WO2000047214A1 - Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes - Google Patents

Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes Download PDF

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Publication number
WO2000047214A1
WO2000047214A1 PCT/US2000/003285 US0003285W WO0047214A1 WO 2000047214 A1 WO2000047214 A1 WO 2000047214A1 US 0003285 W US0003285 W US 0003285W WO 0047214 A1 WO0047214 A1 WO 0047214A1
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bone
resoφtive
agent
cement
cement dough
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PCT/US2000/003285
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English (en)
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WO2000047214A9 (fr
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John H. Healey
Gene R. Diresta
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Sloan-Kettering Institute For Cancer Research
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Priority to EP00911738A priority Critical patent/EP1150684A4/fr
Priority to AU33588/00A priority patent/AU776555B2/en
Priority to CA002360319A priority patent/CA2360319A1/fr
Priority to JP2000598166A priority patent/JP2002536123A/ja
Publication of WO2000047214A1 publication Critical patent/WO2000047214A1/fr
Publication of WO2000047214A9 publication Critical patent/WO2000047214A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention concerns an anti-resorptive bone cement.
  • the present invention also relates to an anti-resorptive allogeneic bone graft, an anti-resorptive autografic bone graft, and an anti-resorptive xenografic bone graft.
  • the present invention concerns a bone cement comprising an anti-resorptive agent, an allogeneic bone graft comprising an anti-resorptive agent, an autografic bone graft comprising an anti-resorptive agent, and a xenografic bone graft comprising an anti- resorptive agent
  • the anti-resorptive agent is selected from the group consisting of bisphosphonates and their pharmaceutically acceptable salts or esters; salts of a Group IIIA elements; cholesterol lowering agents; bisphosphonate-chemotherapeutic agent conjugates; estrogen-bisphosphonate conjugates; and proteinaceous or hormonal anti-resorptive agents, such as estrogens, prostaglandins, and cytokines.
  • Bone Loss and Orthopaedic Implants Progressive bone loss and pathologic fracture are major sources of skeletal pain and prosthetic failure in cancer patients. Bone cement is used to grout most orthopaedic joint replacements. The greatest problem plaguing the durability of the implant fixation is aseptic loosening. This is induced by particulate debris shed from the implant and mediated by osteoclastic bone resorbing cells.
  • Cemented orthopaedic implants undergo time dependent aseptic loosening (Martell, J.M., Berdia, S., “Determination of polyethylene wear in total hip replacement with use of the digital radiographs", J. Bone Joint Surg. Am., 79: 11, 1635-1642 (1997); Madey, S.M., Callaghan, J.J., Olejniczak, J.P., Goetz, D.D., Johnston, R.C., "Charnley total hip arthroplasty with use of improved techniques of cementing. The results after a minimum of fifteen years of follow-up", J. Bone Joint Surg.
  • Ultra-high molecular polyethylene debris has been associated with 20 percent greater bone resorption than PMMA debris. Further, debris particle size less than 10 microns, regardless of the chemical make-up, evoked the loosening process. The debris induces macrophage infiltration and a granulomatous response. Macrophage activities with the particles are linked to the biochemical environment that stimulates the formation of a periprosthetic membrane that is, in turn, associated with osteoclast mediated bone resorption.
  • Inhibiting this osteoclast activity by anti-resorption drugs is expected to block the bone resorption step that is responsible for prosthetic loosening (Horowitz, S.M., Algan, S.A., Purdon, M.A., "Pharmacologic inhibition of particulate-induced bone resorption", J. Biomed. Mat. Res., 3J . :1, 91-96, (1996).
  • Clohisy et al. have shown that osteoclasts mediate tumor induced local bone resorption (Clohisy, D.R., Ogilvie, CM., Carpenter, RJ., Ramnaraine, M.L., "Localized, tumor-associated osteolysis involves the recruitment and activation of osteoclasts", J. Orth. Res., 149: 1, 2-6, (1996)).
  • Bisphosphonates are widely used FDA-approved drugs that have been used to treat conditions characterized by excessive bone resorption. Bisphosphonates are being used experimentally to prevent morbidity from bone metastases and retard bone loss around loose orthopaedic where resorption of host bone is induced by accumulated particulate debris. Bisphosphonates are also used to treat alveolar bone resorption in dentistry.
  • Bisphosphonates are potent inhibitors of osteoclast activity (Mallmin et al, "Short- term effects of pamidronate disodium on biochemical markers of bone metabolism in osteoporosis - a placebo-controlled dose-finding study", Upsala Journal of Medical Sciences, 96:3, 205-12, (1991); Fitton, A., McTavish, D., "Pamidronate: A review of its pharmacological properties and therapeutic efficacy in resorptive bond disease", Drugs, 41_:2, 289-318, (1991)) and have been used clinically to treat hypercalcemia of malignancy, Paget's disease of bone, and high turnover forms of osteoporosis.
  • Bisphosphonates act by blocking osteoclast function, retarding osteoblastic bone formation, and interfering with bone mineralization in a dose dependent fashion. The relative significance of the actions varies with each drug in the class. Second and third generations of bisphosphonates preferentially emphasize the desirable osteoclastic inhibitory activity (lOOx) and minimize or eliminate the undesirable effects.
  • anti-resorptive bisphosphonates strongly bind to the hydroxyapatite of bone and remain bound indefinitely.
  • the inhibition mechanism involves prevention of osteoclasts and their precursors from recognizing the bisphosphonate-hydroxyapatite matrix (Papapoulos, S.E., Hoekman, K., Lowik, C.W.G. M., Vermeij, P., Bijvoet, O.L.M.," Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate", J. Bone Min. Res., 4:5, 775-782, (1989)), and by other mechanisms still being elucidated.
  • Bisphosphonates are used systemically to halt generalized forms of bone resorption. Experimental attempts are underway to use these drugs to treat local problems such as bone pain in monostotic fibrous dysplasia and alveolar bone resorption, but these are rare indications for systemic therapy. Systemic administration of alendronate, a bisphosphonate, reportedly inhibited osteolysis associated with wear debris in a canine un-cemented hip arthroplasty model (Shanbhag et al, supra).
  • Yaffe et al. (Yaffe, A., Iztkovich, M., Earon, Y., Alt, I., Lilov, R., Binderman, I., "Local Delivery of an amino bisphosphonate prevents the reso ⁇ tive phase of alveolar bone following mucoperiosteal flap surgery in rats", J. Periodontal, 68, 884-889, (1997)) using a rat mucoperiosteal flap surgery model, administered alendronate adjacent to the animal's alveolar bone using a pellet soaked with the drug. The pellet was allowed to remain against the bone for 2 hours and was subsequently removed. The drug's impact to the area of pellet application was monitored 21 days later.
  • Bisphosphonates do not interfere with the underlying mechanism of debris induced osteolysis. Bisphosphonates impede the osteoclast activity.
  • Ceramic hydroxyapatite dental implants for releasing bisphosphonate is discussed in Denissen, H., van Beek, E., L ⁇ wik, C, Papapoulos, S., Nan den Hooff, A., "Ceramic hydroxyapatite implants for the release of bisphosphonate, Bone and Material, 25, 123-134 (1997) and Denissen, H., van Beek, E., Martinetti, R., Klein, C, van den Zer, E., Ravaglioli, A., "Net-shaped hydroxyapatite implants for release of agents modulating periodontal-like tissues", J. Periodont Res., Y2, 40-46 (1997).
  • anti-reso ⁇ tive agents have heretofore been used systemically to treat diseases that induce osteolytic processes.
  • the anti-reso ⁇ tive agents are distributed to bone via its capillary network in proportion to its blood flow.
