Treatment and prevention of bone loss using resolvins

Abstract

The invention provides new methods for inducing or promoting bone growth and/or for reducing or preventing bone deterioration in a mammal subject. The inventive methods generally comprise administering to the subject an effective amount of a resolving. In particular, the inventive methods may be useful for treating or preventing conditions associated with bone degradation, deterioration or degeneration such as periodontal disease, osteoarthritis, and metastatic bone disease and osteolytic bone disease. Pharmaceutical compositions and kits comprising at least one resolving are also provided that can be used to performed the inventive methods.

1 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising at least one resolvin, at least one therapeutic agent that promotes bone growth or inhibits bone resorption, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the therapeutic agent that promotes bone growth or inhibits bone resorption is selected from the group consisting of bone morphogenetic factors, anti-resorptive agents, osteogenic factors, cartilage-derived morphogenetic proteins, growth hormones, estrogens, bisphosphonates, statins, differentiating factors, growth factors, connective tissue activating peptides (CTAPs). minerals, vitamins, hormones. prostaglandins, inhibitors of 15-lipoxygenase. dexamethasone, bone morphogenic proteins, progestins, estrone, estriol, 17α-ethynyl estradiol, 17β-ethynyl estradiol, SB242784, polyphosphonates, and combinations thereof. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein said at least one resolvin is selected from the group consisting of members of the Resolvin E series, members of the Resolvin D series, and combinations thereof. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein said at least one resolvin is selected from the group consisting of di-hydroxy members of the Resolvin E series, di-hydroxy members of the Resolvin D series, tri-hydroxy members of the Resolvin E series, tri-hydroxy members of the Resolvin D series, and combinations thereof. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein said at least one resolvin comprises Resolvin El, Resolvin D1, or Resolvin D2. 
     
     
         23 . The pharmaceutical composition of  claim 18 , wherein said composition is formulated to be administered topically. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein said composition is formulated to be topically administered to a subject that is susceptible to or is suffering from a bone condition associated with bone loss. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein said bone condition is selected from the group consisting of periodontal disease, bone fracture, bone deficiency, metastatic bone disease, osteoarthritis, and osteolytic bone disease. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein periodontal disease is gingivitis or periodontitis. 
     
     
         27 . The pharmaceutical composition of  claim 23 , wherein said composition is formulated to be administered topically to the subject's oral cavity. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said composition is formulated as a preparation selected from the group consisting of solution, suspension, dispersion, ointment, cream, gel, toothpaste, tooth powder, lozenge, salve, chewing gum, aerosol, mouth spray, pastille, sachet, mouthwash, toothpick, tablet, capsule, and dental floss. 
     
     
         29 . The pharmaceutical composition of  claim 18 , wherein said composition further comprises at least one additional therapeutic agent selected from the group consisting of analgesics, anesthetics, antimicrobial agents, antibacterial agents, antiviral agents, antifungal agents, antibiotics, anti-inflammatory agents, antioxidants, antiseptic agents, immunostimulating agents, antiprotozoan agents, and combinations thereof. 
     
     
         30 . The pharmaceutical composition of  claim 18 , wherein administration of said composition to a subject in need thereof results in one or more of: prevention of bone deterioration, prevention of bone degradation, prevention of bone degeneration, prevention of loss of bone mass, prevention of loss of bone density, stabilization of bone deterioration, stabilization of bone degradation, stabilization of bone degeneration, stabilization of loss of bone mass, stabilization of loss of bone density, decrease of bone deterioration, decrease of bone degradation, decrease of bone degeneration, decrease of loss of bone mass, decrease of loss of bone density, increase of bone mass, increase of bone density, and combinations thereof. 
     
     
         31 - 46 . (canceled) 
     
     
         47 . The pharmaceutical composition of  claim 19 , wherein the growth factor is selected from the group consisting of IGF-1, IGF-2, macrophage growth factor, platelet derived growth factors (PFGDs), fibroblast growth factors (FGFs), epidermal growth factors (EGFs), and transforming growth factors (TGFs), optionally wherein the TGF is TGFβ. 
     
     
         48 . The pharmaceutical composition of  claim 19 , wherein the bone morphogenic protein is selected from the group consisting of BMP-1, BMP-2α, BMP-2β, BMP-3β, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8β, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, and BMP-15. 
     
     
         49 . The pharmaceutical composition of  claim 19 , wherein the statin is selected from the group consisting of lovastatin, pravastatin, velostatin, simvastatin, fluvastatin, cerivastatin, mevastatin, dalvastatin, fluindostatin, atorvastatin, and a prodrug, or a physiologically acceptable salt thereof. 
     
