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(12) Patent Application Publication (10) Pub. No.: US 2004/0224884 A1 Manolagas Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0224884 A1 Manolagas Et Al US 20040224884A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224884 A1 Manolagas et al. (43) Pub. Date: Nov. 11, 2004 (54) METHODS OF SCREENING FOR Related U.S. Application Data APOPTOSIS-CONTROLLING AGENTS FOR BONE ANABOLIC THERAPES AND USES (63) Continuation of application No. 09/413,785, filed on THEREOF Oct. 7, 1999, now abandoned. (76) Inventors: Stavros C. Manolagas, Little Rock, AR (60) Provisional application No. 60/116,409, filed on Jan. (US); Robert L. Jilka, Little Rock, AR 19, 1999. Provisional application No. 60/103,385, (US); Robert S. Weinstein, Little filed on Oct. 7, 1998. Rock, AR (US); Teresita Bellido, Little Rock, AR (US) Publication Classification Correspondence Address: (51) Int. Cl." ..................................................... A61K 38/29 HAMILTON, BROOK, SMITH & REYNOLDS, (52) U.S. Cl. ................................................................ 514/12 P.C. 530 VIRGINA ROAD (57) ABSTRACT P.O. BOX 91.33 CONCORD, MA 01742-9133 (US) The invention as disclosed provides a method to increase bone mass without compromising bone Strength or quality, (21) Appl. No.: 10/743,360 through the administration to a host of a compound that binds to the estrogen or androgen receptor without causing (22) Filed: Dec. 22, 2003 hormonal transcriptional activation. Patent Application Publication Nov. 11, 2004 Sheet 1 of 13 US 2004/0224884 A1 1 2 1 O vehicle DEVO FG. 6 - 1 2 - PTH - -- - -- - -- Vehicle dex TNFO. Patent Application Publication Nov. 11, 2004 Sheet 2 of 13 US 2004/0224884 A1 24 20 - s U 16 "C (A CD 12 O SS 8 4 O PTH - - - - - -- vehicle dex NFO. FG 3 40 -- vehicle d U co C a Gls O. an GP D O R1 P6 F.G. 4 Patent Application Publication Nov. 11, 2004 Sheet 3 of 13 US 2004/0224884 A1 R1 global P6 O 1 2 3 4 O 1 2 3 4. -- r p 2 t 2 N 0 1 2 3 4. 0 1 2 3 4. weeks Weeks O Vehicle O 80 ng LPTH (1-34) /g body wit - v 400 ng LPTH (1-34) /g body wit - F.G. 5 Patent Application Publication Nov. 11, 2004 Sheet 4 of 13 US 2004/0224884 A1 H r CN ve d C o c C C (p.1%) eley uoleuo euog e d d o w (%) Jeleujed SedoeSO Patent Application Publication Nov. 11, 2004 Sheet 5 of 13 US 2004/0224884 A1 e d 9 C s O) o SS bPTH(1-34.) - 100 nM - 1 OOM bPTH (3-34) sea f 100 nM 10,000 nM E 100 nM Dex (6 h) * p-0.05 by ANOVA F.G. 7 Patent Application Publication Nov. 11, 2004 Sheet 6 of 13 US 2004/0224884 A1 PTH (M) - 0-10 10-9 10-8 10-7 10-6 C ES 100 nM Dex (6 h) * p-0.05 by ANOVA FIG. 8 Patent Application Publication Nov. 11, 2004 Sheet 7 of 13 US 2004/0224884 A1 bPTH(1 -34) 100 nM s 100 nM bPTH (3-34) 1 OOW 10,000 nM 100 nM Dex (6 h) * pg.0.05 by ANOVA FG. 9 Patent Application Publication Nov. 11, 2004 Sheet 8 of 13 US 2004/0224884 A1 20 s | T -- 9 m d 1 O - "t wn - - - T --T SS T | | | | O PTH (M) - 10-10 10-9 10-8 10-7 10-6 - DBA (M) - - - - - - 10-3 C 1 OO nM Dex (6 h) DBA: dibutyryl CAMP x pCO.05 by ANOVA F.G. 10 Patent Application Publication Nov. 11, 2004 Sheet 9 of 13 US 2004/0224884 A1 -C- vehicle -- PTH r FG. A Initial SAMR1 SAMP 6 F.G. 11B Patent Application Publication Nov. 11, 2004 Sheet 10 of 13 US 2004/0224884 A1 s Patent Application Publication Nov. 11, 2004 Sheet 11 of 13 US 2004/0224884 A1 - 9 G D. O O C 9. C. S. - in Cs O e O Patent Application Publication Nov. 11, 2004 Sheet 12 of 13 US 2004/0224884 A1 vehicle a PTH Calvarial osteoblasts MLO-Y4 osteocytes SO T 40 40 30 T s rts 15 2) - it a E. C basal etop diex TNF basa e top diex TNF MC3T3 - E1. Osteoblasts MG-63 Osteoblasts basa e top basal etop F.G. 13B Patent Application Publication Nov. 11, 2004 Sheet 13 of 13 US 2004/0224884 A1 33-3PAAssists St. Oh s N Š 4 SN +' 'i ' 3: ŠSt 4 t t E : kHŠ Y . t C t i i US 2004/0224884 A1 Nov. 11, 2004 METHODS OF SCREENING FOR originally assembled at the remodeling site die by apoptosis APOPTOSIS-CONTROLLING AGENTS FOR BONE (Jilka et al, JBMR 13:793-802, 1998). ANABOLIC THERAPIES AND USES THEREOF 0009 Most metabolic disorders of the adult skeleton RELATED APPLICATION result from an imbalance between the resorption of old bone by osteoclasts and its Subsequent replacement by Osteo 0001. This application is a continuation of U.S. applica blasts. Chances in cell numbers, as opposed to individual tion Ser. No. 09/414,091, filed Oct. 7, 1999, which claims cell activity (Manolagas and Jilka, NEJM 332:305-311, the benefit of U.S. Provisional Application No. 