Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1993-01-25
2001-12-11
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S079000, C514S080000, C514S086000, C514S167000, C514S170000, C514S182000
Reexamination Certificate
active
06329354
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods of building bone in humans and other animals, i.e., for the treatment of osteoporosis and related disorders. In particular, this invention relates to such methods of treatment by administration of bone-active phosphonates and estrogen.
The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. “Secondary osteoporosis” is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is idiopathic “primary osteoporosis”. Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
For some osteoporotic individuals the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of “bone remodeling”. Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called “basic multicellular units” or “BMUs”. BMUs primarily consist of “osteoclasts”, “osteoblasts”, and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an “activated” BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by an osteoblast.
Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in osteoporotics, there is an increase in the number of BMUs that are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.
Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
Many compositions and methods are described in the medical literature for the “treatment” of osteoporosis. Many of these compositions and methods attempt to either slow the loss of bone or to produce a net gain in bone mass. See, for example, R. C. Haynes, Jr. et al., “Agents affecting Calcification”,
The Pharmacological Basis of Therapeutics,
7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); G. D. Whedon et al., “An Analysis of Current Concepts and Research Interest in Osteoporosis”,
Current Advances in Skeletogenesis
(A. Ornoy et al., Editors, 1985); and W. A. Peck, et al.,
Physician's Resource Manual on Osteoporosis
(1987), published by the National Osteoporosis Foundation.
Among the treatments for osteoporosis suggested in the literature is the administration of bisphosphonates or other bone-active phosphonates. See, for example, Storm et al., “Effect of Intermittent Cyclical Etidronate Therapy on Bone Mineralization and Fracture Rate in Women with Post-Menopausal Osteoporosis”, 322
New England Journal of Medicine
1265 (1990); and Watts et al., “Intermittent Cyclical Etidronate Treatment of Post-Menopausal Osteoporosis”, 323
New England Journal of Medicine
73 (1990). Such treatments using a variety of bisphosphonates are described in U.S. Pat. No. 4,761,406, Flora et al., issued Aug. 2, 1988; U.S. Pat. No. 4,812,304, Anderson et al., issued Mar. 14, 1989; U.S. Pat. No. 4,812,311, Uchtman, issued Mar. 14, 1989; and U.S. Pat. No. 4,822,609, Flora, issued Apr. 18, 1989. The use of such phosphonates for the treatment of osteoporosis, and other disorders involving abnormal calcium and phosphate metabolism, is also described in U.S. Pat. No. 3,683,080, Francis, issued Aug. 8, 1972; U.S. Pat. No. 4,330,537, Francis, issued Oct. 28, 1980; U.S. Pat. No. 4,267,108, Blum et al., issued May 12, 1981; European Patent Publication 298,553, Ebetino, published Jan. 11, 1989; and Francis et al., “Chemical, Biochemical, and Medicinal Properties of the Diphosphonates”,
The Role of Phosphonates in Living Systems
55 (1983).
Administration of estrogen is also used as a means to prevent osteoporosis in postmenopausal women. This therapy typically involves daily administration of from about 0.625 milligrams to about 1.25 milligrams of conjugated estrogens, or equivalent amounts of other estrogen hormones. Estrogen may also be used to treat osteoporosis (i.e., actual building of bone in osteoporotics), although this has not been fully established. See, for example, Barzel, “Estrogens in the Prevention and Treatment of Post-Menopausal Osteoporosis: a Review”, 85
American Journal of Medicine
847 (1988); Barzel, “Estrogen Therapy for Osteoporosis: Is it Effective?”,
Hospital Practice
95 (1990); Ettinger, et al., “Post-Menopausal Bone Loss is Prevented by Treatment with Low-Dosage Estrogen with Calcium”, 106
Annals in Internal Medicine
40 (1987); Lindsay, et al., “The Minimum Effective Dose of Estrogen for Prevention of Post-Menopausal Bone Loss”, 63
Obstetrics and Gynecology
759 (1984); and “Estrogen”,
Drug Information
1765 (1990). Furthermore, the use of estrogen has been associated with certain side effects, such as uterine bleeding. See, Rudy, “Hormone Replacement Therapy—How to Select the Best Preparation and Regimen,” 88
Postgraduate Medicine
157 (1990).
Applicant has found, surprisingly, that osteoporosis may be prevented or treated by administering bone-active phosphonates with low, otherwise ineffective, doses of estrogen. Further, these methods also allow the use of low, otherwise marginally or ineffective, doses of the phosphonates. Accordingly, the methods of this invention provide effective methods of preventing and treating osteoporosis, with reduced side effects compared to such methods known in the art.
SUMMARY OF THE INVENTION
The present invention provides methods of treatment for osteoporosis in a human or other animal subject, comprising: administering a bone-active phosphonate to said subject, at a level of at least about 0.1 LED per day of said treatment; and administering an estrogen hormone to said subject at a level of from about 0.2 to about 0.8 LED per day of said treatment. The bone-active phosphonate is preferably a bisphosphonate, or a phosphonoalkyl phosphonate.
DESCRIPTION OF THE INVENTION
The methods of the present invention comprise the administration of bone-active phosphonates and estrogen hormones to a human or other animal subject. Specific compounds and compositions to be used in these processes must, accordingly, be pharmaceutically-acceptable. As used herein, such a “pharmaceutically-acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. Further, as used herein, the term “safe and effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific “safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
Active Materials
Bone-Active Phosphonates:
The methods of this invention involve the administration of a bone-active phosphonate. As
Corstanje Brahm
Criares Theodore J.
Roof Carl J.
Suter David
The Procter & Gamble & Company
LandOfFree
Methods for the treatment of osteoporosis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for the treatment of osteoporosis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for the treatment of osteoporosis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2591110