WO2009064465A1 - Methods for treating and preventing bisphosphonate-induced osteonecrosis - Google Patents

Abstract

The invention also features a method for treating or preventing bisphosphonate-induced osteonecrotic bone (e g, bone of a tooth socket or other part of the jaw bone) by administering to a patient (e g, a human) in need thereof, the composition of the first aspect of the invention The administration method includes the implantation of the composition into the site of extracted teeth (tooth sockets) following their removal The method includes surgically extracting necrotic bone from an extraction site in the jaw, implanting the composition at the extraction site, and surgically closing the extraction site In another embodiment, the composition releases the bisphosphonate inhibitor, the bisphosphonate binding agent, or other active agent into the tooth socket or extraction site following implantation of the composition

Description

METHODS FOR TREATING AND PREVENTING BISPHOSPHONATE-INDUCED OSTEONECROSIS

BACKGROUND OF THE INVENTION Osteonecrosis of the jaw (ONJ) has become a recognized complication of bisphosphonate treatment. Initially described in cancer patients receiving intravenous formulations of nitrogen-containing bisphosphonates, ONJ has also been noted in patients being treated with per oral bisphosphonates for the prevention of osteoporosis. It is believed that the therapeutic benefit of bisphosphonates is based on their ability to attenuate osteoclast activity and is mediated through inhibition of farnesyl disphosphate synthase and its associated pathways.

Despite being recognized as a clinical entity since 2003, the mechanism(s) underlying ONJ is unresolved. For the most part ONJ has been attributed to bisphosphonates direct impact on osteoclast and osteoblast activity. The possible involvement of bacteria (Actinomyces) has also been suggested. Recently, Reid et al. (Bone 41 :318-320, 2007) proposed that an alternative mechanism might be a direct effect of bisphosphonates on the inhibition of epithelial proliferation. This concept was based on observations of soft tissue injury, i.e. esophagitis, as a common adverse event associated with bisphosphonate use. There is currently no preventive or active treatment for ONJ.

Since bisphosphonates preferentially bind to active bone, the level of the drug in the jaws is markedly higher than in long bones. Consequently, it seems likely that manipulation of the jaws, as happens in a tooth extraction or inflammatory dental diseases, could easily release bound bisphosphonate, which could produce high, biologically active levels of the drug within the tissues of the subniucosa that could damage the epithelium, inhibit healing, and predispose or lead to bone necrosis. There exists a need in the art for methods and compositions for treating or preventing this result.

SUMMARY OF THE INVENTION

The invention features a composition that includes an implant material and an active agent selected from a bisphosphonate inhibitor (e.g., a pyrophosphate, such as a geranylgeranyl pyrophosphate), a bisphosphonate binding agent (e.g., a calcium phosphate, such as a hydroxyapatite), and other agents (e.g., nuclear factor-kappa B (NF-κB) inhibitors) capable of treating or reducing osteonecrosis of the jaw (ONJ). The implant material can be a porous material or a buccal patch (e.g., a flexible film that is capable of adhering to the oral mucosa). The implant material can be formulated to provide sustained release of the bisphosphonate inhibitor, the bisphosphonate binding agent, or other active agent. The compositions of the invention can further include one or more additional biologically active agents.

The invention also features a method for treating or preventing bisphosphonate-induced osteonecrotic bone (e.g., bone of a tooth socket or other part of the jaw bone) by administering to a patient (e.g., a human) in need thereof, the composition of the first aspect of the invention. In an embodiment, administration according to the method includes the implantation of the composition into the site of extracted teeth (tooth sockets) following their removal. The soft tissue bordering the socket may or may not be sutured. In another embodiment, the method includes surgically extracting necrotic bone from an extraction site in the jaw, implanting the composition at the extraction site, and surgically closing the extraction site. In another embodiment, the composition releases the bisphosphonate inhibitor, the bisphosphonate binding agent, or other active agent into the tooth socket or extraction site following implantation of the composition. In another embodiment, administration includes placing the composition on irritated epithelial oral mucosa, e.g., so that the composition releases the bisphosphonate inhibitor, the bisphosphonate binding agent, or other active agent into the mucosa following the placing of the composition. In yet another embodiment, the bisphosphonate inhibitor treats or prevents osteonecrosis by inhibiting the action of free bisphosphonate (e.g., by binding to free bisphosphonate).

