EP0929216A4 - Methode destinee a traiter des maladies post-menopausiques, dont l'osteoporose - Google Patents

Methode destinee a traiter des maladies post-menopausiques, dont l'osteoporose

Info

Publication number
EP0929216A4
EP0929216A4 EP97940773A EP97940773A EP0929216A4 EP 0929216 A4 EP0929216 A4 EP 0929216A4 EP 97940773 A EP97940773 A EP 97940773A EP 97940773 A EP97940773 A EP 97940773A EP 0929216 A4 EP0929216 A4 EP 0929216A4
Authority
EP
European Patent Office
Prior art keywords
idoxifene
estrogen
bone
osteoporosis
ere
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.)
Withdrawn
Application number
EP97940773A
Other languages
German (de)
English (en)
Other versions
EP0929216A1 (fr
Inventor
Jeremy N Bradbeer
Maxine Gowen
Mitchell Dowsett
Michael Jarman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0929216A1 publication Critical patent/EP0929216A1/fr
Publication of EP0929216A4 publication Critical patent/EP0929216A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to therapeutic agents that bind to the estrogen receptor and have been found to be useful in the treatment of osteoporosis.
  • ERT estrogen replacement therapy
  • An ideal therapy would retain the desirable skeletal and cardiovascular effects of estrogen without having the unwanted effects on reproductive tissues.
  • Tamoxifen is an antiestrogen that has been shown to lower cholesterol levels and protect against bone loss in postmenopausal women. Tamoxifen is also effective in the ovariectomized rat model of osteoporosis.
  • tamoxifen has been shown to have unwanted side effects, in particular by causing endometrial hype ⁇ lasia and endometrial cancer. See 1. Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, Feyzi J, DeMets DL. (19 1). Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Annals of Internal Medicine, 115, 860-864. 2. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL. ( 1992). Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer.
  • This invention provides a method for the prevention and treatment of postmenopausal diseases without having an overt uterotrophic effect.
  • the method comprises administering to a human in need thereof an effective amount of a compound of formula I
  • X represents 3- or 4- iodo or bromo and the Rl and R ⁇ symbols, which may be the same or different, represent C1.3 alkyl, especially methyl or ethyl, groups or R! represents a hydrogen atom and R ⁇ a Cj_3 alkyl group or R 1 and R ⁇ together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6 ring atoms, especially a pyrrolidino, piperidino, 4- methylpiperidino or mo ⁇ holino group, and their pharmaceutically acceptable acid addition salts.
  • the present invention is a therapeutic method for treating postmenopausal diseases with a group of compounds that have been previously prepared and evaluated as effective in the treatment of estrogen receptor-positive breast cancer. These compounds are described in formula I above and in U.S. patent 4,839,155.
  • the preferred compound for the described method of treatment is
  • postmenopausal diseases refers to osteoporosis and atherosclerotic cardiovascular diseases such as myocardial infarction and stroke and an increase in plasma cholestrerol.
  • the method of this invention is useful in preventing bone loss and in producing a plasma lipid profile that is associated with a reduced risk of atherosclerosis.
  • the ability to prevent bone loss is assessed by studies in an ovariectomized rat model of osteoporosis and by studies in postmenopausal women.
  • BMD Baseline bone mineral density
  • DXA dual energy x-ray abso ⁇ tiometry
  • OVX bilaterally ovariectomized
  • Idoxifene was prepared for oral dosing as a suspension in a 1 % aqueous solution of carboxymethyl cellulose. Rats were dosed by oral gavage once daily. In each experiment one OVX group and the sham group received oral dosing vehicle by gavage once daily. Dosing commenced on the day following surgery.
  • Plasma cholesterol levels were determined after 2 weeks of treatment.
  • Lumbar and tibial BMDs were measured at 1 month intervals. The animals were sacrificed, the uteri removed and the wet weight determined. Tibiae were collected post mortem and embedded and sectioned for histomo ⁇ hometry (15). Cancellous bone area and perimeter were measured in the secondary spongiosa, 1.2 mm from the growth plate. Cancellous bone area (Cn.B. Ar) was expressed as a percent of the medullary area. The secondary structural parameters, trabecular width, trabecular number and trabecular separation, were calculated from the primary area and perimeter measurements using equations developed by Parfitt et al. Initial dose-ranging study of the effect of idoxifene on bone loss, plasma cholesterol and uterine weight in the ovariectomized rat model of osteoporosis.