  • the amount of drug that reach sites adjacent to bone cement is lower than that adjacent to normal bone.
  • the medullary blood supply of bone is compromised by the reaming of the femoral canal in hip replacement surgery and other arthroplasty procedures.
  • Cementation of prostheses has other deleterious effects, including bone necrosis from the exothermic PMMA polymerization, monomer release, and impairment to the bone's capillary network (Lewis, supra).
  • the net effect of cemented prostheses is that the local bioavailability of any drug given systemically will be relatively low.
  • the drug levels at the bone-cement interface may be insufficient to adequately inhibit the osteoclasts.
  • the durability to the response to systemic therapy is unknown.
  • PMMA Cement Polymethyl methacrylate (PMMA) cement is effective for anchoring a prosthesis to bone.
  • PMMA Polymethyl methacrylate
  • the PMMA polymerization reaction causes some degree of osteonecrosis and disrupts bone blood flow.
  • bisphosphonates administered systemically may not reach the affected bone-cement interface in an adequate concentration to be of significant therapeutic value.
  • a local delivery mechanism for anti-reso ⁇ tion drugs to the bone surrounding the cement may be a more effective means to overcome the reduced perfusion and inhibit the wear debris induced osteoclast activity in surrounding bone.
  • Drugs used with inorganic cements include bone mo ⁇ hogenetic proteins, and therapeutic peptides.
  • PMMA has been impregnated with a variety of drugs, including antibiotics (Duncan, C.P., Masri, B.A., "The role of antibiotic-loaded cement in the treatment of an infection after a hip replacement", Lnstructional Course Lectures, 44: 305-313, (1996); Wininger, D.A., Fass, R.J., "Antibiotic-impregnated cement and beads for orthopaedic infections", Antimicrobial Agents and Chemotherapy, 40: 12, 2675-2679, (1996); Elson, R. A., Jephcott, A.E., McGechie, D.B., Verettas, D., "Antibiotic-loaded Acrylic Cement", J. Bone Joint Surg., 59-BJ.
  • Antibiotics have been mixed into cement to treat bone and periprosthetic infection.
  • Antineoplastic drugs such as methotrexate and cis-platinum
  • Iontophoresis has been reported to for encouraging inco ⁇ oration of antibiotics into allografts (Megson, S., Day, R., Wood, D.J., "Iontophoresis as a means of antibiotic delivery in allograft bone", Int. Soc. of Limb Salvage, 9th Int. Symp., Sept. 10-12, 1997, page 35, Transactions, inco ⁇ orated herein by reference).
  • Drug elution tests have identified a "biphasic" elution profile, e.g., an initial, high concentration, short duration elution phase followed by a low concentration, long duration elution phase. These elution tests have also determined that the vast majority of drug remains trapped in the PMMA matrix. Elution tests performed using radiolabeled antibiotic tracers showed detectable levels of drug eluted from the matrix for periods in excess of 2 years (Elson, R.A., et al, supra). The initial rate of elution was shown to be dependent on the level of drug mixed with the PMMA cement and upon the porosity of the final matrix.
  • Matrix porosity is directly related to drug elution rate, but inversely related to material strength.
  • the porosity is, in turn, a function of the mixing technique and the formulation of the cement.
  • PALACOS® cement was shown to have a higher porosity and subsequently faster drug elution rate. Centrifugation mixing of the drug-PMMA mixture resulted in the lowest porosity, "strongest" matrix, but slowest elution rate.
  • Another object of the present invention is to provide a bone cement, such as a polymethyl methacrylate (PMMA) bone cement, useful as a local drug-delivery system for an anti-reso ⁇ tion agent (e.g., an anti-reso ⁇ tive drug) to periprosthetic bone.
  • PMMA polymethyl methacrylate
  • the invention relates to a moldable composition
  • a moldable composition comprising (a) a bone cement material selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone-cement dough and (b) an anti- reso ⁇ tive amount of one or more anti-reso ⁇ tive agents.
  • the anti-reso ⁇ tive agent is preferably selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; and an estrogen-bisphosphonate conjugate.
  • the anti-reso ⁇ tive agent is a bisphosphonate selected from the group consisting of pamidronate, etidronate, and alendronate or a pharmaceutically acceptable salt or ester thereof.
  • the bone- cement dough is an acrylic bone-cement dough, more preferably polymethyl methacrylate bone-cement dough.
  • the invention relates to a moldable composition comprising
  • a bone-cement dough selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone-cement dough and (b) an anti-reso ⁇ tive amount of one or more proteinaceous or a hormonal anti-reso ⁇ tive agents.
  • the invention relates to a moldable composition
  • a moldable composition comprising (a) a bone-cement dough selected from the group consisting of an organic bone- cement dough, an inorganic bone-cement dough, and a composite bone-cement dough and (b) a pharmaceutically effective amount of a bone-formative agent.
  • the invention relates to an ex-vivo bone graft impregnated with an anti-reso ⁇ tive amount of an anti-reso ⁇ tive agent.
  • the anti-reso ⁇ tive agent is selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; and an estrogen-bisphosphonate conjugate.
  • the invention comprises a method of making a moldable anti-reso ⁇ tive bone cement, comprising contacting a bone cement material selected from the group consisting of an inorganic bone-cement dough, an organic bone- cement dough, and a composite bone-cement dough with an anti-reso ⁇ tive amount of an anti-reso ⁇ tive agent.
  • the anti reso ⁇ tive agent is selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; a chemotherapeutic agent- bisphosphonate conjugate; and an estrogen-bisphosphonate conjugate.
  • the invention in another embodiment, relates to a method of making a moldable anti-reso ⁇ tive bone-cement dough, comprising contacting an organic bone-cement dough, an inorganic bone-cement dough, or a composite bone-cement dough with an anti- reso ⁇ tive amount of a proteinaceous or hormonal anti-reso ⁇ tive agent or with a pharmaceutically effective amount of a bone-formative agent.
  • the invention comprises a method of making an anti- reso ⁇ tive bone graft comprising contacting a bone graft selected from the group consisting of an allogeneic bone graft, an autografic bone graft, and a xenografic bone graft, with a fluid vehicle comprising an anti-reso ⁇ tive amount of one or more anti-reso ⁇ tive agents.
  • the anti-reso ⁇ tive agent is selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; a chemotherapeutic agent-bisphosphonate conjugate; and an estrogen-bisphosphonate conjugate.
  • the invention relates to a moldable composition
  • a moldable composition comprising (a) a bone cement material selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone-cement dough; (b) an anti-reso ⁇ tive amount of one or more anti-reso ⁇ tive agents; and (c) a chemotherapeutic agent.
  • the anti-reso ⁇ tive agent is selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; and an estrogen-bisphosphonate conjugate. More preferably the anti-reso ⁇ tive agent is a bisphosphonate and the chemotherapeutic agent preferably is doxorubicin or methotrexate.
  • the invention relates to a method for reducing a bone void (e.g., reducing or filling cavities or defects in bone) in a patient, in need thereof, comprising adding to the void an amount of a anti-reso ⁇ tive moldable bone-cement dough composition sufficient to reduce the void.
  • a bone void e.g., reducing or filling cavities or defects in bone
  • the moldable bone-cement dough composition comprises (a) a bone cement material selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone- cement dough and (b) an anti-reso ⁇ tive amount of one or more anti-reso ⁇ tive agents, preferably selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol lowering agent; a chemotherapeutic agent-bisphosphonate conjugate; and an estrogen-bisphosphonate conjugate.
