Methods For Bone Treatment By Modulating An Arachidonic Acid Metabolic or Signaling Pathway

Abstract

Methods for promoting osteogenesis to accelerate or enhance bone fracture healing, treat bone defects, and enhance bone formation are disclosed. The methods modulate an arachidonic acid metabolic or signaling pathway in general, and, in particular, utilize 5-lipoxygenase inhibitors. These molecules can be delivered alone or in combination with one or more agents that inhibit bone resorption, regulate calcium resorption from bone, enhance bone accumulation, enhance bone formation, induce bone formation, impair growth of microorganisms, reduce inflammation, and/or reduce pain.

We claim: 
     
         1 . A method for promoting osteogenesis to treat a mammalian subject in need thereof, comprising: administering to said subject a pharmaceutically effective amount of compound that reduces a 5-lipoxygenase activity, wherein said 5-lipoxygenase activity reduction promotes osteogenesis to treat a condition selected from the group consisting of a bone fracture, a bone defect, and a condition treated by inducing bone formation. 
     
     
         2 . The method of  claim 1 , wherein said condition is a bone fracture. 
     
     
         3 . The method of  claim 2 , wherein said bone fracture is a non-osteoporotic fracture, an osteoporotic fracture, a fracture associated with a congenital disease, a fracture associated with an acquired disease, or an osteotomic fracture. 
     
     
         4 . The method of  claim 3 , wherein said bone fracture is a non-osteoporotic fracture. 
     
     
         5 . The method of  claim 3 , wherein said bone fracture is an osteoporotic fracture. 
     
     
         6 . The method of  claim 3 , wherein said bone fracture is an osteotomic fracture. 
     
     
         7 . The method of  claim 1 , wherein said condition is a condition treated by inducing bone formation. 
     
     
         8 . The method of  claim 7 , wherein said condition is a condition treated by a spine fusion, or a joint arthrodesis. 
     
     
         9 . The method of  claim 1 , wherein said condition is a bone defect. 
     
     
         10 . The method of  claim 1 , wherein said administration is in vivo. 
     
     
         11 . The method of  claim 1 , wherein said administration is ex vivo. 
     
     
         12 . The method of  claim 1 , wherein said compound reduces a 5-lipoxygenase activity by inhibiting a five lipoxygenase activating protein (FLAP). 
     
     
         13 . The method of  claim 1 , wherein said compound comprises a small molecule. 
     