  • the aim of this study was to determine the optimal dose of idoxifene for the prevention of bone loss in the OVX rat model of osteoporosis.
  • BMD was measured after 1, 2 and 3 months of treatment.
  • the femora and vertebrae were removed for the ex vivo measurement of BMD (femur only) and mechanical testing.
  • Idoxifene was dosed at 2, 8, 40 and 200 micrograms/kg d.
  • the no-effect dose of idoxifene was 2 ⁇ g/kg according to all measured parameters.
  • Bone mineral density measured ex vivo showed that 200 ⁇ g/kg idoxifene maintained proximal femoral BMD at the level of sham controls. This dose also maintained femoral mid-shaft medullary cross-sectional area at the level of sham controls, an indication that idoxifene prevents cortical as well as cancellous bone loss. Idoxifene did not adversely affect the mechanical strength of either the femoral diaphysis in a 3-point bending test or the L2 vertebral body in an axial compression test.
  • Histomo ⁇ hometry revealed a small but non-significant effect of idoxifene on proximal tibial cancellous bone area after 3 months of treatment , which was in agreement with BMD measurements. There were no differences between any of the groups with respect to trabecular width. Despite its lack of effect on tibial cancellous bone area in the long term, activity of idoxifene at doses as low as 40 ⁇ g/kg were apparent with respect to trabecular number and separation. Idoxifene (200 ⁇ g/kg) significantly reduced plasma cholesterol (figure 5). After 3 months of treatment, all doses of idoxifene caused a very slight but statistically significant increase in uterine weight.
  • the aim of this study was to determine the optimal dose of idoxifene for the prevention of bone loss in the OVX rat model of osteoporosis.
  • BMD was measured at 1 month and treatment continued for a further 2 weeks before collection of the uteri and tibiae.
  • Histomo ⁇ hometry revealed that idoxifene optimally prevented OVX- induced loss of cancellous bone at 500 ⁇ g/kg. Prevention of OVX-induced reduction in trabecular width occured significantly at 200 and 500 ⁇ g/kg idoxifene. Trabecular number was significantly preserved at 500 and 1000 ⁇ g/kg idoxifene. Idoxifene at 200- 1000 ⁇ g/kg significantly prevented the OVX-induced increase in trabecular separation.
  • the dose 500 ⁇ g/kg of idoxifene was consistently identified by all measured parameters as optimal after 6 weeks of treatment in the OVX rat.
  • the optimal dose of idoxifene was found to be 500 ⁇ g/kg.
  • the minimally effective dose for prevention of bone loss in the spine was 200 ⁇ g/kg and 100 ⁇ g/kg for its cholesterol-lowering effect.
  • the bone-protective and cholesterol-lowering effects of idoxifene are useful in the prevention of postmenopausal diseases without having an overt uterotrophic effect.
  • HDL/LDL ratio 2.2 (1.6) 7.1 (2.6) 5.2 (2.1) 21.7 (3.1)** lipoprotein (a) 5.0 (3.0) -2.0 (6.0) 1.0 (4.0) -6.0 (4.0) triglycerides 1.3 (3.8) 1.8 (3.9) -3.2 (3.6) 3.8 (3.8)
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or coloring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmacuetical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmacuetical carrier(s) routinely used for preparing solid formulations.
  • such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • a typical suppository composition comprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats.
  • a typical transdermal formulation comprises a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane.
  • the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts.
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting and bodying agents, as for example, polyethylene glycols; antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride; antioxidants such as sodium metabisulfite; and other onventional . ingredients such as sorbitan monolaurate.
  • the composition is in unit dose form.
  • Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficiacious, non- toxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably .1 - 100 mg/kg.