  • a bone cement material selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone- cement dough
  • an anti-reso ⁇ tive amount of one or more anti-reso ⁇ tive agents preferably selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol
  • the invention comprises a bone cement kit comprising a polymer component and a liquid monomer component packaged in association with instructions, the instructions comprising: preparing a bone-cement dough comprising an anti-reso ⁇ tive agent.
  • the polymer component or the liquid monomer component comprises the anti-reso ⁇ tive agent.
  • Fig. 1 is a graph depicting compression strength vs. drug level for a pamidronate disodium-loaded PMMA cement.
  • Fig. 2 is a graph depicting compression strength vs. drug level for an etidronate disodium-loaded PMMA cement.
  • Fig. 3 is an electrophorogram of an eluted sample of etidronate disodium- impregnated PMMA.
  • Fig. 4 is a graph depicting the elution of pamidronate disodium from PMMA. 5.
  • the bone cement of the invention can be used for bonding prosthetic bones, joints, or bone grafts to skeletal tissue and reducing bone voids.
  • the bone cement of the invention is used in surgery, more preferably, dental or orthopedic surgery.
  • the bone grafts of the invention can be used in place of traditional bone grafts in all known surgeries involving bone grafts or in any surgery involving skeletal tissue reconstruction wherein a bone graft is called for.
  • the bone cement and the bone grafts of the invention can be used for surgeries involving reconstruction of the hip, illium, jaw, shoulder, wrist, head, neck, face, nasal cavity, oral cavity, breast, prostate, and knee.
  • the bone cement of the invention is especially useful for anchoring prosthetic bone and bone grafts to living bone tissue in animals, particularly mammals, more particularly humans.
  • the bone cement of the invention is suitable for use with any prosthetic device, for example, those comprising stainless steel, titanium, cobalt chrome, ceramic, rubber, plastic, or silicone.
  • ex-vivo means outside of a living organism.
  • an ex-vivo bone graft means a bone graft outside of a patient before the bone graft is implanted in the patient by grafting the bone graft to the patient's bone.
  • a bone graft may be implanted in a patient by grafting a bone graft (e.g., and allogeneic, autrios, or xenografic bone graft) to a patient's bone during reconstructive bone surgery.
  • a bone graft e.g., and allogeneic, autografic, or xenografic bone graft
  • Organic bone cements can comprise acrylics such as polymethyl methacrylate (PMMA) formulations, for example, “SIMPLEX®” (Howmedica, Allendale, NJ), “PALACOS®” (Smith and Nephew,
  • PMMA polymethyl methacrylate
  • acrylics useful as bone cement polymers include polymers derived from C,-C 12 alkyl acrylates (e.g., methyl acrylate, ethyl acrylate, propyl acrylate, tso-propyl acrylate, n-butyl acrylate, sec-butyl acrylate, wo-butyl acrylate, tert- butyl acrylate, hexyl acrylate, heptyl acrylate, 2-heptyl acrylate, 2-ethylhexyl acrylate, 2- ethylbutyl acrylate, dodecyl acrylate, hexadecyl acrylate, 2-ethoxyethyl acrylate, isobornyl acrylate, cyclohexyl acrylate); C,
  • Inorganic cements include calcium hydroxyapatite (may be prepared according to Hayek et al. Inorganic Synth. 7, 63-69 (1963)), Apatite- Wollostonite glass ceramic (Nippon Electric Glass Co., see Kawanabe et al. J. Bone Joint Surg. 80-B:3. 527-530) and hydraulic calcium phosphate (prepared as described in Bohner et al. J. Pharm. Sci. 86:5, 565-572 (1997)).
  • Composite cements are mixtures of organic or inorganic materials or salts with organic or inorganic binders. Suitable organic and inorganic binders include the organic and inorganic bone cements described above.
  • Suitable inorganic materials suitable for use in composite bone cements include, but are not limited, to titanium fibers and glass fibers.
  • Organic material suitable for use in composite bone cements include but are not limited to carbon fibers and graphite.
  • Examples of composite bone cements include graphite-in- acrylic bone cement (United States Patent No. 4,064,566, inco ⁇ orated herein by reference) and alumina-polylactic acid-PMMA (prepared as described in Vallet-Regi et al. J. Biomed. Mater. Res. 139, 423-428 (1998), inco ⁇ orated by reference herein).
  • Salts suitable for use in composite cements include both organic and inorganic salts, for example, tricalcium phosphate particles or sodium salicylate.
  • Composite bone cements include, for example, a poly (propylene glycolfumarate- methyl methacrylate) matrix mixed with calcium carbonate and tricalcium phosphate particulates; a polymethyl methacrylate bone cement comprising titanium fibers; a crosslinked gelatin matrix containing tricalcium phosphate particles; glass fibers suspended in a solution of bis-phenol-A-glycidyl-methacrylate and triethylene-glycol-dimethacrylate; a composite matrix made of gelatin, water and sodium salicylate in which particulate tricalcium phosphate is entrapped; a polymethyl methacrylate bone cement comprising carbon fibers; and alumina impregnated in polymethyl (methyl methacrylate) beads.
  • a poly (propylene glycolfumarate- methyl methacrylate) matrix mixed with calcium carbonate and tricalcium phosphate particulates include, for example, a poly (propylene glycolfumarate- methyl methacrylate) matrix mixed
  • Bone cements are generally prepared by mixing bone-cement components to give a bone-cement dough, which is particularly useful for reducing a bone void in a patient. After the bone void is reduced, the bone-cement dough can harden or cure to a bone cement.
  • bone-cement components are those materials that when admixed initially form a bone-cement dough. Bone-cement components are optionally mixed in the presence of additional chemicals, solvents, ingredients or materials.
  • a bone-cement dough is a moldable, pliable, ductile, or deformable composition that can be manually molded by the skilled artisan to a desired shape.
  • a bone-cement dough can be of a consistency that can be pressed into a bone void to reduce and preferably fill the bone void and conform to the void's shape.
  • a bone-cement dough can be used to reduce a bone void resulting from reconstructive bone surgery.
  • a bone-cement dough can also be of a consistency amenable to injection into bone voids via a syringe designed for injection of bone-cement dough.
  • bone cement dough can be used to bond a prosthetic device to a bone.
  • the bone can be drilled, forming a void that can be reduced with bone-cement dough.
  • a connecting portion of the prosthetic device can be inserted in the bone-cement dough-containing bone. The bone cement dough hardens, bonding the prosthetic device to the bone.
  • the bone cement comprises an organic preferably an acrylic polymeric material.
  • an acrylic bone cement is prepared from two components: a dry polymer component, (e.g., an acrylic powder or particulate component, such as one of the polyacrylate homopolymers and co-polymers listed above) and a liquid monomer component.
  • the components are mixed together, preferably at room temperature, to form bone-cement dough, which is then used as desired (e.g., filling a bone void during reconstructive bone surgery or filling a bone void prior to attaching a prosthetic device to a bone)and allowed to cure to a bone cement.
  • suitable liquid acrylate monomers include, but are not limited to, C,-
  • C 12 alkyl acrylates e.g., methyl acrylate, ethyl acrylate, propyl acrylate, tso-propyl acrylate, n-butyl acrylate, sec-butyl acrylate, tso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, heptyl acrylate, 2-heptyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutyl acrylate, dodecyl acrylate, hexadecyl acrylate, 2-ethoxyethyl acrylate, isobornyl acrylate, cyclohexyl acrylate); C r C, 2 -alkyl methacrylates (e.g., methyl methacrylate, ethyl methacrylate, propyl methacrylate, /so-propyl methacrylate,
  • polymethyl methacrylate is the polymer component and methyl methacrylate is the monomer component.