In an embodiment of the invention, the compositions and methods treat osteonecrosis of the jaw, reduce or inhibit the likelihood of an initial or subsequent occurrence of osteonecrosis of the jaw, or reduce the severity of, or reverse, one or more symptoms of osteonecrosis of the jaw. In a desired embodiment, the compositions and methods of the invention reduce the severity of, or reverse, one or more symptoms of osteonecrosis by at least 20% or more as determined using any standard rubric. By "biologically active agent" is meant any agent that produces a preventative, healing, curative, stabilizing, ameliorative or other beneficial therapeutic effect. Preferably, a biologically active agent of the present invention demonstrates one or more of these effects on bisphosphonate-induced osteonecrosis of the jaw in a patient in need thereof. Examples of biologically active agents include, e.g., an antiinflammatory agent, antimicrobial agent, antifungal agent, antiviral agent, antiproliferative agent, analgesic, anesthetic, immunomodulator, or a lubricant. The anti-inflammatory agent may be, e.g., ibuprofen, tacrolimus, rofecoxib, celecoxib, flubiprofen, diclofenac, or ketarolac. The antimicrobial agent may be, e.g., penicillin, ampicillin, methicillin, oxacillin, amoxicillin, cefadroxil, ceforanid, cefotaxime, ceftriaxone, doxycycline, minocycline, tetracycline, amikacin, gentamycin, kanamycin, neomycin, streptomycin, tobramycin, azithromycin, clarithromycin, erythromycin, ciprofloxacin, lomefloxacin, moxifloxacin, norfloxacin, chloramphenicol, clindamycin, cycloserine, isoniazid, rifampin, or vancomycin. In an embodiment, the anti-inflammatory agent is an NF-κB inhibitor. The antiviral agent may be, e.g., ribavirin, 9-2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo- 2'-deoxyuridine, trifluorothymidine, interferon, adenine arabinoside, acyclovir, penciclovir, valacyclovir, or ganciclovir. The antiproliferative agent may be, e.g., asparaginase, bleomycin, busulfan carmustine (BCNU), chlorambucil, cladribine (2- CdA), CPTl 1, cyclophosphamide, cytarabine (Ara-C), dacarbazine, daunorubicin, dexamethasone, doxorubicin (adriamycin), etoposide, fludarabine, 5-fluorouracil (5FU), hydroxyurea, idarubicin, ifosfamide, interferon-α (native or recombinant), levamisole, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, paclitaxel, pentostatin, prednisone, procarbazine, tamoxifen, taxol-related compounds, 6-thioguanine, topotecan, vinblastine, or vincristine. The antifungal agent may be, e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, or ketoconazole. The analgesic may be, e.g., morphine, codeine, hydrocodone, oxycodone, acetaminophen, aspirin, codeine, naproxen, or ibuprofen. The anesthetic may be, e.g., procaine, lidocaine, tetracaine, dibucaine, benzocaine, p- buthylaminobenzoic acid 2-(diethylamino) ethyl ester HCl, mepivacaine, piperocaine, or dyclonine. The lubricant may be, e.g., hyaluronic acid, a proteoglycan, chondroitin sulfate, a cellulose derivative, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, collagen, a viscosifier, polyvinyl alcohol, polyvinylpyrrolidone, or a carboxyvinyl polymer. The immunomodulator may be, e.g., ascomycin, cyclosporine, everolimus, pimecrolimus, rapamycin, tacrolimus, beclomethasone, budesonide, dexamethasone, fluorometholone, fluticasone, hydrocortisone, loteprednol etabonate, medrysone, rimexolone, or triamcinolone.

By "bisphosphonate" is meant a class of drugs used to in the treatment of bone resorption disorders. Bone is in a constant state of remodeling, whereby new bone is laid down by cells called osteoblasts while old bone is removed by cells called osteoclasts. Bisphosphonates inhibit bone removal (resorption) by osteoclasts. Bisphosphonates are used to treat osteoporosis and the bone pain from diseases such as metastatic breast cancer, multiple myeloma, and Paget' s disease. The bisphosphonates include but are not limited to FOSAMAX™ (alendronate sodium), AREDIA™ (pamidronate sodium), ACTONEL™ (risedronate sodium), BONIV A™ (ibandronate sodium), DIDRONEL™ (etidronate), and ZOMET A™ (zolendronic acid).

