Treatment of osteoporosis and metabolic bone disorders with nitric oxide substrate and/or donors

• US 5,898,038 A
• Filed: 03/19/1996
• Issued: 04/27/1999
• Est. Priority Date: 03/19/1996
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Wimalawansa, Sunil J., Yallampalli, Chandrasekhar
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/616,470
• Time in Patent Office: 1,134 Days
• Field of Search: 514/108, 514/742
• US Class Current: 514/742
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/295 Iron group metal compounds
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Primary and secondary osteoporosis in a female or a male mammal is treated by administering thereto a nitric oxide synthase substrate, a nitric oxide donor or both, optionally; in further combination with one or more of an estrogen, a progestin, an anabolic steroid. Nitric oxide substrate or donor also can be combined with one or more of other medications acting on bone, such as bisphosphonate, calcitonin, fluoride, androgen and other novel therapeutic agents. Either nitric oxide donor or substrate by itself or combination with other medications as described above can be used in both women and men, (preferably human) for prevention and treatment of osteoporosis and other metabolic bone disorders.

Claims

1. A method for prevention or treatment of primary and secondary osteoporosis of a female or male mammal comprising administering, to an afflicted mammal or one in need thereof, nitroglycerin and a bisphosphonate in effective synergistic amounts.

2. The method of claim 1 where the mammal is female, further comprising administration of at least one of an estrogen and progestin.

3. The method of claim 1 where the mammal is male, further comprising administration of an androgen.

4. The method of claim 1 further comprising administration of an additional agent affecting bone metabolism.

5. The method of claim 4 where the agent is at least one of calcitonin, anabolic steroid and fluoride.

6. The method of claim 1 wherein the mammal is a female human suffering from primary or secondary osteoporosis.

7. The method of claim 1 wherein the mammal is a female human subject to hormone replacement therapy, a candidate for hormone replacement therapy or for osteoporosis therapy.

8. The method of claim 1 wherein the mammal is a male human having osteoporosis or being a candidate for osteoporosis therapy.

9. The method of claim 1 wherein the nitroglycerin is administered orally or parenterally.

10. The method of claim 1 where the administration is transdermal, by inhalation, percutaneous, intravenous, intramuscular, subcutaneous, depot preparation, sublingual or rectal.

11. The method of claim 1 wherein the mammal is a human female and the method further comprises treatment with an estrogen.

12. The method of claim 11, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17b-estradiol, estrone or estriol.

13. The method of claim 11 where the estrogen is an estrogen analog and an antiestrogen.

14. The method of claim 1 wherein the mammal is a female human and the method further comprises treatment with a progestin.

15. The method of claim 14, wherein the progestin is progesterone, dyprogesterone, medroxyprogesterone, norethisterone, levonorgestrel, or norgestrel.

16. The method of claim 14 where the progestin is a progestational compound or progestin analog.

17. The method of claim 1 wherein the mammal is a female human and the treatment further comprises estrogen or progestin administered continuously.

18. The method of claim 1 wherein the mammal is a female human and the treatment further comprises estrogen or progestin administered cyclically.

19. The method of claim 1 wherein the bisphosphonate is disodium etidronate, pamidronate, clodronate, residronate or alendronate.

20. The method of claim 1 wherein the mammal is a human and the nitroglycerin is administered in combination with calcitonin.

21. The method of claim 20, wherein the calcitonin is salmon calcitonin, eel calcitonin, human calcitonin, α

calcitonin, β

calcitonin or active calcitonin analog.

22. The method of claim 1, wherein the mammal is a human and the method further comprises treatment with a fluoride salt.

23. The method of claim 22, wherein the fluoride salt is a rapid or slow release sodium fluoride formulation.

24. The method of claim 1 wherein the mammal is a human and the treatment further comprises treatment with an anabolic steroid.

25. The method of claim 24, wherein the anabolic steroid is nondrolone decanoate.

26. The method of claim 1 wherein the mammal is a human and the treatment further comprises bisphosphonate, calcitonin, fluoride, or anabolic steroid administered continuously.

27. The method of claim 1 wherein the mammal is a human and the treatment further comprises bisphosphonate, calcitonin or fluoride administered cyclically.

28. The method of claim 1 wherein the male mammal is a human and the nitroglycerin is administered in combination with an androgen.

29. The method of claim 28, wherein the androgen is testosterone.

30. The method of claim 1 wherein the mammal is a male human and the treatment further comprises androgen administered continuously.

31. The method of claim 3, wherein the mammal is a male human and the treatment further comprises androgen administered cyclically.

32. The method of claim 1 defined further as comprising the administration of testosterone.

33. The method of claim 1 defined further as comprising the administration of nondrolone.

34. The method of claim 1 defined further as comprising the administration of nondrolone decanoate.

35. A pharmaceutical composition comprising synergistic effective amounts of nitroglycerin, and a bisphosphonate.

36. The composition of claim 35 wherein the nitroglycerin is in an amount effective, upon administration to raise nitric oxide levels to about 1-1000 nmolar.

37. The composition of claim 35 further comprising estrogen in an amount equivalent to 1-2 mg of estradiol.

38. The composition of claim 35 further comprising progestin in an amount bioequivalent to 50-300 mg of injected progesterone.

39. The composition of claim 35 wherein bisphosphonate is in an amount equivalent to 5-10 mg/kg of disodium etidronate.

40. The composition of claim 35 further comprising calcitonin in an amount equivalent to 10-200 I.U. of human calcitonin.

41. The composition of claim 35 further comprising fluoride in an amount equivalent to 10-50 mg of sodium fluoride.

42. The composition of claim 35 further comprising anabolic steroid in an amount equivalent to 50 mg of nondrolone decanoate, and androgens are in an amount equivalent to 100 mg of testosterone.

43. The composition according to claim 35, further comprising L-arginine.

44. The composition according to claim 35, further comprising a natural or synthetic estrogen or antiestrogen.

45. The composition according to claim 35, further comprising progestin.

46. The composition according to claim 35, wherein the bisphosphonate is disodium etidronate, pamidronate, clodronate, residronate, or alendronate.

47. The composition according to claim 35, further comprising calcitonin.

48. The composition according to claim 41 wherein the fluoride is sodium fluoride or a slow release fluoride preparation.

49. The composition according to claim 35, further comprising an anabolic steroid.

50. The composition according to claim 35, further comprising androgen.