  • the polymer component is an acrylic, such as PMMA, it is preferably in the form of small polymer beads or amo ⁇ hous particles.
  • the polymer component is PMMA powder, it generally has the consistency of flour. For example, in a typical PMMA
  • the polymer component may comprise a mixture a particle sizes where about 65 to about 70 percent polymer particles have an average diameter of about 25 microns, and about 30 to about 35 percent of the polymer beads are about 13 to about 17 microns in diameter.
  • the desired particle sizes and distributions are readily obtained by sifting through the appropriate screen mesh (e.g., see United States Patent No. 4,341,691,
  • composition of the liquid monomer component of a typical bone cement comprises: about 95 to about 98 percent (by volume) of an acrylic monomer, preferably methyl methacrylate monomer; about 2.5 to about 3 percent (by volume) of an accelerator, such as N, N-dimethyl-p-toluidine; and about
  • accelerators for use with the invention, include but are not limited to, amines, such as p-toluidine, ⁇ , ⁇ -hydroxypropyl-p-toluidine, N,N-dimethyl-p-arninophenethanol, trihexylamine, and trioctylamine; polyamines, such as 0 N,N,N',N'-tetramethylethylenediamine; barbituric acids, such as dimethyl barbituric acid and diethyl barbituric acid; and dimethylamino-benzene-sulphonamide; or mixtures thereof.
  • amines such as p-toluidine, ⁇ , ⁇ -hydroxypropyl-p-toluidine, N,N-dimethyl-p-arninophenethanol, trihexylamine, and trioctylamine
  • polyamines such as 0 N,N,N',N'-tetramethylethylenediamine
  • barbituric acids such as dimethyl barbituri
  • the stabilizer advantageously prevents premature polymerization, which can occur when the liquid monomer component and the polymer component are mixed in the presence of heat, light or other materials.
  • stabilizers suitable for use with the 5 invention include, but are not limited to, hydroquinones and alkylated hydroquinones, such as toluhydroquinone, methyl-tert-butylhydroquinone, 2,5-di-t-butylhydroquinone 2,6-di- tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4- hydroxyanisole, 3 ,5-di-tert-butyl-4-hydroxyanisole, 3 ,5-di-
  • the composition of the polymer component of a preferable bone cement comprises about 80 to about 100 percent (by weight) poly methyl methacrylate, preferably about 90 percent; and optionally about 9 to about 11 percent (by weight) barium sulfate, U.S.P., preferably about 10 percent.
  • the barium sulfate when present, provides radiopacity so that the cement appears visible in X-ray-sensitive film when developed.
  • the polymer component optionally comprises a polymerization initiator, such as benzoyl peroxide, in an amount of about 0.5 to about 1 percent by weight, preferably about 0.75 percent, for initiating a free-radical polymerization process upon mixing the polymer and liquid monomer components.
  • small particles e.g., about the same size or smaller than the particle size of the polymer component's particles
  • the initiator can be inco ⁇ orated therein during the bead preparation process.
  • initiators suitable for use with the invention include but are not limited to, organic peroxides, such as di-tert-butyl peroxide, dicumyl peroxide, di-tert-amyl peroxide, dibenzoyl peroxide, diacetyl peroxide, dilauroyl peroxide, succinic acid peroxide, diisononanoyl peroxide, tert-butyl peroxybenzoate, tert-butyl peroxy acetate, ethyl 3,3-di- (tert-amylperoxy)-butyrate; inorganic peroxides, such as potassium peroxy disulfate; and azo-compounds, such as 2,2'azobis[4-methoxy-2,4-dimethyl]pentanenitrile and 2,2'- azobis[2,4-dimethyl]-pentanenitrile; or mixtures thereof. Further examples of useful initiators can be found in the The Encyclopedia of Chemical Technology
  • the ratio of the liquid monomer component to the polymer component is about one milliliter of the liquid monomer component to about two grams of the polymeric component.
  • the liquid monomer is added to the polymer component.
  • the resulting mixture is stirred until a bone-cement dough is formed that preferably does not adhere to rubber gloves.
  • the bone-cement dough is then kneaded to the consistency amenable to digital application to bone or injection into a bone void formed, for example, by drilling into a bone.
  • a connecting portion of a prosthetic device can be inserted in the bone-cement dough-containing bone. The bone-cement dough cures, bonding the prosthetic device to the bone.
  • the liquid monomer component When the liquid monomer component is mixed with the polymer component, initially, the liquid monomer wets the polymer component. Since the polymer component is generally at least partially soluble in the liquid monomer, the solid polymer beads partially begin to dissolve or swell in the liquid monomer.
  • the polymerization reaction preferably starts as soon as the two components are mixed. During the next 2 to 4 minutes, the polymerization process proceeds, changing the viscosity of the initial mixture from a syrup-like consistency (relatively lower viscosity) to a dough-like consistency (relatively higher viscosity).
  • PMMA for example, can serve as a matrix appropriate to both support a prosthetic implant and deliver the anti-reso ⁇ tive agent to adjacent bone osteoclast activity and thus minimize the osteolytic bone reso ⁇ tion.
  • the bone-cement dough can be impregnated with one or more anti-reso ⁇ tive agents.
  • a bone cement impregnated with an anti-reso ⁇ tive agent results.
  • the bone-cement dough can be impregnated with an anti-reso ⁇ tive agent by mixing the anti-reso ⁇ tive agent with one or more of the bone cement's components before the components are mixed. Preferably, such mixing results in a uniform mixture.
  • the components are then mixed according to the methods well-known in the art.
  • the anti-reso ⁇ tive agent can also be mixed into freshly prepared bone-cement dough by well-known mixing techniques.
  • PMMA bone cements can be obtained by following known methods (e.g., United States Patent Nos. 4,064,566; 4,341,691; 4,554,686; 5,334,626; 5,795,922; and 4,791,150, all of which are inco ⁇ orated herein by reference) or instructions or package inserts accompanying commercial PMMA bone cement kits, e.g., "SIMPLEX®”, “PALACOS®”, “Zimmer®”, or "C.M.W®”). These bone cements can be impregnated with an anti-reso ⁇ tive agent mixing the anti-reso ⁇ tive agent into either the polymer component or the liquid monomer component at room temperature before the two components are mixed.
  • an anti-reso ⁇ tive agent mixing the anti-reso ⁇ tive agent into either the polymer component or the liquid monomer component at room temperature before the two components are mixed.
  • the anti-reso ⁇ tive agent is mixed into the polymer component before the polymer component is mixed with the liquid monomer component.
  • the anti-reso ⁇ tive agent may be impregnated in the bone cement by thoroughly mixing freshly made acrylic bone-cement dough with the anti-reso ⁇ tive agent.
  • the anti-reso ⁇ tive agent is added to one or more of the components before preparing the bone-cement dough according to the manufacturer's instructions or according to the standard procedures well-known in the art (e.g., Denissen et al. J. Periodont. Res. 32:42-46 (1997) for calcium hydroxyapatite bone cement and United States Patent No.
  • the anti-reso ⁇ tive agent may be impregnated in the bone cement by thoroughly mixing freshly made bone-cement dough with anti-reso ⁇ tive agent.
  • the anti-reso ⁇ tive agent can be applied to the surface of a bone-cement dough (organic, inorganic, or composite cements) by contacting pre-mixed bone-cement dough with the anti-reso ⁇ tive agent.
