Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1999-11-19
2002-07-09
Dees, Jose G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S009600, C436S103000, C436S104000, C436S106000, C436S111000, C436S127000, C514S075000, C514S102000, C514S114000, C514S141000
Reexamination Certificate
active
06416737
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of bone physiology and morphology, and specifically, describes the identification and use of selected bisphosphonates and calcitonin derivatives to increase bone mass which (i) inhibit the apoptosis of osteocytes and/or osteoblasts (ii) without substantially affecting the activity of osteoclasts.
BACKGROUND OF THE INVENTION
Bones consist of living cells embedded within a matrix of proteins and minerals. Bones provide support and protection to the vital organs of the animal, and give strength and form to its structure. Diseases of the bone, therefore, may have significant deleterious effects on humans as well as other vertebrates.
Osteoporosis is a decrease in bone mass in combination with microarchitectural deterioration which leads to bone fragility and fractures. Treatments for osteoporosis have historically focused on the prevention of further bone loss. In contrast, a bone anabolic agent is one that substantially increases bone mass. An increase in bone mass does not necessarily lead to a decrease in bone fragility. To date, while there have been several drugs approved by the U.S. Food and Drug Administration for the treatment of osteoporosis, it is believed that no drug has yet been approved in the United States to be used as a bone anabolic agent, for either humans or other animals.
Bone is a dynamic tissue which undergoes continual resorption and formation through a remodeling process, which is accomplished by two types of cells: osteoclasts, which erode cavities, and osteoblasts that synthesize new bone matrix. Remodeling takes place mainly on the internal surfaces of bone and it is carried out not by individual cells, but rather by temporary anatomical structures, termed basic multi-cellular units (BMUs), comprising teams of osteoclasts in the front and osteoblasts in the rear. In an established BMU, bone resorption and formation happens at the same time.
After osteoclasts stop resorbing bone, they die by apoptosis and are quickly removed by phagocytes. During the longer lifespan of the osteoblasts (about three months, as compared to three weeks for osteoclasts), some osteoblasts convert to lining cells that cover quiescent bone surfaces and some are entombed within the mineralized matrix as osteocytes (Parfitt, In: Bone, Telford and CRC Press, PP351-429, 1990). However, the majority (65%) of osteoblasts that originally assembled at the remodeling site die by apoptosis (Jilka et al., JBMR 13:793-802, 1998).
Osteocytes are the most abundant bone cell type and are buried deep in the mineralized bone matrix within lacunae connected with canaliculi through which the long and slender cytoplasmic processes of osteocytes are connected with neighboring osteocytes and with the cells on the bone surface and of the bone marrow.
Because of their sheer number, regular spacing throughout the mineralized matrix and their anatomical connections with other bone cells, osteocytes are believed to be the sensors of the local need for bone augmentation or reduction during functional adaptation of the skeleton, the detection of microdamage, and the transmission of signals that lead to bone repair by remodeling. Specifically, it is thought that mechanical strains on bone cause deformations that result in flow of fluid within the osteocytic lacunae and canaliculi. The changes in fluid flow are sensed by the osteocytes, which, in turn, transmit signals to osteoblasts (new bone-forming cells) and osteoclasts (old bone-removing cells). Osteoblasts and osteoclasts react by remodeling the mineral tissue so that it is permanently adapted to daily mechanical deformations. When this system fails, the tissue becomes fragile, and bone structure proves inadequate and brittle.
