver.se effects on bone mineralization.
~0 94/1445~ PCT/US93/12302 ~ ~5~2~0 - However, these studies did not sugge,st the use of other bispho,sphonate,s including alendronate.
There are situation,s where a female patient is undergoing estrogen therapy for a menopau,sal or postmenopau,sal-related condition, (e.g., vasomotor symptoms, atrophy of the vaginal mucosa, increased cardiovascular risk, etc.) and is also discovered to be suffering from osteoporosi,s (i.e. rarefaction of bone) or to be at ri,sk for developing osteoporosi,s.
0 Although e,strogens/hormone replacement therapy (HRT) are known to help prevent the development of o,steoporosis, there are instances, which are not at all uncommon, where HRT or a weak estrogen is prescribed at dosage.s which do not provide adequate protection against osteoporosi,s. There are also some women who continue to lose bone mass despite treatment with higher estrogen/HRT
doses or who have established osteoporosi,s but fail to increase their bone mass on estrogen/HRT alone.
What is de,sired in these cases is a therapy to optimally treat both the menopausal and postmenopausal-related conditions and the development of osteoporosis or osteoporosis n,sk concurrently.
SUMMARY OF THE INVENTION
The present invention di,scloses 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.
Also described is a pharmaceutical composition containing the combination described above in a pharmaceutically acceptable 3 o Carrler.
2~12~ --DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
By the term "e.strogen" as u,sed herein is meant " 17-beta estradiol" and includes those equivalent material~ contained in the MERCK INDEX - Eleventh Edition (19~s9). E,strogens, e.g. estradiol and its steroidal and non-steroidal e~uivalent~ which can be used herein include (page numbers taken from the above indicated MERCK
INDEX):
ESTROGEN
Nonsteroidal Benzestrol, 10~2 Broparoestrol, 143~
Chlorotrianisene, 2173 Dienestrol, 3094 Diethylstilbe~strol, 311 g Diethylstilbestrol Dipropionate, 3119 Dimestrol, 319g Fosfestrol, 416~S
Hexestrol, 4621 Methallenestril, 5~56 Methestrol, 5~
Tamoxifen, 9019 Steroidal Colpormon, 24g5 Conjugated Estrogenic Horrnones, 2504 Equilenin, 35~1 Equilin, 35~2 Estradiol, 3653 Estradiol Benzoate, 3655 Estradiol 17~-Cypionate, 3656 Estriol, 3659 ~WO 94/14455 PCT/US93/12302 21~4~
Estrone, 3660 Ethinyl Estradiol, 36~9 Me.stranol, 5~19 Moxestrol, 6203 Mytatrienediol, 6254 Progesterone, 77~S3 Quinestradiol, ~065 Quinestrol, ~s066 and including estrogen/progestin combinations.
By the term "bisphosphonates" as used herein is meant bisphosphonates of the structure:
R2 - C (P03H)2 Rl irl which R 1 is OH or H and R2 is an C 1 -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. Also included within the term "bisphosphonates" are the bisphosphonates described above, and those in the US Patents 4,732,99~; 4,~70,063; 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 ~nim~l~, and humans.
The term "inhibition of bone resorption" 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, 30 through direct or indirect alteration of osteoclast formation or activity.
Thus, the term "inhibitor of bone resorption" as used herein refers to agents that prevent bone loss by the direct or indirect alteration of osteoclast formation or activity.
WO 94/14455 PCT/US93/12302 ~
2~ ~12~
The term "osteogenically effective" means that amount which effects the turnover of mature bone. As used herein, an osteogenically effective dose is al,so "pharmaceutically effective."
The term "subject" as used herein refer.s to a living vertebrate ~nim~l such as a m~mm~l or bird in need of treatment, i.e., in need of bone repair or replacement. Such need arises locally in c~ses of bone fracture, non-union, defect, prosthesi~i implantation, and the like. Such need also ari.ses in cases of systemic bone disease, as in osteoporosis, osteoarthritis, Paget's disea.se, o.steomalacia, multiple myeloma and other forms of cancer, steroid therapy, and age-related loss of bone mass. Particularly preferred is a human female subject.
The term "treatment" or "treating" as used herein 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 elimin~te a disease state and/or the ,symptoms of a disease state, and a weakened and/or unhealthy state.
METHOD OF USE
Drugs which prevent bone loss and/or add back lo,st bone may be evaluated in the ovariectomized rat. This ~nim~l model is well established in the art (see, for example, Wronski, et al. (19~5) Calcif.
Tissue Int. 37:324-32~; Kimmel, et al. (1990) Calcif. Tissue Int.