  • a bone-cement dough organic, inorganic, or composite cements
  • the bone-cement dough is formed in the shape of a sphere and contacted with the anti-reso ⁇ tive agent, preferably a bisphosphonate, by rolling the dough sphere in the anti -reso ⁇ tive agent, preferably in particulate form, until the external surface of the sphere is covered with the anti-reso ⁇ tive agent.
  • the sphere is covered with the anti- reso ⁇ tive agent such that it is approximately evenly distributed over the surface of the sphere.
  • the sphere is covered to the extent that it does not pick up more anti- reso ⁇ tive agent with further rolling.
  • about 60 grams (about 50 cm 3 ) of bone- cement dough may be prepared from a standard PMMA bone cement kit according manufacture's instructions.
  • the resulting dough can be divided into 10 spheres (about 6g and about 5 cm 3 each) and rolled in the anti-reso ⁇ tive agent, preferably a bisphosphonate, until the sphere is covered with the anti-reso ⁇ tive agent evenly distributed on the sphere's surface.
  • anti-reso ⁇ tive agent's particle size is about the same or less than the size of the bone cement's particles.
  • bisphosphonates are generally in crystal form and should be reduced to the correct particle size. The appropriate particle size of anti-reso ⁇ tive agent is readily achieved by grinding and sifting through the appropriately sized mesh screens.
  • the anti-reso ⁇ tive agent is impregnated in the bone-cement dough or applied to the surface of the bone-cement dough in an anti-reso ⁇ tive amount.
  • an "anti- reso ⁇ tive amount” means an amount of the anti-reso ⁇ tive agent sufficient to prevent loosening of the bone cement from the living bone to which it is attached for an extended period of time, preferably, about 2 to about 4 years, more preferably about 5 to about 10 years, most preferably, about 11 to about 50 years and, optimally, for the life of the patient. Detecting whether the bone cement loosens from the living bone can be readily accomplished by well-known methods. For example, a radiologist or other skilled artisan can detect loosening of the bone cement by performing Gruen-zone analysis of the bone cement/bone bond and then measuring the thickness of the radiolucent line between the bone cement and the bone.
  • the amount of the anti-reso ⁇ tive agent that is impregnated in the bone cement is dependent on the type of bone cement and anti-reso ⁇ tive agent.
  • the anti- reso ⁇ tive agent is present in an amount of about 1 microgram to about 11 grams per 60 grams of bone-cement dough, preferably, about 0J grams to about 10 grams per 60 grams of cement dough, and is more preferably about 0.5 grams per 60 grams of bone-cement dough.
  • Anti-reso ⁇ tive agent levels higher than these may be used until the cement's chemical or mechanical properties are compromised relative to anti-reso ⁇ tive agent-free cement controls, or until local elution drug levels comprise bone remodeling processes.
  • the anti- reso ⁇ tive agent preferably a bisphosphonate
  • the bone-cement dough can be impregnated with an anti-reso ⁇ tive agent in an amount of from about 1 microgram to about 5 milligrams of the anti -reso ⁇ tive agent per 60 grams of bone-cement dough, preferably about 2 microgram to about 0J milligrams of the anti-reso ⁇ tive agent per 60 grams of bone-cement dough.
  • the amount of anti-reso ⁇ tive agent impregnated in the bone-cement dough is that amount used for antibiotic drugs impregnated in bone cement (e.g., Duncan et al, Instructional Course Lectures, 44, 305-313, (1996); Wininger et al, Antimicrobial Agents and Chemotherapy, 40: 12, 2675-2679, (1996); Elson et al, J. Bone Joint Surg., 59-B:2. 200-205, (1977); Baker et al, J. Bone Surg, 70-A:10. 1551-1557, (1988), all of which are inco ⁇ orated herein by reference).
  • antibiotic drugs impregnated in bone cement e.g., Duncan et al, Instructional Course Lectures, 44, 305-313, (1996); Wininger et al, Antimicrobial Agents and Chemotherapy, 40: 12, 2675-2679, (1996); Elson et al, J. Bone Joint Surg., 59-B:2.
  • the final level of the anti-reso ⁇ tive agent impregnated in the bone-cement dough will be determined by the skilled artisan and will be subject to the nature and potency of the ant-reso ⁇ tive agent; the type of bone cement dough, particularly the relationship of its mechanical strength versus the amount of anti-reso ⁇ tive agent; and the physical conditions required to make the bone-cement dough (e.g., time, temperature, etc.).
  • the anti-reso ⁇ tive agent When the anti-reso ⁇ tive agent is to be applied to the surface of bone-cement dough (organic, inorganic, or composite cements) by contacting bone-cement dough with the anti- reso ⁇ tive agent, the anti-reso ⁇ tive agent is preferably contacted with the bone-cement dough until the dough surface will no longer pick up any of the anti-reso ⁇ tive agent.
  • the temperature stability of the anti-reso ⁇ tive agent should be considered.
  • PMMA for example, reaches temperatures of 70 °C during its polymerization. This is high enough to inactivate many organic molecules, e.g., proteins, etc.
  • Another consideration is the hydration state of the anti-reso ⁇ tive agent and its impact on cement polymerization or setting; for example, the PMMA polymerization reaction is adversely impacted by water inco ⁇ orated within anti- reso ⁇ tive salt molecules.
  • anti-reso ⁇ tion agents can chemically interfere with or be inactivated by the reaction chemistry of the cement during its polymerization or setting.
  • the bone cement which contains an anti-reso ⁇ tive agent according to the present invention, can be made by pre-mixing an anti-reso ⁇ tive agent, such as a bisphosphonate with, for example, a methyl methacrylate powder before adding a catalyst.
  • an anti-reso ⁇ tive agent such as a bisphosphonate
  • a methyl methacrylate powder before adding a catalyst.
  • the bone cement can made with the anti-reso ⁇ tive agent, such as a bisphosphonate, impregnated therein, admixed with the anti-reso ⁇ tive agent, or one such as a surgeon (or other skilled artisan) can prepare the bone-cement dough at the time of use, e.g., in the operating or medical procedure room. Formation of bone-cement dough according to these methods overcomes the heretofore difficult problem of reducing the longevity of joint replacements.
  • the anti-reso ⁇ tive agent such as a bisphosphonate
  • the bone-cement dough can be loaded into a syringe while still quite fluid for injection into the prepared area.
  • the bone-cement dough can be kneaded for about several more minutes then it is of the proper consistency to be formed into a suitable shape for placement in the attachment site.
  • bone-cement dough particularly the polymethyl methacrylate bone-cement dough, cures extremely rapidly, and unless it is used quickly, it will not flow effectively into the irregularities and projecting cavities within the prepared bone tissue.
  • the bone-cement dough is added to the bone void within about three or four minutes following its preparation. Even then, the resulting bone cement to bone bond is generally stronger if the cement and prosthesis are placed into the prepared site early within this time period rather than later. However, bleeding can occur until there is sufficient counte ⁇ ressure to resist it, late in the stiffening of the cement.
  • the skilled artisan may need to balance the competing concerns of maximum cement interdigitation and minimizing bleeding at the cement-bone interface. The sooner after its preparation the bone-cement dough is applied, the less viscous it is, and the more likely that it will flow into surface irregularities and projecting cavities.
  • the prosthesis is then advantageously held in the proper position for several more minutes while the bone-cement dough continues to harden.
  • the types of grafts for use in the present invention include allogeneic bone grafts, autografic bone grafts and xenografic bone grafts.
  • the types of allogeneic bone grafts for use in the present invention include the following:
  • an allogeneic bone graft from a cadaver which can be obtained, for example, from a bone bank;
  • Cadaveric allogeneic bone grafts can be preserved by freezing to decrease immunogenicity of the bone.