By "microbe" is meant a bacterium or a fungus. By "microbial" is meant of or relating to bacteria or fungi. Exemplary bacteria include, e.g., staphylococci (e.g., Staphylococcus epidermidis or Staphylococcus aureus), Actinomyces sp., Enter ococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and other gram-positive and gram-negative bacteria. A fungus may be, e.g., Candida albicans, Candida glabrata, Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, Absidia corymbifera, Rhizomucor pusillus, and Rhizopus arrhizus.

By "patient" is meant any mammal (e.g., a human). A patient who is being treated using a method or device described herein may be one who has been diagnosed by a medical practitioner as being in need of such a method or device. Diagnosis may be performed by any suitable means. One skilled in the art will understand that patients described herein may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age, a family history of a disease, prior or present treatment with a bisphosphonate, etc.

DETAILED DESCRIPTION The present invention features methods and devices for treating or preventing the development of ONJ in patients who are about to receive, are receiving, or who have received treatment with a bisphosphonate. Prophylactic treatment can occur before the patient begins treatment with a bisphosphonate or after treatment with a bisphosphonate but before the patient exhibits signs of osteonecrosis or irritation of the oral mucosa. Preferably, a composition of the invention is used for prophylactic treatment in patients who undergo an oral surgical procedure and are about to start bisphosphonate therapy and in patients who are receiving biphosphonate treatment and require a surgical procedure. For example, a patient who undergoes a dental procedure (e.g., a tooth extraction) prior to bisphosphonate treatment, can be administered a composition of the invention at the site of the dental procedure (e.g., the composition can be placed directly in the tooth socket). Alternatively, treatment with a composition of the invention can occur after the patient exhibits signs of osteonecrosis or irritation of the oral mucosa following bisphosphonate treatment. For example, a patient who has already received treatment with a bisphosphonate and who undergoes a dental procedure (e.g., a tooth extraction or extraction of a region of the jaw can be administered a composition of the invention at the site of the dental procedure (e.g., the composition can be placed directly in the tooth socket or at the site of region of the osteonecrotic jaw).

The invention features the use of a porous, gel-like matrix (similar to GELFOAM^®, hydrophilic gels, polylactic acid) a patch version (e.g., freeze-dried gel patch similar to ORAP ATCH™), or a membrane into which is incorporated a biologically active agent that reverses the biological effects of bisphosphonates on cell proliferation (growth arrest). Examples of biologically active agents include, e.g., pyrophosphate (e.g., a geranylgeranyl pyrophosphate or other pyrophosphate, e.g., those described in United States Patent Application Publication No. 2002/0035058, which is incorporated herein by reference in its entirety), materials that preferentially bind to free bisphosphonate, such as hydroxyapatite, other biologically active agents, such as those described herein (e.g., an NF-κB inhibitor), or combinations thereof. In a first aspect, the invention features the use of a porous material (e.g., formulated as a gel-like matrix, such as GELFO AM^®) for treating or preventing bisphosphonate-induced osteonecrosis of the jaw (BONJ) following a tooth extraction, either surgically or non-surgically, or any surgical manipulation of the jaw (e.g., removal of a cyst or other extraction of jaw bone material). The porous material is to be placed into the extraction site (e.g., a socket) immediately following tooth extraction. At the time of surgery, the surgical site (extraction) will be implanted immediately postoperatively with the porous material impregnated with a biologically active agent, such as a compound or other agent known to inhibit the action of bisphosphonate (i.e., a "bisphosphonate inhibitor"), a material, such as hydroxyapatite, that will preferentially bind to free bisphosphonate (i.e., a "bisphosphonate binding agent"), an agent that will treat, reduce, or reverse the effects of BONJ, or combination thereof. The overlying mucosa is to be sutured in a conventional fashion. The bisphosphonate excreted from bone will be inactivated by the bisphosphonate inhibitor or bisphosphonate binding agent and, consequently, the bisphosphonate will not reach a tissue level of sufficient concentration to retard epithelial and bony healing. The porous material can also include one or more additional biologically active agents.

In several embodiments, the bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combination thereof incorporated into the porous material makes up at least 1 wt% of the composition, preferably at least about 5, 10, or 15 wt% of the composition, more preferably at least about 20, 25, and 30 wt% of the composition, and most preferably at least about 35, 40, 45, and 50 wt% of the composition. The bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combination thereof is released (e.g., continuously) into tissue following its placement at the extraction site(s) for at least 24 hours (e.g., 1-3 days), preferably for at least 1 week (e.g., 1-2 weeks), more preferably for at least 3 weeks (e.g., 3-4 weeks), and most preferably for at least 1 month or more (e.g., 1 , 2, 3, 4, 5, or 6 months).