60/151,486 1995), appear to be the cause of most metabolic bone filed Aug. 30, 1999, No. 60/136,260 filed May 27, 1999 and diseases, including the three most common forms of No. 60/119,080 filed Feb. 8, 1999. The entire teachings of Osteoporosis: Osteoporosis due to Sex Steroid deficiency in the above applications are incorporated herein by reference. females and males (Jilka et al., Science 257:88-91, 1992; Jilka et al., JCI 101:1942-1950, 1998; Bellido et al., JCI FEDERAL FUNDING 95:2886-2895, 1995; Weinstein et al., Endocrinology 138:4013-4021, 1997); osteoporosis due to old ace (Jilka et 0002 This invention was funded in part through a grant al., JCI 97:1732-1740, 1996); and osteoporosis due to glu from the National Institutes of Health. Therefore, the federal cocorticoid-excess (Weinstein et al., JCI 102:274-282, 1998; government has certain rights in this invention. Weinstein et al, Bone, 23:S461, 1998; Bellido et al, Bone, 23:S324, 1998). BACKGROUND OF THE INVENTION 0010 Agents that reduce bone turnover by inhibiting the 0003) 1. Field of the Invention activation of bone remodeling (commonly but inaccurately referred to as “antiresorptive”) increase bone mass by a 0004. This invention is in the field of bone physiology, maximum of 6-10%, and more typically, 2-3%, as measured and in particular provides methods and compositions that by Dual Energy X-Ray Absorptiometry (DEXA). Most of include compounds to increase bone mass, i.e., to achieve this increase is in the first 1-2 years and is due to contraction bone anabolism. The compounds bind to the estrogen or of the remodeling space. Modest further increases may result androgen receptor without causing Significant hormonal from more complete Secondary mineralization. Improve transcriptional activation. ment of focal balance due to reduction of resorption depth 0005 2. Description of the Related Art has been demonstrated in animal experiments, but not yet in human Subjects. Regardless of the mechanism, an increase 0006 Bones consist of living cells embedded within a of less than 10% will in almost all cases fail to restore bone matrix of proteins and minerals. Bones provide Support and mass to its peak value and fail to reestablish trabecular protection to the Vital organs of the animal, and give Strength connectivity So that fracture risk will remain increased. and form to its structure. 0011. There are a wide variety of needs for bone anabolic 0007 Osteoporosis is a decrease in bone mass in com agents for humans as well as animals. Examples of uses for bination with microarchitectural deterioration which leads to bone anabolic agents in humans, besides patients with bone fragility and fractures. Treatments for Osteoporosis Osteoporosis, include the Strengthening of bone in healthy have historically focused on the prevention of further bone Subjects who engage in Strenuous physical activities Such as loSS. In contrast, a bone anabolic agent is one that Substan Sports or manual labor, and the Strengthening of bone in tially increases bone mass. To date, while there have been perSons who do not have osteoporosis but might be Subject several drugs approved by the U.S. Food and Drug Admin to Osteoporosis in the future because the perSon is in a risk istration for the treatment of osteoporosis, it is believed that group for that disease. Other uses for a bone anabolic agent no drug has yet been approved in the United States to be in humans include the treatment of perSons who fail to used as a bone anabolic agent, for either humans or other obtain an adequate bone mass at the completion of growth animals. Bone is a dynamic tissue which undergoes con or perSons who are born with unusually fragile bones, tinual resorption and formation through a remodeling pro perSons who have a genetic predisposition to a bone cata ceSS, which is accomplished by two types of cells: osteo bolic disease, or an Orthopedic bone disease Such as joint clasts, which erode cavities, and Osteoblasts that Synthesize degeneration, non-union fractures, orthopedic problems new bone matrix. Remodeling takes place mainly on the caused by diabetes, periimplantitis, poor responses to bone internal Surfaces of bone and it is carried out not by grafts, implants, fracture. individual cells, but rather by temporary anatomical Struc tures, termed basic multi-cellular units (BMUs), comprising 0012 Likewise, there are many uses for bone anabolic teams of Osteoclasts in the front and Osteoblasts in the rear.
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