  • the process may include the use of cryopreservatives, such as ethylene glycol or DMSO, to maintain chondrocyte viability.
  • Allogeneic bone grafts may be also treated in several of the following ways prior to implantation:
  • demineralization such as by using 6N HC1, to leave only the protein portion of the bone, or
  • demineralized allogeneic bone grafts in combination with vehicles such as glycerine or formulated into temperature sensitive putty to best treat surfaces or cavities requiring bone reducers.
  • the freeze-drying method of preserving bone grafts reduces the immunogenicity of graft material most effectively and allows grafts to be stored conveniently at room temperature in small vacuum-sealed bottles.
  • Fresh grafts from other living humans or frozen grafts from cadavers may contain attached soft tissue ligaments and tendons.
  • an autografic bone graft is a bone structure taken from one portion of the skeleton of an individual to be grafted to another portion of the skeleton of that individual, for example, a bone segment taken from the iliac bone of a patient to be grafted to the spine of the patient.
  • a xenografic bone graft is a bone structure taken from one species and transplanted to a different species.
  • Methods that can be used to carry out the active impregnation of the anti-reso ⁇ tive agent in allogeneic bone grafts, autografic bone grafts or xenografic bone grafts, so as to permanently and chemically bind the anti-reso ⁇ tive agent to allogeneic bone grafts, autografic bone grafts or xenografic bone grafts include the following: (1) Iontophoresis of bone sections. Iontophoresis is a technique useful for delivering ions into a graft by placing a the anti-reso ⁇ tive agent in a fluid vehicle, preferably an aqueous vehicle in contact with or close proximity to the graft.
  • the fluid vehicle solution is typically carried by a first electrode pouch or receptacle.
  • a second or dispersive electrode is placed against the graft within some proximity of the first electrode. Ions are caused to migrate from the ion- carrying medium through the graft by the application of an electrical potential or voltage of the appropriate polarity to the two electrodes.
  • a controlled current is established by providing a sufficient voltage differential between the first and second electrodes and placing a limiting resistance or other current-limiting device elsewhere in the circuit.
  • Iontophoresis is used in the present invention to optimize the efficiency and effectiveness of the delivery of the anti-reso ⁇ tive agent. Iontophoresis current levels and duration can be increased to attempt to drive more of the anti-reso ⁇ tive agent into the bone graft matrix.
  • Iontophoresis enhances simple diffusion of the anti-reso ⁇ tive agent by the use of an electric-field gradient across the bone. This provides high local concentrations of the anti-reso ⁇ tive agent to prevent premature reso ⁇ tion of the graft before the intended healing can occur.
  • the procedures and apparatus for carrying out iontophoresis are described in United States Patent Nos. 5,668,120, 5,730,715, and 5,735,810, all three of which are inco ⁇ orated herein by reference, and can be adapted for use in the present invention.
  • the graft is then removed from the vehicle and washed with water.
  • High-pressure pumping of a solution of anti-reso ⁇ tive agent, such as a bisphosphonate, through a graft matrix, such as an allogeneic bone graft is an efficacious method for delivering anti-reso ⁇ tive agent, e.g., a bisphosphonate, to internal bone regions. It is an alternative that delivers drugs primarily to surface bone.
  • High-pressure pumping involves pumping a filtered aqueous solution of the anti-reso ⁇ tive agent, such as a bisphosphonate, at a pH of approximately 1 and at a temperature of approximately 37°C
  • Such solution may include polymeric substances and/or surfactants to reduce the surface tension of the solution.
  • This technique may require using a holding mechanism that attaches to the graft and serves as the fluid delivery point to the graft.
  • a solution of the anti-reso ⁇ tive agent is pumped via a positive pressure pump, e.g., gear, piston, etc., at pressures sufficient to drive the fluid through the graft.
  • the pump output pressure is approximately 50 psi or more.
  • a constant flow system is preferred, where the pump provides the requisite pressure to achieve flow through the matrix. This pressure will be influenced directly by the resistance inherent to the graft matrix.
  • Flow is preferably slow, e.g., 5-10 milliliters/min., to facilitate the binding reaction of the anti-reso ⁇ tive agent, e.g., a bisphosphonate, to the graft matrix.
  • the flow advantageously continues for approximately 1 hour or until the concentration of the anti-reso ⁇ tive agent, e.g., a bisphosphonate, in the input and output fluid streams is equal, implying bone saturation.
  • the graft is then removed from the vehicle and washed with water.
  • the allograft may be soaked in a solution of the anti-reso ⁇ tive agent, preferably with gentle stirring.
  • the graft is then removed from the vehicle and washed with water.
  • the concentration of the anti-reso ⁇ tive agent solution should be such that the bone graft is impregnated, preferably, saturated with the anti-reso ⁇ tive agent within about one to about five days.
  • the bone graft is saturated when the anti-reso ⁇ tive agent's concentration in the impregnating solution remains constant as measured by techniques well known in the art (e.g., density measurements, titration of the anti-reso ⁇ tive agent, etc.).
  • the concentration of the anti-reso ⁇ tive solution is about 0J grams to about 10 grams of the anti-reso ⁇ tive agent per liter, more preferably, about 1 gram to about 5 grams per liter of fluid vehicle.
  • concentration is about 0J grams to about 10 grams of the anti-reso ⁇ tive agent per liter, more preferably, about 1 gram to about 5 grams per liter of fluid vehicle.
  • the vehicle can be any fluid vehicle that is soluble in water and in which the anti-reso ⁇ tive agent is soluble or partially soluble.
  • One of skill in the art will readily choose the fluid vehicle in accordance with the anti-reso ⁇ tive agent and the type and dimensions of the bone graft.
  • Preferred vehicles include water, physiological saline or buffer solutions, glycols such as ethylene and propylene glycol, aqueous solutions of glycols, solutions of dimethyl sulfoxide and water, and mixtures thereof.
  • the most preferred vehicle is water.
  • the surface tension and the viscosity of the fluid vehicle may be adjusted by including one or more polymeric substances, salts, or surfactants. A large range of suitable polymeric substances, salts, and surfactants are available, and one of skill in the art will readily be able select such substances depending on the anti-reso ⁇ tive agent, the fluid vehicle, and the method of impregnation.
  • the grafts according to the present invention which are actively impregnated with an anti-reso ⁇ tive agent as discussed hereinabove, block digestion sites of osteoclast cells and thus prevent destruction of the graft.
  • an embodiment of the present invention involves the pretreatment of grafts in vitro before their use in vivo in a bone grafting procedure.
  • Bone grafting is a common procedure in skeletal reconstructive and trauma surgery to reestablish the integrity of the skeleton. It provides (1) structural support to the skeleton, principally through cortical grafts and (2) bone healing assistance to the skeleton via osteoinduction, osteoconduction, and cellular mechanisms. Various techniques are used to bridge gaps between and reduce cavities in bone. Different materials are chosen to obtain the optimal clinical combination of healing potential, biocompatibility, and convenience.
  • graft choices include an autografic bone grafts, allografts, xenografic bone grafts, or other sources.
  • Other graft choices include naturally- occurring materials such as coral, or alloplastic materials.
  • inorganic materials include, but are not limited to, hydroxyapatite and tricalcium phosphate synthetic implants that are readily available source material. These can be mixed with protein constituents of bone such as collagen to redcue defects and heal bones. Such materials are easily sculpted to fit the defect or impacted into a cavity.
  • Hydroxyapatite cements comprise various concentrations of calcium and phosphorus that harden in an aqueous environment at body temperature. Examples include dicalcium phosphate and tetracalcium phosphate.