46:101-110; and Durbridge, et al. (1990) Calcif. Tissue Int 47:383-387;
these references are hereby incorporated in their entirety). Wronski, et al. ((19g5) Calcif. Tissue lnt. 43:179-183)) describe the association of bone loss and bone turnover in the ovariectomized rat.
Pharmaceutical formulations of the invention which include a bone growth factor and/or an inhibitor of bone resorption for ~lmini~tration 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 ~ministration, including water, ,saline, Ringer's solution, Hank's solution, and solutions of glucose, lactose, ~WO 94/14455 ~CT/US93/12302 2 1 5 ~
r dextrose, ethanol, glycerol, albumin, and the like. These compo.sitions may optionally include .stabilizer~, antioxidants, antimicrobial~, preservatives, buffering agents, .surfactants, and other acce.ssory additives. The inhibitor of bone resorption may also be delivered in sustained release form from a suitable carrier.
A presently preferred vehicle comprises about 1 mg/ml serum albumin (species-specific) in phosphate-buffered saline (P~S) or isotonic citrate buffer. A thorough di.scussion of suitable vehicles for parenteral ~clministration may be found in E. W. Martin. "Remington'~
Pharmaceutical Science,s" (Mack Pub. Co., current edition section~
relating to the excipient vehicles and formulating being incorporated herein by reference to disclo.se such). Such formulations are generally known to those skilled in the art and are a-lministered systemically to provide systemic treatment.
The estrogen and bisphosphonate may be ~lmini.stered sequentially or concurrently in separate dosages or as a single composition to the subject. If administered sequentially, the period between the ~lmini~tration of the estrogen and bisphosphonate will typically be one week to one year, and optimally, one week to six months.
If the estrogen and bisphosphonate are ~lmini~tered a.s a single composition, 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. Furthermore, if ~mini~tered as a single composition the estrogen and bisphosphonate may be separate components of the composition, or they may be conjugated to each other. Methods for conjugating bone growth factor~
to other agents are described above.
The precise dosage necessary will vary with the age, size, sex and condition of the subject, the nature and severity of the disorder to be treated, and the like; thus, a precise effective amount cannot be specified in advance and will be determined by the caregiver. However, appropriate amounts may be determined by routine experimentation with ~nim~l models, as described below. In general terms, an effective WO 94/14455 PCT/US93/12302 ~
~ 21~112~
dose of estrogen for systemic treatment will range from about 0.001 !lg/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 !lg/kg of body weight and preferably about 10 ,ug/kg to about 200 g/kg of body weight.
Effective doses for local ~lministration would be about 0.001 ,ug to 1 mg per application site.
The methods and composition,s of the invention are useful o 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 lo,ss resulting from side effect,s of other medical treatment (such a,s steroids), and age-related los,s of bone 1 5 mass.
In accordance with one method of use the estrogen and bisphosphonate may be ~lmini.~tered systemically either orally and/or parenterally, including subcutaneous or intravenous injection.
Additionally, the estrogen and bisphosphonate make be delivered in .slow release form from a suitable carrier.
In accordance with another method of use, the estrogen may be ~lmini~tered locally to a specific area in need of bone growth or repair, with either the concomitant ~lmini~tration of the bi.sphosphonate at the site, or the ~lmini~tration of the bisphosphonate in a separate 2 vehicle, or the inhibitor of bone resorption may be provided locally with the ~lmini~tration of the estrogen in a separate vehicle. Thus, 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 carrier.s include hydrogels, controlled- or sustained-relea,se devices (e.g., an Alzet(~) minipump), f polylactic acid, and collagen matrice.s. Presently preferred carriers are formulations of atelopeptide collagen cont~ining particulate calcium phosphate mineral components, such combinations of homologous or xenographic fibrillar atelopeptide collagen (for example Zyderm(~
Collagen Implant, available from Collagen Corporation, Palo Alto, _WO 94/14455 PCT/US93/12302 -- ~ 21~2~
Calif.) with hydroxapatitetricalcium phosphate (HA-TCP, available from Zimmer, Inc., Warsaw, ln.). It is presently preferred to a(lminicter implant compositions cont~ining and/or an bi.sphosphonate in 5 a collagen/mineral mixture implant.
Estrogen and/or an bisphosphonate delivered in sustained-relea.se vehicles is also particularly useful for improving implant fixation, for example for improving in growth of new bone into a metal pro.sthesis in joint reconstruction and dental or orthopedic implants.
o Alternatively, 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. Alternatively, the estrogen can be used to 15 coat the implant, and the bisphosphonate can be ~mini~tered concomitantly or sequentially in a separate vehicle, and vice-versa.