In a second aspect, invention features the use of a material (e.g., formulated as a tissue patch) for treating or preventing BONJ following mucosal irritation. The material is impregnated with a bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combination thereof. The material is to be placed over the area of irritation at least once every 24 hrs and is to remain at the site for at least 1 hour, preferably at least 6, 12, or 18 hours, and more preferably at least 24 hours or more. The material may be replaced daily for up to 1-2 weeks (or more, if necessary) until epithelial (mucosal) healing is complete. The bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combination thereof incorporated into the material makes up at least 1 wt% of the composition, preferably at least about 5, 10, or 15 wt% of the composition, more preferably at least about 20, 25, and 30 wt% of the composition, and most preferably at least about 35, 40, 45, and 50 wt% of the composition. The bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combinations thereof is released (e.g., continuously) at the site of irritation. In another embodiment, the bisphosphonate inhibitor, bisphosphonate binding agent, other agent that treats, reduces, or reverses the effects of BONJ, or combination thereof is incorporated into a sustained release material that can be applied to a tissue site periodically, e.g., daily, 2-3 times weekly, 1-2 times monthly, etc., and that releases the bisphosphonate inhibitor, bisphosphonate binding agent, or other agent that treats, reduces, or reverses the effects of BONJ for at least 24 hours (e.g., 1-3 days), preferably for at least 1 week (e.g., 1-2 weeks), more preferably for at least 3 weeks (e.g., 3-4 weeks), and most preferably for at least 1 month or more (e.g., 1, 2, 3, 4, 5, or 6 months). In an embodiment, the material is applied to a tissue site daily for up to 2 weeks. The "patch" material can also include one or more additional biologically active agents. Examples of materials for use as a "patch" can be found in, e.g., U.S. Pat. No. 3,598,122; U.S. Pat. No. 3,972,995; U.S. Pat. No. 4,517,173; U.S. Pat. No. 4,573,996; U.S. Pat. No. 4,572,832; U.S. Pat. No. 4,704,1 19; U.S. Pat. No. 4,713,243; U.S. Pat. No. 4,715,369; U.S. Pat. No. 4,740,365; U.S. Pat. No. 4,855,142; U.S. Pat. No. 4,876,092; U.S. Pat. No. 4,900,552; U.S. Pat. No. 4,900,554; U.S. Pat. No. 5,137,729; U.S. Pat. No. 5,298,256; U.S. Pat. No. 5,346,701 ; U.S. Pat. No. 5,516,523; U.S. Pat. No. 5,578,315; U.S. Pat. No. 5,599,554; U.S. Pat. No. 5,639,469; U.S. Pat. No.

5,766,620; U.S. Pat. No. 5,800,832; U.S. Pat. No. 5,863,555; U.S. Pat. No. 5,900,247; U.S. Pat. No. 6,159,498; U.S. Pat. No. 6,210,699; U.S. Pat. No. 6,319,510; and U.S. Patent No. 7,276,246; each of which is incorporated herein by reference in their entirety.

In a third aspect, the invention features the application of a material that includes a bisphosphonate inhibitor, a bisphosphonate binding agent, an agent that treats, reduces, or reverses the effects of BONJ, or combinations thereof (with or without one or more additional biologically active agents) for use in periodontal or dental surgery, in which the material is to be placed under an elevated gingival flaps to cover the alveolar bone. The gingiva would then be sutured.

In an embodiment of all aspects of the invention, the implant material is or additionally includes one or more of the following: a bone substituting agent, a biocompatible binder (e.g., a natural or synthetic polymer), a liquid, a gel, and a pharmaceutically acceptable carrier substance. In another preferred embodiment, the implant material includes an additional biologically active agent.

In another embodiment of all aspects of the invention, the implant material, whether a porous material or a patch, is prepared by combining with a pharmaceutically acceptable carrier substance, e.g., a biocompatible binder, such as a natural or synthetic polymer (e.g., collagen, polyglycolic acid, and polylactic acid), a bone substituting agent (e.g., a calcium phosphate (e.g., tricalcium phosphate or hydroxy apatite), calcium sulfate, or demineralized bone (e.g., demineralized freeze- dried cortical or cancellous bone), or a commercially available gel or liquid (i.e., a viscous or inert gel or liquid).