  • the most often-used technique for reconstructing damaged bone tissue involves initially preparing the bone tissue by cutting and drilling the bone tissue so that it conforms to the shape of the securement portion of a prosthesis. Then, a number of shallow holes are generally drilled or cut into the surfaces of the bone tissue adjacent to the prosthesis in order to form projecting cavities into which bone-cement dough will flow so as to form a strong mechanical interlock between the bone cement and the bone tissue.
  • the prepared bone surfaces are then thoroughly cleansed of all blood, fatty marrow tissue, bone fragments, and the like, so that the bone-cement dough conforms to all of the surface irregularities of the prepared bone tissue. Finally, particularly in the case of acrylic polymeric cements, the two components of the unpolymerized bone cement are mixed.
  • Anti-reso ⁇ tive agent means any material, compound, or drug, known or to be discovered, that prevents or retards bone reso ⁇ tion in a patient when administered systemically or locally to the patient.
  • the anti-reso ⁇ tive agent functions to block osteoclast activity when administered to the patient.
  • classes of anti-reso ⁇ tive agents include, but are not limited to, bisphosphonates and their pharmaceutically acceptable salts or esters; salts of a Group IIIA elements; cholesterol lowering agents; bisphosphonate-chemotherapeutic agent conjugates; estrogen- bisphosphonate conjugates; and proteinaceous or hormonal anti-reso ⁇ tive agents, such as estrogens, prostaglandins, and cytokines.
  • cholesterol lowering agent means any compound, material, or drug that either partially or completely interferes with the mevalonate
  • Suitable cholesterol lowering agents for use with the invention include, but are not limited to, mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin.
  • bisphosphonate-conjugate means any compound, complex, material, or drug that comprises an anti-reso ⁇ tive bisphophonate associated with
  • a "bisphosphonate-chemotherapeutic agent conjugate” comprises an anti-reso ⁇ tive bisphophonate associated with a chemotherapeutic agent via a covalent bond or an ionic bond and a "bisphosphonate-estrogen conjugate” comprises an anti-reso ⁇ tive bisphophonate associated with an estrogen via a covalent bond or an ionic bond.
  • Suitable bisphosphonate-estrogen conjugates for use with the invention include 17beta-estradiol-bisphosphonate conjugates (E2-BPs), such as
  • estrogen means any female sex hormone, for example, estrone, estradiol, diethyletilbestrol, diethylstilbestol diphosphate, progesterone, norethynodrel, norethindrone, and ethnylestradiol.
  • estrone estradiol
  • diethyletilbestrol diethylstilbestol diphosphate
  • progesterone norethynodrel
  • norethindrone norethindrone
  • ethnylestradiol ethnylestradiol.
  • estrogen also encompasses estrogen like compounds, such as selective estrogen receptor modulators (SERMs).
  • SERMs selective estrogen receptor modulators
  • estrogen like compounds suitable for use with the invention include but are not limited to triphenylethylenes, such as tamoxifen and its derivatives, toremifene, droloxifene, and idoxifene; benzothiophenes, such as raloxifene and LY353381; chromans such as levormeloxifene; naphthalenes, such as CP336J56; and dihydronapthylenes, such as nafoxidine.
  • triphenylethylenes such as tamoxifen and its derivatives, toremifene, droloxifene, and idoxifene
  • benzothiophenes such as raloxifene and LY353381
  • chromans such as levormeloxifene
  • naphthalenes such as CP336J56
  • dihydronapthylenes such as nafoxidine.
  • prostaglandin means a C 20 -carboxylic acid that contains a
  • prostaglandins include, but are not limited, to misoprostol, prostaglandin E 2 , prostaglandin F l ⁇ , and prostaglandin
  • cytokine means a low molecular weigh hormone-like protein secreted by cells, which cells regulate the intensity and duration of the immune response.
  • cyctokines include but are not limited to, interleukins (e.g., II- 1 to
  • tumor necrosis factor- ⁇ tumor necrosis factor- ⁇
  • tuomor necrosis factor- ⁇ tumor necrosis factor- ⁇
  • transforming growth factor- ⁇ tumor necrosis factor- ⁇
  • drugs such as estrogen (to provide specificity of action) to a small peptide (as a vehicle to provide specificity of location) that to localize on hydroxyapatite or a matrix protein such as osteocalcin conferring specificity to bone.
  • a protype is an (Asp) 6 conjugate with estrogen (see Abstract SA 231 of The Second Joint Meeting of The American Society for Bone and Mineral Research and The International Bone and Mineral Society, December 16, 1998, inco ⁇ orated herein by reference. Any anti -reso ⁇ tive agent may used in combination with one or more of any other anti-reso ⁇ tive agent.
  • Anti-reso ⁇ tive agents for admixture with inorganic, organic, and composite bone- cement doughs in accordance with the present invention include bisphosphonates, analogs of bisphosphonates, and salts of Group IIIA elements (B, Al, Ga, In and Tl), preferably gallium salts, such as gallium nitrate, gallium chloride, gallium fluoride, gallium sulfate and gallium citrate, preferably gallium fluoride.
  • Analogs of bisphosphonates include pharmaceutically acceptable salts and one or more phosphate esters thereof.
  • Inorganic bone cements or composite bone cements can include an anti-reso ⁇ tive amount of a proteinaceous or hormonal anti-reso ⁇ tive agents, such as estrogen, prostaglandin or cytokines, and in addition thereto, or in place thereof, a pharmaceutically effective amount of a bone- formative agent can be employed such as OP-1 (BMP- 7), LIM Mineralizaton Protein 1 ("LMP-1"), preferably OP-1, or a pharmaceutically effective amount of bone mo ⁇ hogenetic protein (“BMP”) such as BMP-2, BMP-3, BMP-4, or BMP-1, preferably BMP-2, BMP-3, or BMP-4. Any combination of proteinaceous or hormonal anti- reso ⁇ tive agents and bone-formative agent may be used.
  • a "pharmaceutically effective amount" of a bone-formative agent or bone mo ⁇ hogenetic protein means an amount that does not compromise the mechanically integrity of the bone cement, that is not toxic, and that amount that promotes bone formation.
  • the BMPs are novel proteins identified by Wozney J. et al. Science 242:1528-34 (1988), inco ⁇ orated by reference herein, using gene cloning techniques, following earlier descriptions characterizing the biological activity in extracts of demineralized bone (Urist M. Science 150:893-99 (1965), inco ⁇ orated by reference herein).
  • Recombinant BMP-2 and BMP-4 can induce new bone formation when they are injected locally into the subcutaneous tissues of rats (Wozney J. Molec Reprod Dev . 32:160-67,(1992), inco ⁇ orated by reference herein).
  • OP-1 also known as BP-7 can also induce new bone growth.
  • BMPs The preparation of BMPs is well-known in the art, for example, see the procedure described in United States Patent No. 5,948,428 inco ⁇ orated herein by reference. BMP's are available commercially from Genetics Institute, Inc (Cambridge, MA). Anti-reso ⁇ tive agents useful for impregnating allogeneic bone grafts, autografic bone grafts or xenografic bone grafts include one of the aforesaid bisphosphonates or analogs thereof, or said gallium salts.
  • Combinations of said anti-reso ⁇ tive agents can be used, such as a combination of a bisphosphonate or an analog thereof or a combination of a bisphosphonate or analog thereof and a gallium salt.
  • Biphosphonates can be used with inorganic, composite, or organic cements. Salts of Group IIIA elements, such as gallium salts, can be used with inorganic or organic cements.