In general, irnplant 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 20 0.01 ~lg/ml to 200 mg/ml in phosphate-buffered saline (PBS) con~ining 2 mg/ml serum albumin. The porous end of an implant is dipped in the solution and is airdried (or Iyophilized) or implanted imrnediately into the bony site. The viscosity of the coating solution is increased, if desired, by ~ ling hyaluronate at a final concentration of 0.1 mg/ml to 25 100 mg/ml or by ~ ling other pharmaceutically acceptable excipients.
Alternatively, the solution cont~ining the estrogen (and the bisphosphonate, if desired) is mixed with collagen gel or hllm~n collagen (e.g. Zyderm~) Collagen Implant, Collagen Corp., Palo alto, Calif.) to a final collagen concentration of 2 mg/ml to 100 mg/ml to 30 form a paste or gel, which is then used to coat the porous end of the implant device. 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 maximi7ing new bone formation into the implant while minimi7.ing the ingrowth of soft tissue into the implant site.
W O 94/14455 PCTrUS93/12302 ~
2 1 3 1 2 ~ ~
The pharmaceutical composition,s 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 ~lmini~tration or for sy.stemic use. The compo.sition.s are advantageously prepared together with inert carriers such as sugars (saccharose, glucose, lactose), starch and derivatives, cellulose and derivatives, gums, fatty acid.s and their salts, polyalcohols, talc, aromatic esters.
Some typical pharmaceutical formulations cont~ining 4-amino-l-hydroxybutane-l,l-diphosphonic acid monosodium salt trihydrate are shown here below:
TABLE
OPERCOLATE~ (~APSULES
4-amino-1-hydroxybutan-1,1- mg 6.5 mg 2.5 biphosphonicacid, sodium salt trihydrate Estradiol 3.0 2.0 Lactose 11 0.0 11 0.0 Avucek PhlOl 80.0 80.0 Aldisol~ Type A 2.0 2.0 Magnesium Stearate 1.0 1.0 Total Total Weight 202.5 Weight 197.5 I I _ EFFERVESCENT
GRANULATES
4-amino- 1 -hydroxybutan- 1,1- mg 5.0 mg10.0 biphosphonic acid Estradiol 3.0 3.0 Anhydrous Sodium Carbonate 12.0 12.0 Sodium Bicarbonate 63.0 63.0 Anhydrous Citric Acid 110.0 110.0 SodiumSaccharinate 5.0 5.0 Saccharose 493.0 493.0 Dehydrated Lemon Juice 55.0 55.0 Natural Essence of Lemon 2.0 2.0 Total Weight 74~s 753 FORMULATIONS
SUITABLE FOR ~NJECTION
4-amino- 1 -hydroxybutan- 1,1- mg 0.5 mg 1.00 biphosphonic acid Estradiol 0.42 0.84 Sodium Hydroxide 0.25 0.25 Sodium Chloride 8.40 16.30 Purified Water q h ml 1.0 ml 12.0 -
GRANULATES
4-amino- 1 -hydroxybutan- 1,1- mg 5.0 mg10.0 biphosphonic acid Estradiol 3.0 3.0 Anhydrous Sodium Carbonate 12.0 12.0 Sodium Bicarbonate 63.0 63.0 Anhydrous Citric Acid 110.0 110.0 SodiumSaccharinate 5.0 5.0 Saccharose 493.0 493.0 Dehydrated Lemon Juice 55.0 55.0 Natural Essence of Lemon 2.0 2.0 Total Weight 74~s 753 FORMULATIONS
SUITABLE FOR ~NJECTION
4-amino- 1 -hydroxybutan- 1,1- mg 0.5 mg 1.00 biphosphonic acid Estradiol 0.42 0.84 Sodium Hydroxide 0.25 0.25 Sodium Chloride 8.40 16.30 Purified Water q h ml 1.0 ml 12.0 -
Claims (19)
1. A method for treating and/or preventing bone loss in a subject, comprising administering a pharmaceutically effective dose of estrogen and a pharmaceutically effective dose of a bisphosphonate selected from the group consisting of: alendronate, clodronate, tiludronate, YM 175, BM 210995, or mixture thereof.
2. The method of Claim 1 wherein the bisphosphonate is alendronate.
3. The method of Claim 1 wherein the subject is human.
4. The method of Claim 1 wherein the estrogen and bisphosphonate are administered sequentially.
5. The method of Claim 1 wherein the estrogen and bisphosphonate are administered concurrently.
6. The method of Claim 1 wherein the bone loss is osteoporosis-related.
7. The method of Claim 1, wherein the bone loss is due to disuse.
8. The method of Claim 1, wherein the bone loss is age-related.
9. The method of Claim 1, wherein the bone loss is related to steroid therapy.
10. The method of Claim 1, wherein the bone loss is rheumatoid-related.
11. The method of Claim l, wherein the bone loss is related to Paget's disease.
12. The method of Claim l, wherein the bone loss is related to cancer.
13. The method of Claim 12, wherein the cancer is multiple myeloma.
14. The method of Claim 1, wherein the treatment is prophylactic.
15. A composition for inducing net bone formation in a subject, comprising a pharmaceutically effective dose of estrogen and a pharmaceutically effective amount of a bisphosphonate selected from the group consisting of: alendronate, clodronate, YM175, BM 210995, or a mixture thereof.
