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(12) United States Patent (10) Patent No.: US 6,399,592 B1 Whiteford (45) Date of Patent: *Jun

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(12) United States Patent (10) Patent No.: US 6,399,592 B1 Whiteford (45) Date of Patent: *Jun USOO6399592B1 (12) United States Patent (10) Patent No.: US 6,399,592 B1 Whiteford (45) Date of Patent: *Jun. 4, 2002 (54) BISHPHOSPHONATE/ESTROGEN 4,970,335 A 11/1990 Isomura et al. ............... 562/13 SYNERGISTIC THERAPY FOR TREATING 5,019,651 A 5/1991 Kieczykowski .............. 562/13 AND PREVENTING BONE LOSS 5,773,477 A 6/1998 MacLean et al. ........... 514/648 (75) Inventor: Donna T. Whiteford, Brooklyn, NY FOREIGN PATENT DOCUMENTS (US) EP 496 520 1/1992 WO WO 92/05187 9/1991 (73) Assignee: Merck & Co., Inc., Rahway, NJ (US) WO WO 92/14474 9/1992 (*) Notice: This patent issued on a continued pros- OTHER PUBLICATIONS S Elisatist sd CE Bone, Henry G., et al., “Alendronate and Estrogen Effects in patent s term provisionsJe. of 35 U.S.C.y y Postmenopausalp Women with Low Bone Mineral Density',y 154(a)(2) J. Clinical Endocrinology & Metabolism, vol. 85, No. 2, pp 720–726, 2000. Subject to any disclaimer, the term of this Lindsay, Robert, et al., “Addition of Alendronate to Ongoing patent is extended or adjusted under 35 Hormone Replacement Therapy in the Treatment of U.S.C. 154(b) by 0 days. Osteoporosis: A Randomized, Controlled Clinical Trial”, J. Clinical Endocrinology & Metabolism, vol. 84, No. 9, pp. (21) Appl. No.: 08/880,735 3076–3081, 2000, Fleisch, Bisphosphonates in Bone Disease (2nd ed. 1995), p. (22) Filed: Jun. 23, 1997 35. O O British Med. Bull. 46 (1), pp. 94-112 (1990). Related U.S. Application Data J. Org. Chem., 32, pp. 4111-4114 (1967). (63) Continuation of application No. 08/491,846, filed on Jun. Abstr. 732 and 732, ASBMR Mtg., Minn. (Fall 1992). 22, R EN. aggersys. hclips Ciminera, N., et al., Ann. Ostet. Ginecol. Med. Perinat., vol. application No.No. 08/880,735, which isilled a continuation-in-part On Jec. If, 2 113, No. 5, pp. 232–237, 1992. of application No. 07/996,418, filed on Dec. 23, 1992, now abandoned. Primary Examiner. Theodore J. Criares (51) Int.Ill. CI.71. A61K 31156; A61 K31/66 (74) Attorney, Agent, or Firm Nicole M. Wallinger; Mark s R. Daniel (52) U.S. Cl. ........................................ 514/109; 514/182 (58) Field of Search ................................. 514/167, 182, (57) ABSTRACT 514/109 Disclosed is a combination therapy for treating and for (56) References Cited preventing bone loSS by the use of estrogen and a bisphos phonate Selected from: alendronate, clodronate, tiludronate, U.S. PATENT DOCUMENTS YM175, BM 210995, or mixture thereof. Also described is a pharmaceutical composition of the above for carrying out 4,621,077 A 11/1986 Rosini et al. ............... 514/108 4,876,248 A 10/1989 Breliere et al. ............. 514/108 the therapeutic method. 4,922.007 A 5/1990 Kieczykowski et al. ...... 562/13 4,927,814 A 5/1990 Gall et al. .................. 514/108 19 Claims, No Drawings US 6,399,592 B1 1 2 BISHPHOSPHONATE/ESTROGEN showed a positive effect on bone loSS in ovaricetomized rats SYNERGISTIC THERAPY FOR TREATING (published in Abstracts 731 and 732 at the Fall 1992 AND PREVENTING BONE LOSS ASBMR meeting in Minnesota. The article, J. Clin. Invest., Jan. 1992, 89 (1), p. 74–78 by CROSS REFERENCE TO RELATED J. Chow et al., describes the effect of estrogen on Ovariec APPLICATIONS tomized rats in which bone resorption was Suppressed by This application is a continuation of U.S. Ser. No. 08/491, pamidronate. They concluded that estrogen inhibits bone 846, filed Jun. 22, 1995, now abandoned, which was a U.S. resorption and also Stimulates bone formation. continuation-in-part national filing of PCT/US93/12302, The article, J. Bone Miner. Res. (USA) 1991, p. 387–394 filed Dec. 17, 1993, which had published as WO 94/14455 by T. J. Wronski et al., describes studies in rats with estrogen on Jul. 7, 1994, which is a C-I-P from parent U.S. Ser. No. and the bisphosphonates etidronate and risedronate. The 07/996,418, filed Dec. 23, 1992, now abandoned. Studies showed that etidronate, (1-hydroxyethylidene) bisphosphonic acid, disodium salt, (Proctor and Gamble) has FIELD OF THE INVENTION 15 long term adverse effects on bone mineralization. The instant invention relates generally to the combination However, these Studies did not Suggest the use of other of estrogen and bisphosphonates and their use in bone bisphosphonates including alendronate. growth and maturation. Specifically, the invention relates to There are situations where a female patient is undergoing the use of estrogen and bisphosphonates to inhibit bone estrogen therapy for a menopausal or postrinenopausal resorption and promote net bone formation. This therapeutic related condition, (e.g., vasomotor Symptoms, atrophy of the combination will result in a decreased rate of bone resorp vaginal mucosa, increased cardiovascular risk, etc.) and is tion with either an increase or Stabilization of bone mass. also discovered to be Suffering from Osteoporosis (i.e. rar efaction of bone) or