In another embodiment of all aspects of the invention, an agent that treats, reduces, or reverses the effects of BONJ includes an NFKB inhibitor. The NFKB inhibitor can be included in a device of the invention or administered separately. The NFKB inhibitor can be selected from one or more of the following: sc-3060 (Santa Cruz Biotechnology, Inc.); MG132; helenalin; dexlipotam; R-flurbiprofen (1,1'- biphenyl)-4-acetic acid, 2-fluoro-alpha-methyl); SP100030 (2-chloro-N-(3,5- di(trifluoromethyl)phenyl)-4-(trifluoromethyl)pyrimidine- -5-carboxamide); AVE- 0545; Viatris; AVE-0547; Bay 1 1-7082; Bay 1 1-7085; 15 deoxy-prostaylandin J2; bortezomib (boronic acid, ((lR)-3-methyl-l -((2S)- -l-oxo-3-phenyl-2- ((pyrazinylcarbonyl)amino)propyl)amino)butyl); benzamide and nicotinamide derivatives that inhibit NF-kappaB, such as those described in U.S. Pat. Nos. 5,561,161 and 5,340,565 (OxiGene), both of which are incorporated herein by reference, and declopramide (benzamide, 4-amino-3-chloro-N-(2-(diethylamino)ethyl; also known as Oxi-104); curcumin; MOL 294 (a triazolo-pyridazinyl-2-butynoate derivate); IPL 576092; acetyl- 1 1-keto-β-boswellic acid (AKβBA); PG490-88Na (or an analogue or derivative thereof); the NFKB inhibitors disclosed in U.S. Patent Nos. 7,300,952 and 6,492,425, both of which are incorporated herein by reference; BXT- 51072 (3 ,4-dihydro-4, 4-dimethyl-2H- 1 , 2-benzoselenazine) ; cyclohexylcycloepoxydone compounds, such as panepoxydone and cycloepoxydone; macrolides; flavinoids; antioxidants, such as n-acetyl cysteine; sulforaphene; dithiocarbamates and complexes with transition metals; estrogen-dependent NF-κB inhibitors; thionamides; berberine; lidamycin; statins; and thalidomide. In several embodiments, the carrier substance of the implant material is, or additionally includes, one or more biocompatible binders. A biocompatible binder is an agent that produces or promotes cohesion between the combined substances. Non- limiting examples of suitable biocompatible binders include polymers selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), polylactic acid, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyglycolic acid, polyhydroxybutyrate (PHB), poly(ε-caprolactone), poly(δ- valerolactone), poly(γ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers and mixtures thereof. Additional binders include alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or sodium dextran sulfate), fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose (e.g., methylcellulose, carboxy methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose), a glucosamine, a proteoglycan, a starch (e.g., hydroxyethyl starch or starch soluble), lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and derivatives and mixtures thereof. In some embodiments, the biocompatible binder is water-soluble. A water-soluble binder dissolves from the implant material shortly after its implantation in vivo, thereby introducing macroporosity into the implant material. This macroporosity increases the osteoconductivity of the implant material by enhancing the access and, consequently, the remodeling activity of the osteoclasts and osteoblasts at the implant site.

The biocompatible binder may be added to the implant material in varying amounts and at a variety of stages during the preparation of the composition. Those of skill in the art will be able to determine the amount of binder and the method of inclusion required for a given application.

In an embodiment, the carrier substance is or includes a liquid selected from water, a buffer, and a cell culture medium. The liquid may be used in any pH range, but most often will be used in the range of pH 5.0 to pH 8.0. In most embodiments, the pH of the liquid will be in the range of pH 5.5 to pH 7.4. Suitable buffers include, but are not limited to, carbonates, phosphates (e.g., phosphate buffered saline), and organic buffers such as Tris, HEPES, and MOPS. Most often, the buffer will be selected for its biocompatibility with the host tissues and its compatibility with the bisphosphonate inhibitor or bisphosphonate binding agent.