     
         50 . The pharmaceutical composition of  claim 19 , wherein the cartilage-derived morphogenetic protein is selected from the group consisting of CDMP-1, CDMP-2, and CDMP-3. 
     
     
         51 . The pharmaceutical composition of  claim 19 , wherein the mineral is selected from the group consisting of calcium, aluminum, strontium and fluoride. 
     
     
         52 . The pharmaceutical composition of  claim 19 , wherein the hormone is parathyroid hormone (PTH) or parathyroid hormone related protein (PTHrP). 
     
     
         53 . The pharmaceutical composition of  claim 19 , wherein the prostaglandin is selected from the group consisting of PDG1, PDG2, PGE2, PGE1, and PGF2. 
     
     
         54 . The pharmaceutical composition of  claim 19 , wherein the bisphosphonate is selected from the group consisting of etidronate, clodronate, tiludronate, alendronate, pamidronate, and ibandronate. 
     
     
         55 . The pharmaceutical composition of  claim 29 , wherein the analgesic is selected from the group consisting of aspirin, ibuprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, and indomethacin. 
     
     
         56 . The pharmaceutical composition of  claim 29 , wherein the anesthetic is selected from the group consisting of xylocaine, lidocaine, benzocaine, and sodium-channel blockers. 
     
     
         57 . The pharmaceutical composition of  claim 29 , wherein the antiviral agent is selected from the group consisting of RNA synthesis inhibitors, protein synthesis inhibitors, immunostimulating agents, protease inhibitors, acyclovir, amantadine hydrochloride, foscarnet sodium, ganeiclovir sodium, phenol, ribavirin, vidarabine, and zidovudine. 
     
     
         58 . The pharmaceutical composition of  claim 29 , wherein the antifungal agent is selected from the group consisting of lactic acid, sorbic acid, Amphotericin B, Ciclopirox, Clotrimazole, Enilconazole, Econazole, Fluconazole, Griseofulvin, Halogropin, Introconazole, Ketoconazole, Miconazole, Naftifine, Nystatin, Oxiconazole, Sulconazole, Thiabendazole, Terbinafine, Tolnaftate, Undecylenic acid, Mafenide, Silver Sulfadiazine, and Carbol-Fushsin. 
     
     
         59 . The pharmaceutical composition of  claim 29 , wherein the antibiotic, antimicrobial, or antibacterial agent is selected from the group consisting of bacitracin, cephalosporins, cycloserine, fosfomycin, penicillins, ristocetin, vancomycin, colistin, novobiocin, polymyxins, aminoglycosides, tetracyclines, carbapenems, monobactams, chloramphenicol, clindamycin, cycloheximide, fucidin, lincomycin, puromycin, rifampicin, streptomycins, macrolides, fluoroquinolones, actinomycin, ethambutol, 5-fluorocytosine, griseofulvin, rifamycins, sulfonamides, trimethoprim, bismuth containing compounds, nitrofurans, metronidazole, tinidazole, nimorazole, and benzoic acid. 
     
     
         60 . The pharmaceutical composition of  claim 29 , wherein the antiseptic agent is selected from the group consisting of benzalkonium chloride, chlorhexidine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol, and cetylpyridinium chloride. 
     
     
         61 . The pharmaceutical composition of  claim 29 , wherein the immunostimulating agent is selected from the group consisting of interleukin 1 agonists, interleukin 2 agonists, interferon agonists, RNA synthesis inhibitors, and T cell stimulating agents. 
     
     
         62 . The pharmaceutical composition of  claim 29 , wherein the anti-inflammatory agent is selected from the group consisting of aspirin, ibuprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, indomethacin, aclomethasone dipropionate, flunisolide, fluticasone, budesonide, triamcinolone, triamcinoline acetonide, beclomethasone diproprionate, betamethasone valerate, betamethasone diproprionate, hydrocortisone, cortisone, dexamethason, mometasone furoate, prednisone, methylprednisolone aceponate, prednisolone. 
     
     
         63 . The pharmaceutical composition of  claim 29 , wherein the antioxidant is selected from the group consisting of vitamin A, vitamin B, vitamin C, α-carotene, β-carotene, γ-carotene, δ-carotene, vitamin E, β-tocopherol, γ-tocopherol, δ-tocopherol, tocoquinone, tocotrienol, butylated hydroxy anisole, cysteine, and active derivatives, analogs, precursors, prodrugs, pharmaceutically acceptable salts or mixtures thereof.