to be at risk for developing Osteoporosis. BACKGROUND OF THE INVENTION Although estrogens/hormone replacement therapy (HRT) 25 are known to help prevent the development of Osteoporosis, The normal bones are living tissues undergoing constant there are instances, which are not at all uncommon, where resorption and redeposition of calcium, with the net effect of HRT or a weak estrogen is prescribed at dosages which do maintenance of a constant mineral balance. The dual proceSS not provide adequate protection against Osteoporosis. There is commonly called “bone turnover”. In normal growing bones, the mineral deposition exceeds the mineral are also Some women who continue to lose bone mass resorption, whereas in certain pathological conditions, bone despite treatment with higher estrogen/HRT doses or who resorption exceeds bone deposition, for instance due to have established osteoporosis but fail to increase their bone malignancy or primary hyperparathyroidism, or in mass on estrogen/HRT alone. Osteoporosis. In other pathological conditions the calcium What is desired in these cases is a therapy to optimally deposition may take place in undesirable amounts and areas treat both the menopausal and postmenopausal-related con leading to e.g. heterotopic calcification, osteoarthritis, kid 35 ditions and the development of Osteoporosis or osteoporosis ney or bladder Stones, atherosclerosis, and Paget's disease risk concurrently. which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition. SUMMARY OF THE INVENTION Most of the currently available therapeutic agents for the 40 The present invention discloses a combination method for treatment of Osteoporosis, e.g. estrogens, act by reducing treating and/or preventing bone loSS in a Subject by the bone resorption in the osteoporotic patient. See the review combination therapy of pharmaceutically effective amounts article, British Medical Bulletin 46 (1), p. 94-112 (1990). of estrogen and of a bisphosphonate Selected from: Bisphosphonates are also known in the art as bone resorp alendronate, clodronate, tiludronate, YM 175, BM 210995, tion inhibitors. 45 or mixture thereof. Alendronate, 4-amino-1-hydroxybutylide ne-1,1- Also described is a pharmaceutical composition contain bisphosphonic acid monosodium trihydrate, is described as ing the combination described above in a pharmaceutically a composition, method of use and synthesis in U.S. Pat. Nos. acceptable carrier. 4,621,077 (Gentili): 4,922,007 and 5,019,651 (Merck). Clodronate, (dichloromethylene)bisphosphonic acid diso 50 DETAILED DESCRIPTION OF THE dium salt (Proctor and Gamble, is described in Belgium INVENTION AND PREFERRED Patent 672.205 (1966) and J. Org. Chem32,4111 (1967) for EMBODIMENTS its preparation. By the term “estrogen” as used herein is meant “ 17-beta Tiluldronate, ((4-chlorophenyl)thiomethylene estradiol” and includes those equivalent materials contained bisphosphonic acid) (Sanofi) is described in U.S. Pat. No. 55 in the MERCK INDEX-Eleventh Edition (1989). 4,876,248 issued Oct. 24, 1989. Estrogens, e.g. estradiol and its Steroidal and non-Steroidal YM 175 (I(cycloheptylamino)methylenebisphosphonic equivalents which can be used herein include (page numbers acid, disodium salt) by Yamanouchi is described in U.S. Pat. taken from the above indicated MERCK INDEX): No. 4,970,335 issued Nov. 13, 1990. 60 BM 210995 (1-Hydroxy-3-(methylpentylamino)- propylidene-bisphosphonate) by Boehringer-Mannheim-is ESTROGEN described in U.S. Pat. No. 4,927,814 issued May 22, 1990. A study by Proctor and Gamble (Norwich Eaton Nonsteroidal Pharmaceuticals) using risendronate, whose chemical name 65 Benzestrol, 1082 is Sodium trihydrogen 1-hydroxy-2-(3-pyridinyl) Broparoestrol, 1438 ethylidenebisphosphonate, in combination with estrogen US 6,399,592 B1 3 4 The term “treatment” or “treating” as used herein shall -continued mean (1) providing a Subject with an amount of a Substance Sufficient to act prophylactically to prevent the development ESTROGEN of a weakened and/or unhealthy State; and/or (2) providing Chlorotrianisene, 2173 a Subject with a Sufficient amount of a Substance So as to Dienestrol, 3094 alleviate or eliminate a disease State and/or the Symptoms of Diethylstilbestrol, 3118 a disease State, and a weakened and/or unhealthy State. Diethylstilbestrol Dipropionate, 3119 Method of Use Dimestrol, 31.98 Fosfestrol, 4168 Drugs which prevent bone loss and/or add back lost bone Hexestrol, 4621 1O may be evaluated in the ovariectomized rat. This animal Methallenestril, 5856 Methestrol, 5888 model is well established in the art (see, for example, Tamoxifen, 9019 Wronski, et al. (1985) Calcif. Tissue Int. 37:324–328; Steroidal Kimmel, et al. (1990) Calcif. Tissue Int. 46:101-110; and Durbridge, et al. (1990) Calcif. Tissue Int 47:383–387; these Colpormon, 2485 15 references are hereby incorporated in their entirety). Conjugated Estrogenic Hormones, 2504 Equilenin, 3581 Wronski, et al. (1985) Calcif. Tissue Int. 43:179-183)) Equilin, 3582 describe the association of bone loSS and bone turnover in Estradiol, 3653 the ovariectomized rat.
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