In another embodiment of all aspects of the invention, the carrier substance of the implant material is, or additionally includes, one or more bone substituting agents. A bone substituting agent is one that can be used to permanently or temporarily replace bone. Following implantation, the bone substituting agent can be retained by the body or it can be resorbed by the body and replaced with bone. Exemplary bone substituting agent include, e.g., a calcium phosphate (e.g., tricalcium phosphate (e.g., β-TCP), hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and octacalcium phosphate), calcium sulfate, or demineralized bone (e.g., demineralized freeze-dried cortical or cancellous bone)). In an embodiment, the carrier substance is bioresorbable. In another embodiment, the bone substituting agent is provided as a matrix of micron- or submicron- sized particles, e.g., nano-sized particles. The particles can be in the range of about 100 μm to about 5000 μm in size, more preferably in the range of about 200 μm to about 3000 μm, and most preferably in the range of about 250 μm to about 2000 μm, or the particles can be in the range of about 1 nm to about 1000 nm, preferably less than about 500 run, and more preferably less than about 250 nm. In another embodiment, the bone substituting agent has a porous composition. Porosity of the composition is a desirable characteristic as it facilitates cell migration and infiltration into the composition so that the cells can secrete extracellular bone matrix. It also provides access for vascularization. Porosity also provides a high surface area for enhanced resorption and release of active substances, as well as increased cell-matrix interaction. Preferably, the composition has a porosity of greater than 40%, more preferably greater than 65%, and most preferably greater than 90%. The composition can be provided in a shape suitable for implantation (e.g., a sphere, a cylinder, or a block) or it can be sized and shaped prior to use. In a preferred embodiment, the bone substituting agent is a calcium phosphate (e.g., hydroxyapatite) .

In another embodiment, the bone substituting agent is admixed with the implant material to form a flowable, moldable paste or putty. Preferably, the bone substituting agent is a calcium phosphate paste that self-hardens to form a hardened calcium phosphate prior to or after implantation in vivo. The calcium phosphate component of the implant material may be any biocompatible calcium phosphate material known in the art. The calcium phosphate material may be produced by any one of a variety of methods and using any suitable starting components.

In several embodiments of all aspects of the invention, the implant material additionally may include one or more biologically active agents. Biologically active agents that can be incorporated into the implant materials of the invention include, without limitation, organic molecules, inorganic materials, proteins, peptides, nucleic acids (e.g., genes, gene fragments, gene regulatory sequences, and antisense molecules), nucleoproteins, polysaccharides, glycoproteins, and lipoproteins. Classes of biologically active compounds that can be incorporated into the implant materials of the invention include, without limitation, anti-cancer agents, antibiotics, antimicrobial agents, antifungal agents, antiviral agents, antiproliferative agents, analgesics, anesthetics, immunomodulators, lubricants, anti-inflammatory agents (e.g., an NFKB inhibitor), immunosuppressants, enzyme inhibitors, antihistamines, anti-convulsants, hormones, muscle relaxants, anti-spasmodics, ophthalmic agents, prostaglandins, anti-depressants, anti-psychotic substances, trophic factors, osteoinductive proteins, growth factors, and vaccines.

Anti-cancer agents include alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists/antagonists, endothelin A receptor antagonists, retinoic acid receptor agonists, immuno- modulators, hormonal and antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

Diagnosis of Osteonecrosis

Bisphosphonate-associated osteonecrosis of the jaw (BONJ), or "dead jaw," is an osteonecrotic bone disease that affects the maxillofacial region of the body. The onset of ONJ may be linked with the temporary or permanent loss of blood to bone tissue, leading to death of the tissue and the eventual collapse of the bone, or may occur as a result of an avascular necrotic event caused by bisphosphonate or bisphosphonate in connection with e.g., an infection, toxicity of the epithelium, or an alteration in bone metabolism. There are approximately 10,000 to 20,000 new cases of osteonecrosis diagnosed each year in the United States, most of which occur as a result of some type of bone injury such as a fracture or dislocation. In addition to being caused as a result of some type of trauma, instances of ONJ have also been caused as a result of using certain bisphosphonate drugs. For example, FOSAMAX^® (alendronate sodium) users run the risk of developing a serious case of osteonecrosis of the jaw and suffering through the extreme pain associated with the death of jawbone tissue. The pain associated with ONJ is said to be similar to that which is suffered by arthritics.