     
         14 . The method of  claim 13 , wherein said small molecule is selected from the group consisting of 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK886); 3-(1-(4-chlorobenzyl)-3-(1-butyl-thio)-5-(quinolin-2-yl-methoxy)-indol-2-yl)-2,2-dimethyl propanoic acid) (MK-591); nordihydroguaiaretic acid (NDGA); 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benzoquinone (AA861); (N-(1-benzo(b)thien-2-ylethyl)-N-hydroxyurea) (zileuton); masoprocol; tenidap; flobufen; lonapalene; tagorizine; AA-861; Abbott A-121798; Abbott A-76745; Abbott A-78773; [(R)(+)N′-[[5-(4-fluorophenoxyl)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175); Abbott ABT 761; Dainippon AL-3264; Bayer Bay-x-1005; Biofor BF-389; bunaprolast; Cytomed CMI-392; Takeda CV-6504; enazadrem phosphate; Leo Denmark ETH-615; flezelastine hydrochloride; Merck Frosst L-663536; Merckle ML-3000; 3M Pharmaceuticals R-840; rilopirox; Schering Plough SCH-40120; tepoxalin; linazolast (TMK-688); Zeneca ZD-2138; Bristol-Myers Squibb BU-4601A; carbazomycin C; lagunamycin; Wellcome BW-70C; Ciba-Geigy CGS-26529; Warner-Lambert CI 1004; Warner-Lambert PD-136005; Warner-Lambert PD-145246; Elsai E-3040; Fujirebio F-1322; Fujisawa FR-110302; Merck Frosst L-699333; Merck Frosst L-739010; Lilly LY-269415; Lilly LY-178002; Hoechst Roussel P-8892; SmithKline Beecham SB-202235; American Home Products WAY-121520; American Home Products WAY-125007; Zeneca ZD-7717; Zeneca ZM-216800; Zeneca ZM-230487; 1,2-dihydro-n-(2-thiazolyl)-1-oxopyrrolo(3,2,1-kl)phenothiazine-1-carboxamide; Abbott A-65260; Abbott A-69412; Abbott-63162; American Home Products AHR-5333; Bayer Bay-q-1531; Boehringer Ingelheim BI-L-357; Boehringer Ingelheim BI-L-93BS; Boehringer Ingelheim BIL 226XX; Bristol-Myers Squibb BMY-30094; carbazomycin B; Wellcome BW-B218C; Chauvin CBS-1114; Ciba-Geigy CGS-21595; Ciba-Geigy CGS-22745; Ciba-Geigy CGS-23885; Ciba-Geigy CGS 24891; Ciba-Geigy CGS-8515; Chiesi CHF-1909; Warner-Lambert CI-986; Warner-Lambert CI 987; cirsiliol; docebenone; Eisai E-5110; Eisai E-6080; enofelast; epocarbazolin-A; eprovafen; evandamine; Fisons FPL 62064; Zeneca ICI-211965; Zeneca ICI-216800; Kyowa Hakko KF-8940; Merck & Co L-651392; Merck & Co L-651896; Merck & Co L-652343; Merck & Co L-656224; Merck & Co L-670630; Merck & Co L-674636; Lilly LY-233569; Merck & Co MK-591; Merck & Co L-655240; nitrosoxacin-A; Ono ONO-5349; Ono ONO-LP-219; Ono ONO-LP-269; Warner-Lambert PD-127443; Purdue Frederick PF-5901; Rhone-Poulenc Rorer Rev-5367; Rhone-Poulenc Rorer RG-5901-A; Rhone-Poulenc Rorer RG-6866; Roussel-Uclaf RU-46057; Searle SC-41661A; Searle SC-45662; Sandoz SDZ-210-610; SmithKline Beecham SK&F-104351; SmithKline Beecham SK&F-104493; SmithKline Beecham SK&F-105809; Synthelabo SL-81-0433; Teijin TEI-8005; Terumo TMK-777; Terumo TMK-781; Terumo TMK-789; Terumo TMK-919; Terumo TMK-992; Teikoku Hormone TZI-41127; American Home Products WAY-120739; American Home Products WY-47288; American Home Products WY-48252; American Home Products WY-50295; Yoshitomi Y-19432; 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide; esculetin; phenidone; BI-L-239; 5,8,11-eicosatriynoic acid (ETI); 5,8,11,14-eicosatetraynoic acid (ETYA); cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate; curcumin; esculeitin; gossypol; caffeic acid; baicalein; 7,7-dimethyleicosadrenoic acid (DEDA); Ly311727; bromoenol lactone; methyl arachidonyl fluorophosphonate; methyl y-linolenyl fluorophosphonate; oleyoxyethyl phosphorylcholine; AACOCF3; n-(p-amylcinnamoyl) anthranilic acid; mepacrine; quinacrine; atabrine; parabromophenacylbromide; aristolochic acid; cortisone Glaxo SmithKline 480848; Glaxo SmithKline 659032; Glaxo SmithKline 677116; BMS-181162; MJ33; and Millennium Pharmaceuticals MLN977. 
     
     
         15 . The method of  claim 14 , wherein said small molecule is selected from the group consisting of masoprocol; tenidap; (N-(1-benzo(b)thien-2-ylethyl)-N-hydroxyurea) (zileuton); flobufen; lonapalene; tagorizine; AA-861; Abbott A-121798; Abbott A-76745; Abbott A-78773; [(R)(+)N′-[[5-(4-fluorophenoxyl)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175); Abbott ABT 761; Dainippon AL-3264; Bayer Bay-x-1005; Biofor BF-389; bunaprolast; Cytomed CMI-392; Takeda CV-6504; Ciba-Geigy CGS-26529; enazadrem phosphate; Leo Denmark ETH-615; flezelastine hydrochloride; Merck Frosst L-663536; Merck Frosst L-699333; Merckle ML-3000, 3M Pharmaceuticals R-840; rilopirox; Schering Plough SCH-40120; tepoxalin; linazolast (TMK-688); Zeneca ZD-7717; Zeneca ZM-216800; Zeneca ZM-230487; Zeneca ZD-2138; and NDGA (nondihydroguaiaretic acid). 
     
     
         16 . The method of  claim 15 , wherein said small molecule is selected from the group consisting of tenidap; zileuton; flobufen; lonapalene; tagorizine; AA-861; Abbott A-121798; Abbott A-76745; Abbott A-78773; [(R)(+)N′-[[5-(4-fluorophenoxyl)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175); Abbott ABT 761; Ciba-Geigy CGS-26529; Biofor BF-389; Cytomed. CMI-392; Leo Denmark ETH-615; Merck Frosst L 699333; Merckle ML-3000; 3M Pharmaceuticals R-840; linazolast (TMK-688); Zeneca ZD-7717; Zeneca ZM-216800; Zeneca ZM-230487; Zeneca ZD-2138, and NDGA (nondihydroguaiaretic acid). 
     