  • the selected dose is administered to a human patient in need of treatment or prevention of osteoporosis or in the lowering of plasma cholesterol or prevention of cardiovascular disease from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
  • Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound. Lower dosages are used generally for parenteral administration. Oral administration is used when safe, effective, and convenient for the patient.
  • Example ⁇ An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelating solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • Example 4 This experiment was conducted to compare the mechanism of action of idoxifene and raloxifene in osteoblasts.
  • idoxifene like estrogen, is a pure agonist through the ERE in osteoblasts.
  • the potency of agonist action was similar between the natural steroid hormone estrogen and idoxifene.
  • Raloxifene at the same concentrations as idoxifene (0.01 to IO ⁇ M), gave an extremely weak signal, which was of similar magnitude to the to vehicle control, through the ERE.
  • the renilla-Luciferase vector was used to correct for transfection efficiency using the dual-luciferase detection method (Promega, Madison, WI). DNA was introduced into rat osteosarcoma (Ros 17/2.8) cells by the lipofectin method (Life Technologies, Gaithersburg, MD). Cells were co-transfected with 2 ⁇ g per well in 6-well plates and 140ng per well in 24-well plates of MMTV ERE-Luc and 25ng of the control renilla-Luciferase vector (pRL-CMV).
  • Transfection efficiency was corrected for by co-transfection with a renilla-Luciferase vector, which utilizes a different substrate, coelenterazine, for its bioluminescent readout (Promega, Madison WI). Cells were incubated overnight. Transfection medium was then removed and cells were incubated for 48 with or without hormones. Cells were washed in phosphate buffered saline and then lysed with 500 ⁇ l/well lx passive lysis buffer (PLB) for 15 minutes while roc-king sample on a rocking platform. Lysates were centrifuged for 30secs. at 12,000g and the clear lysate was transferred to a tube prior to reporter enzyme analysis.
  • PLB passive lysis buffer
  • Luciferase activity provides a surrogate of transcriptional activation of estrogen responsive gene that contains the estrogen response element (ERE). Therefore upregulation of luciferase activity is indicative of an agonist effect, whereas down-regulation indicates antagonism through the ERE.
  • Idoxifene is an agonist through the estrogen response element (ERE) in osteoblasts.
  • raloxifene is an antagonist through the ERE in osteoblasts at the doses tested, which suggests a distinct mechanism for the bone sparing effects seen with raloxifene.
  • raloxifene is able to exert its biological effect through a non-ERE containing sequence present on the 5'-untranslated region of the human TGF ⁇ 3 promoter.
  • raloxifene inhibited the ERE -containing vitellogenin promoter expression and exhibited therefore pure estrogen antagonism.
  • the raloxifene response element (Yang, N, N., Venugopalan, M., Hardikar, S., and Glasebrook, A. (1996) Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene Science 273: 1222-1225) is not present on the same genes as the ERE suggesting modulation through this response element will result in effects on different genes. This distinguishes the mechanism of action of idoxifene from that of the selective- estrogen receptor modulator (SERM) raloxifene and aligns idoxifene to the more classic estrogenic type mechanism exerting its biological agonist effect in osteoblasts through the ERE.
  • SERM selective- estrogen receptor modulator
  • the effects of idoxifene and estrogen are specific to reporter gene constructs that carry the classical ERE. This system was shown to be sensitive to cell specific factors and is thus a valid model for effects on endogenous gene transcription.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne une nouvelle méthode destinée à traiter l'ostéoporose. L'idoxifène est le composé préféré.
EP97940773A 1996-09-06 1997-09-03 Methode destinee a traiter des maladies post-menopausiques, dont l'osteoporose Withdrawn EP0929216A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US2543996P 1996-09-06 1996-09-06
US25439P 1996-09-06
US5066697P 1997-06-24 1997-06-24
US50666P 1997-06-24
PCT/US1997/015474 WO1998009519A1 (fr) 1996-09-06 1997-09-03 Methode destinee a traiter des maladies post-menopausiques, dont l'osteoporose