Bone fragility is a pathologic condition that may be caused by various factors, including a poor quality of mineralized tissue or more usually by weak structure, unable to respond competently to the customary mechanical requirements of the skeleton. Poor osteocytic activity is related to this state of fragility (Duncan R L et al.,
Calcif. Tissue Int
. 1995, 57:344; Mullender M G et al.,
Bone
1997, 20:527; Turner C H et al.,
Bone
1998, 22:463). The bone structures that jointly constitute the human skeleton and that of vertebrate animals are permanently distorted by the application of external forces, in which muscular force usually intervenes (Ferretti J L et al.,
Calcif. Tissue Int
. 1995, 57:399; Frost H M,
Bone
1997, 20:385). Consistent with the critical role of osteocytes in bone maintenance, it has recently been demonstrated that glucocorticoid excess, traditionally a cause of severe boneloss and osteonecrosis leading to the collapse of joints, dramatically increases osteocyte and osteoblast apoptosis (Weinstein et al.,
J. Clin. Invest
., 102:274); whereas, intermittent administration of parathyroid hormone, a method of anabolic bone therapy, has the opposite effect on osteocyte and osteoblast apoptosis (Jilka et al.,
J. Clin. Invest
., 104:439-446, 1999).
Most metabolic disorders of the adult skeleton result from an imbalance between the resorption of old bone by osteoclasts and its subsequent replacement by osteoblasts. Changes in cell numbers, opposed to individual cell activity (Manolagas and Jilka, NEJM 332:305-311, 1995), appears to be the cause of most metabolic bone diseases, including the three most common forms of osteoporosis: osteoporosis due to sex steroid deficiency in females and males (Jilka et al., Science 257:88-91, 1992; Jilka et al., JCI 101:1942-1950, 1998; Bellido et al., JCI 95:2886-2895, 1995; Weinstein et al., Endocrinology 138:4013-4021, 1997); osteoporosis due to old age (Jilka et al., JCI 97:1732-1740, 1996); and osteoporosis due to glucocorticoid-excess (Weinstein et al., JCI 102:274-282, 1998; Weinstein et al., Bone, 23:S461, 1998; Bellido et al., Bone, 23:S324, 1998). Structural bone alterations caused by decreased osteocyte life span predisposes the bone to irreversible deformations and fractures. This condition is designated “skeletal fragility.”
Agents that reduce bone turnover by inhibiting remodeling (commonly but inaccurately referred to as “antiresorptive”) increase bone mass by a maximum of 6-10%, and more typically, 2-3%, as measured by Dual Energy X-Ray Absorptiometry (DEXA). Most of this increase is in the first 1-2 years and is due to contraction of the remodeling space. Modest further increases may result from more complete secondary mineralization. Improvement of focal balance due to reduction of resorption depth has been demonstrated in animal experiments, but not yet in human subjects. Regardless of the mechanism, an increase of less than 10% will in almost all cases fail to restore bone mass to its peak value and fail to reestablish trabecular connectivity so that fracture risk will remain increased.
Over the past three decades, bisphosphonates (BP's), stable analogs of pyrophosphate and calcitonin have been developed as potent inhibitors of bone resorption and effective agents for the management of osteoporosis and other bone diseases (Fleisch, H. 1997. Bisphosphonates in bone disease. From the laboratory to the patient. The Partenon Publishing Group Inc., One Blue Hill Plaza, New York 10965, USA.; Papapoulos, S. 1996. Bisphosphonates. Pharmacology and use in the treatment of osteoporosis. In Osteoporosis. R. Marcus, D. Feldman, and J. Kelsey, editors. Academic Press, San Diego, Calif. 1209-1234 Rodan, G. A. and H. A. Fleisch. 1996
. J. Clin. Invest
. 97:2692-2696; Azria, et al., 1996. Calcitonin. In Principles of Bone Biology. J. P. Bilezikian, et al., eds, Academic Press, San Diego, Calif. 1083-1097). Decreased osteoclast progenitor development, decreased osteoclast recruitment, and promotion of apoptosis of mature osteoclasts leading to decreased bone remodeling are thought to be the main mechanisms of the antiresorptive actions of BPs (Hughes, et al., 1995
. J. Bone Miner. Res
. 10:1478-1487; Hughes, et al., 1989
. J. Clin. Invest
. 83:1930-1935; Parfitt, et al., 1996
. J. Bone Miner. Res
11:150-15
Bellido Teresita
Manolagas Stavros C.
Bennett-Paris Joseph M.
Board of Trustees of the University of Arkansas
Choi Frank
Dees Jos,e G.
King & Spalding
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