     
         17 . The method of  claim 11 , wherein said compound comprises a nucleic acid comprising a sequence selected from the group consisting of 5′-AAC TGG GCG AGA TCC AGC TGG-3′, 5′-AAG CTC CCG GTG ACC ACG GAG-3′, 5′-AAG GAA GCC ATG GCC CGA TTC-3′, 5′-AAT CGA GAA GCG CAA GTA CTG-3′, 5′-AAG GAG TGG ACT TTG TTC TGA-3′, 5′-AAC TTC GGC CAG TAC GAC TGG-3′, 5′-AAG TTG GCC CGA GAT GAC CAA-3′, 5′-AAC ACA TCT GGT GTC TGA GGT-3′, 5′-AAC CAT GCG AGC CCC GCC ACC-3′, 5′-AAG CAA ACA TGG ATC AAG AAA-3′, 5′-AAG TTC CTG CTG CGT TTG CTG-3′, 5′-AAT TCA GCT CTT GAG AGC ATT-3′, 5′-AAT GGA TTC TTT GCC CAT AAA-3′, 5′-AAG TAC TTT GTC GGT TAC CTA-3′, 5′-AAT CTA TTG GCC ATC TGG GCT-3′, 5′-AAC CAG AAC TGT GTA GAT GCG-3′ 5′-AAG TGA CTT TGA AAA CTA CAT-3′, and 5′-AAT GAT GTC ATG TCA GCT CCG-3′. 
     
     
         18 . The method of  claim 11 , wherein said compound comprises a nucleic acid comprising a sequence selected from the group consisting of 5′-GCA GGT GCT TCT CGC TGC AGC C-3′, 5′-GCC AGT ACT TGC GCT TCT CG-3′, 5′-CCA TCG ATA TTG TTT TTG CC-3′, 5′-GGA GCT TCT CGG GCA GCT CTG TGC-3′, 5′-CCA GGT TCT TAT ACA GCA AGC-3′, 5′-CCA GCA GCT TGA AAA TGG GGT GC-3′, 5′-GCC CCG GGC CTT GAT GGC C-3′, 5′-CCA CGC CCT TGG CAG TCG G-3′, 5′-GCG GAA TCG GGC CAT GGC TTC C-3′, 5′-GTT CCG GTC CTC TGG AAG CTC C-3′, 5′-CGC AGA CCA GAG CAC AGC G-3′, 5′-GCA AAC GCA GCA GGA AC-3′, 5′-CGT TTC CCA AAT ATG TAG CC-3′, 5′-GTT TTC AAA GTC ACT TCC G-3′, 5′-GGT TAA CTC AAG CTG TGA AGC-3′, 5′-GGA GCT GAC ATG ACA TC-3′, and 5′-GGC CAC GGT CAT GTT CAA GG-3′. 
     
     
         19 . The method of  claim 1 , further comprising administering to said subject a pharmaceutically effective amount of a compound that reduces a COX-1 activity. 
     
     
         20 . The method of  claim 19 , wherein said compound is selected from the group consisting of SC-560, FR122047, Valeroyl salicylate, Aspirin, Dexketoprofene, Keterolac, Flurbiprofen, and Suprofen. 
     
     
         21 . The method of  claim 1 , further comprising administering to said subject a pharmaceutically effective amount of a compound that increases a COX-2 activity. 
     
     
         22 . The method of  claim 21 , wherein said compound is selected from the group consisting of Prostaglandin E2, butaprost, sulprostone, CP-536,745-01, CP-043,305-02, CP-044,519-02, CP432, ONO-4819, CP-533,536, prostaglandin F 2α , bimatoprost, cloprostenol, latanoprost, tafluprost, bone morphogenetic protein-2 (BMP2), platelet derived growth factor (PDGF), interleukin-1α, interleukin-1β, tumor necrosis factor-alpha (TNF-α), fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), epidermal growth factor (EGF), parathyroid hormone (PTH), parathyroid hormone related peptide (PTHrP), and teraparatide. 
     
     
         23 . The method of  claim 1 , comprising administering to said subject an ultrasound therapy or exposing said subject to a pulsed electromagnetic field in an amount sufficient to increase a COX-2 activity in said subject.