Publications (2)

Publication Number Publication Date
EP0929216A1 EP0929216A1 (fr) 1999-07-21
EP0929216A4 true EP0929216A4 (fr) 2001-04-04

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Family Applications (2)

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EP97942388A Withdrawn EP0927029A4 (fr) 1996-09-06 1997-09-03 Procedes nouveaux
EP97940773A Withdrawn EP0929216A4 (fr) 1996-09-06 1997-09-03 Methode destinee a traiter des maladies post-menopausiques, dont l'osteoporose

Family Applications Before (1)

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EP97942388A Withdrawn EP0927029A4 (fr) 1996-09-06 1997-09-03 Procedes nouveaux

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EP (2) EP0927029A4 (fr)
JP (2) JP2002515046A (fr)
KR (2) KR20000068473A (fr)
CN (2) CN1236313A (fr)
AR (1) AR008155A1 (fr)
AU (2) AU4409797A (fr)
BR (2) BR9711676A (fr)
CA (2) CA2264943A1 (fr)
CO (2) CO5070658A1 (fr)
CZ (1) CZ76699A3 (fr)
IL (1) IL128645A0 (fr)
NO (2) NO991097D0 (fr)
PL (2) PL332278A1 (fr)
TR (2) TR199900506T2 (fr)
TW (1) TW411273B (fr)
WO (2) WO1998009619A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5749998A (en) * 1997-02-11 1998-08-26 Novo Nordisk A/S Methods for treatment or prophylaxis of menopausal symptoms
GB9827121D0 (en) * 1998-12-09 1999-02-03 Orion Corp Agent for lowering endothelin levels
DE19905961A1 (de) * 1999-02-12 2000-08-17 Stefan Neubauer Verwendung von Östrogenen zur Behandlung der Herzinsuffizienz
US6528681B2 (en) * 2000-04-05 2003-03-04 Bristol-Meyers Squibb Pharma Company Halogenated triphenylethylene derivatives as selective estrogen receptor modulators
TWI303990B (en) 2000-10-17 2008-12-11 Pfizer Prod Inc New use of estrogen agonists/antagonists for improving vascular health

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1997031640A1 (fr) * 1996-02-28 1997-09-04 Pfizer Inc. Therapie combinee de l'osteoporose

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GB2196003A (en) * 1986-09-11 1988-04-20 Nat Res Dev Iodo-and bromo-tamoxifen derivatives
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US6197789B1 (en) * 1995-06-07 2001-03-06 Neorx Corporation Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
US5681835A (en) * 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US5604248A (en) * 1994-05-05 1997-02-18 Eli Lilly And Company Method for minimizing the uterotrophic effect of tamoxifen and tamoxifen analogs
US5470883A (en) * 1994-05-23 1995-11-28 Stromberg; Brent V. Method of treating peripheral vasoconstriction with tamoxifen citrate
US6069175A (en) * 1996-11-15 2000-05-30 Pfizer Inc. Estrogen agonist/antagonists treatment of atherosclerosis

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Publication number Priority date Publication date Assignee Title
WO1997031640A1 (fr) * 1996-02-28 1997-09-04 Pfizer Inc. Therapie combinee de l'osteoporose

Non-Patent Citations (4)

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Title
EVANS G L ET AL: "Tissue-selective actions of estrogen analogs.", BONE (NEW YORK), vol. 17, no. 4 SUPPL., 1995, pages 181S - 190S, XP002115406, ISSN: 8756-3282 *
JORDAN V C: "ALTERNATE ANTIESTROGENS AND APPROACHES TO THE PREVENTION OF BREAST CANCER", JOURNAL OF CELLULAR BIOCHEMISTRY,US,WILEY-LISS INC, vol. 58, no. SUPPL. 22, 1995, pages 51 - 57, XP002054374, ISSN: 0730-2312 *
RIBOT C ET AL: "Anti-oestrogens and bone.", ANNALES D'ENDOCRINOLOGIE, vol. 56, no. 6, 1995, pages 603 - 608, XP000973914, ISSN: 0003-4266 *
See also references of WO9809519A1 *

Also Published As

Publication number Publication date
TW411273B (en) 2000-11-11
WO1998009619A1 (fr) 1998-03-12
AR008155A1 (es) 1999-12-09
PL332278A1 (en) 1999-08-30
JP2002515047A (ja) 2002-05-21
TR199900504T2 (xx) 1999-06-21
WO1998009519A1 (fr) 1998-03-12
KR20000068473A (ko) 2000-11-25
JP2002515046A (ja) 2002-05-21
CO4920218A1 (es) 2000-05-29
CO5070658A1 (es) 2001-08-28
NO991097L (no) 1999-03-05
CN1236299A (zh) 1999-11-24
NO991097D0 (no) 1999-03-05
AU4247397A (en) 1998-03-26
NO991096D0 (no) 1999-03-05
BR9711676A (pt) 1999-08-24
EP0927029A4 (fr) 2001-06-13
NO991096L (no) 1999-03-05
CA2264943A1 (fr) 1998-03-12
CN1236313A (zh) 1999-11-24
EP0927029A1 (fr) 1999-07-07
EP0929216A1 (fr) 1999-07-21
CZ76699A3 (cs) 1999-08-11
CA2264775A1 (fr) 1998-03-12
IL128645A0 (en) 2000-01-31
PL332038A1 (en) 1999-08-16
AU4409797A (en) 1998-03-26
BR9711681A (pt) 1999-08-24
KR20000068472A (ko) 2000-11-25
TR199900506T2 (xx) 1999-07-21

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