16. The composition of Claim 15, wherein the molar ratio of estrogen to bisphosphonate, is 50:1 to 1:50.
17. The composition of Claim 15, wherein the molar ratio of estrogen to bisphosphonate, is 5:1 to 1:5.
18. The composition of Claim 15, wherein the estrogen is conjugated to the bisphosphonate.
19. The composition of Claim 15, further comprising a sustained-release vehicle.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99641892A | 1992-12-23 | 1992-12-23 | |
| US996,418 | 1992-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2151240A1 true CA2151240A1 (en) | 1994-07-07 |
Family
ID=25542895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002151240A Abandoned CA2151240A1 (en) | 1992-12-23 | 1993-12-17 | Biophosphonate/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) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL173026B1 (en) * | 1993-05-15 | 1998-01-30 | Boehringer Mannheim Gmbh | Tablet of improved biological accessibility, containing dichloromethylene biphosphonic 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 |
| ZA956029B (en) * | 1994-07-22 | 1997-01-20 | Lilly Co Eli | Combination treatment for inhibiting bone loss |
| US5780455A (en) * | 1994-08-24 | 1998-07-14 | Merck & Co., Inc. | Intravenous alendronate formulations |
| AU713824B2 (en) * | 1995-05-12 | 1999-12-09 | Merck Sharp & Dohme Corp. | 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 |
| IL120270A0 (en) * | 1996-02-28 | 1997-06-10 | Pfizer | Combination therapy to treat osteoporosis |
| IL120265A0 (en) * | 1996-02-28 | 1997-06-10 | Pfizer | Combination therapy to treat osteoporosis - polyphosphonates or progestins and estrogen agonists |
| US5853759A (en) * | 1996-05-17 | 1998-12-29 | Merck & Co.. Inc. | Effervescent alendronate formulation |
| DE69726879T2 (en) * | 1996-05-17 | 2004-10-14 | Merck & Co., Inc. | BIPHOSPHONATE FORMULATION WITH EFFECT |
| EP1378234A1 (en) * | 1996-05-17 | 2004-01-07 | MERCK & CO. INC. | Effervescent bisphosphonate formulation |
| 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 |
| EP0949928A4 (en) * | 1996-11-25 | 2000-09-13 | Merck & Co Inc | Androgenic and bisphosphonic agents coadministered to treat diseases |
| 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 |
| WO2000064516A1 (en) * | 1999-04-22 | 2000-11-02 | Hydromed Sciences A Division Of Gp Strategies Corporation | 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 |
| CA2435552C (en) * | 2001-02-06 | 2010-04-27 | The Royal Alexandra Hospital For Children | A drug for the treatment of osteonecrosis and for the management of patients at risk of developing osteonecrosis |
| US20040157798A1 (en) * | 2001-04-03 | 2004-08-12 | Little David Graham | 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 |
Family Cites Families (4)
| 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 |
| DE4029499A1 (en) * | 1990-09-18 | 1992-03-19 | Boehringer Mannheim Gmbh | NEW 17- (BETA) -OESTRADIOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| EP0496520A1 (en) * | 1991-01-22 | 1992-07-29 | Merck & Co. Inc. | Novel bone acting agents |
| DK0573604T3 (en) * | 1991-02-26 | 1995-05-29 | Procter & Gamble Pharma | Method of treating osteoporosis |
-
1993
- 1993-12-17 CA CA002151240A patent/CA2151240A1/en not_active Abandoned
- 1993-12-17 JP JP6515312A patent/JPH08505142A/en active Pending
- 1993-12-17 AU AU59538/94A patent/AU5953894A/en not_active Abandoned
- 1993-12-17 WO PCT/US1993/012302 patent/WO1994014455A1/en not_active Application Discontinuation
- 1993-12-17 EP EP94905419A patent/EP0675723A4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP0675723A4 (en) | 1998-08-05 |
| AU5953894A (en) | 1994-07-19 |
| EP0675723A1 (en) | 1995-10-11 |
| JPH08505142A (en) | 1996-06-04 |
| WO1994014455A1 (en) | 1994-07-07 |
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