There are a variety of symptoms that a skilled artisan can use to diagnose osteonecrosis of the jaw in a patient. Oftentimes, ONJ may be asymptomatic throughout the early stages of disease development. It may take several weeks or months before a sufferer begins to experience some of the symptoms common to osteonecrosis of the jaw. When ONJ symptoms develop, it is often the result of some type of dental work (like tooth extraction) that bares the jawbone and helps to accelerate symptomatic presentation. Common ONJ symptoms can include: loose teeth, exposed bone, jaw / gum pain, jaw / gum swelling, jaw / gum infection; jaw numbness; loss of sensation; and dramatic gum loss. Bisphosphonate users displaying any of the aforementioned ONJ symptoms or those patients considering bisphosphonate treatment can be treated using the compositions and methods of the present invention.

EXAMPLE The present invention is illustrated by the following example, which is in no way intended to be limiting of the invention.

Example 1

Studies of the natural history, pathogenesis, and risk factors for ONJ have been limited by the need for human material and the absence of clinical predictability. To overcome this constraint, we developed an animal model of the condition by using Sprague-Dawley rats treated with a nitrogen-containing bisphosphonate. Our studies demonstrate that mucosal ulceration was an integral part of ONJ development. Female Sprague-Dawley rats can be treated with a nitrogen-containing bisphosphonate and used to test the implant material of the present invention, e.g., a porous material or a patch material, combined with a bisphosphonate inhibitor, e.g., a geranylgeranyl pyrophosphate, or a bisphosphonate binding agent, e.g., hydroxyapatite. The implant material is implanted into the animal at either a tooth extraction site or at a site of mucosal irritation following the administration of bisphosphonate therapy. The implant material can be implanted prior to or after the development of symptoms associated with ONJ. For those animals receiving a patch, the patch will be replaced three times per week for two weeks. The animals will be monitored for improvement and any side effects.

Other Embodiments All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth.

What is claimed is:

Claims

1. A composition comprising an implant material and one or more of a bisphosphonate inhibitor, a bisphosphonate binding agent, or an agent that treats, reduces, or reverses the effects of bisphosphate-induced osteonecrosis of the jaw (BONJ).

2. The composition of claim 1, wherein said implant material is a porous material.

3. The composition of claim 1, wherein said implant material is a buccal patch.

4. The composition of claim 3, wherein said buccal patch comprises a flexible film that is capable of adhering to the oral mucosa.

5. The composition of claim 1, wherein said bisphosphonate inhibitor is a pyrophosphate.

6. The composition of claim 5, wherein said pyrophosphate is a geranylgeranyl pyrophosphate.

7. The composition of claim 1, wherein said bisphosphonate binding agent is hydroxyapatite.

8. The composition of claim 1, wherein said implant material is formulated to provide sustained release of said bisphosphonate inhibitor or said bisphosphonate binding agent.

9. The composition of claim 1 , wherein said agent that treats, reduces, or reverses the effects of bisphosphate-induced osteonecrosis of the jaw is an inhibitor of nuclear factor-kappa B (NFKB).

10. The composition of claim 1, wherein said composition further comprises a biologically active agent.

11. A method for treating or preventing bisphosphonate-induced osteonecrotic bone comprising administering to a patient in need thereof, the composition of any one of claims 1 to 10.

12. The method of claim 11, wherein said patient is a human.

13. The method of claim 11, wherein said bone is in the jaw.

14. The method of claim 11, wherein said administration comprises surgically extracting bone from an extraction site, implanting said composition at the extraction site, and surgically closing the extraction site.

15. The method of claim 14, wherein the bone is a tooth and the extraction site is a tooth socket.

16. The method of claim 14, wherein said composition releases said bisphosphonate inhibitor, said bisphosphonate binding agent, or said agent that treats, reduces, or reverses the effects of bisphosphate-induced osteonecrosis of the jaw (BONJ) into the extraction site following the implantation of said composition.

17. The method of claim 1 1, wherein said administration comprises placing the composition on irritated epithelial oral mucosa.

18. The method of claim 17, wherein said composition releases said bisphosphonate inhibitor, said bisphosphonate binding agent, or said agent that treats, reduces, or reverses the effects of BONJ into the mucosa following the placing of said composition on irritated epithelial oral mucosa.

19. The method of claim 1 1 , wherein said bisphosphonate inhibitor treats or prevents said osteonecrosis by inhibiting the action of free bisphosphonate.

20. The method of claim 1 1, wherein said bisphosphonate binding agent treats or prevents said osteonecrosis by binding to free bisphosphonate.