  • the bisphosphonate may be in its acid or salt form. Preferably the bisphosphonate is in its most clinically relevant form, for example, the commercial form marketed for and used by physicians.
  • Non-limiting examples of bisphosphonates for use in the invention have the general structure according to formula I below:
  • R 1 and R 2 are independently, hydrogen, an alkali metal, an alkaline earth metal, a C,-C 4 quaternary ammonium cation, C]-C 10 alkyl, C,-C 10 unsaturated alkyl, aryl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl, or/>-nitrophenyl;
  • R 3 is hydrogen, chloro, amino, or hydroxy;
  • R 4 and R 5 are independently hydrogen, C C 4 alkyl, or C 2 -C 4 unsaturated alkyl; n is an integer ranging from 1 to 7; X is -NH-, -O-, or -S-; y is 0 or 1 ; and R 6 is hydrogen, -NH 2 , -N(R 7 )(R 7 ), -N + (R 7 )(R 7 )(R 7 ), a 5- to 7-membered aryl or cycloalkyl group, or a 5- to 7-membered heteroaryl or heterocycloalkyl group having from 1 to 3 heteroatoms one or more of which, when nitrogen, is optionally quaternary; each R 7 is independently hydrogen or a C r C 4 alkyl group; and when R° is -N + (R 7 )(R 7 )(R 7 ) or a 5- to 7-membered heteroaryl or heterocycloalkyl group having from 1 to 3 heteroatoms one
  • R 1 and R 2 are independently sodium, potassium, or ammonium cation; R 3 is hydroxy;
  • R 4 and R 5 or independently hydrogen, C,-C 4 alkyl, or C 2 -C 4 unsaturated alkyl; n is and integer ranging from 1 to3; y is 0 or 1
  • R 6 is a 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms; and R 7 is a C,-C 4 alkyl group.
  • n is 1; the 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms is imidazolyl or pyridyl, most preferably, 1 -imidazolyl or 3-pyridyl.
  • substituted means having one or more -CN, - OH, oxo, -O-C,-C 4 -alkyl, -O-C 6 -aryl, -CO 2 H, -NH 2 , -NH(C,-C 4 -alkyl), N(C,-C 4 -alkyl) 2 , - NH(C 6 -aryl), -N(C 6 -aryl) 2 , CO(C,-C 4 -alkyl), -CO 2 (C,-C 4 -alkyl), -CO(C 6 -aryl), or -CO 2 (C 6 - aryl) groups.
  • alkyl group means a straight or branched chain monovalent radical comprised of hydrogen and carbon atoms having no unsaturation, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, heptyl, octyl, and the like which rings may be unsubstituted or substituted by one or more suitable substituents as defined above.
  • an "unsaturated alkyl group” means a straight or branched chain monovalent radical comprised of hydrogen and carbon atoms having one or more double bonds therein, conjugated or unconjugated, such as allyl, butenyl, pentenyl, hexenyl, heptenyl, butadienyl, pentadienyl, hexadienyl, and the like, which rings may be unsubstituted or substituted by one or more suitable substituents as defined above.
  • an "aryl group” means a mono- or polycyclic aromatic radical comprising carbon atoms.
  • the aromatic ring (or rings when the aryl group is polycyclic), may be unsubstituted or substituted by one or more suitable substituents as defined above.
  • suitable aryl groups include phenyl, tolyl, indanyl, fluorenyl, indenyl, azulenyl, and naphthyl.
  • heteroaryl group means a monocyclic aromatic ring comprising carbon atoms, preferably 3, 4, or 5 ring carbon atoms, and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which ring may be unsubstituted or substituted by one or more suitable substituents.
  • unsubstituted heteroaryl groups include, but are not limited to furyl, pyrrolyl, imidazolyl, pyridyl, pyrazyl, pyrazolyl, pyrimidyl, thiophenyl, and phienyl.
  • cycloalkyl group means a monocyclic radical comprising carbon atoms, preferably 5 or 6 ring carbon atoms, and having no unsaturation, which may be unsubstituted or substituted by one or more suitable substituents.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl group means a monocyclic radical comprising carbon atoms, preferably 4 to 6 ring carbon atoms, and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation, which may be unsubstituted or substituted by one or more suitable substituents.
  • unsubstituted heterocycloalkyl groups include pyrrolidenyl, piperidinyl, piperazinyl, mo ⁇ holinyl, and pyranyl.
  • Other preferred bisphosphonates useful in the present invention are represented by formula II below:
  • Bisphosphonates for use in the present invention can be classified into two general categories: amino bisphosphonates and non-amino bisphosphonates.
  • the OH groups may be modified to form analogs of bisphosphonates, e.g., pharmaceutically acceptable esters of bisphosphonates.
  • Non-limiting examples of bisphosphonates for use in the present invention include aldronic acid, etidronic acid, and pamidronic acid, which have the following formulas:
  • Non-limiting examples of bisphosphonates salts for use in the present invention include alendronate sodium, as well as etidronate disodium, and pamidronate disodium, which have the following formulas:
  • bisphosphonate includes both the acid form and the salt forms of the bisphosphonate.
  • bisphosphonates for use in the present invention include, but are not limited to risedronate, ibandronate, zoledronate, olpadronate, icandronate, and neridronate (6- amino- 1 -hydroxyexilidene-1, 1 -bisphosphonate); 1 -hydroxyethane- 1 , 1 -bisphosphonic acid; dichloromethane bisphosphonic acid;
  • N-cycloheptylaminomethanebisphosphonic acid S-(p-chlorophenyl) thiomethane-bisphosphonic acid; 4-amino- 1-hydroxybutylidene- 1,1 -bisphosphonic acid; (7-dihydro-l-pyrindine)methane bisphosphonic acid;
  • esters include those wherein the hydrogen of one or more of the hydroxyl groups of the above bisphosphonates is replaced by C,-C 10 alkyl, C,-C 10 unsaturated alkyl, aryl, 2-chloroethyl, 2,2,2-trichloroethyl, 2JJ-trifluoroethyl, benzyl, j-nitrophenyl;
  • Bisphosphonates for use in the present invention further include the bisphosphonates described in United States Patent Nos. 5,668,120; 5,730,715; and 5,735,810, all three of which are inco ⁇ orated by reference herein.
  • Etidronate has chemical properties that are representative of the general class of bisphosphonates. Etidronate has been used for many years to inhibit bone reso ⁇ tion. Its long-term use has, however, been called into question because of reports that it may impair mineralization (Mallmin et al, "Short-term effects of pamidronate on biochemical markers of bone metabolism in osteoporosis - a placebo-controlled dose-finding study", Upsala
  • Pamidronate has been shown to inhibit osteoclast activity and their recruitment from precursors (Mallmin et al, supra). On a molar basis, it is also one of the more potent bisphosphonates. These capabilities suggest that its action may be of longer duration than other bisphosphonates (Fitton and McTavish, supra, Mallmin et al, supra).
  • a bisphosphonate For impregnation into bone-cement dough, a bisphosphonate should be used without the additional buffering agents, etc., normally found in the clinical packaging.
  • the amount of the bisphosphonate to be utilized is an amount that will not compromise the short-term strength or the long-term durability of the bone cement or the allograft bone.
  • the biologic effect of the bisphosphonate should be optimized to inhibit osteoclasts enough to prevent osteolysis from particulate debris. Since the problem of particulate debris generation is time dependent, long-term delivery of bisphosphonates may be necessary to prevent the osteolytic effect. The retention of bisphosphonates in the bone matrix makes these agents excellent choices as anti-reso ⁇ tive agents.
  • the impact of bisphosphonates on bone reso ⁇ tion is accessed using radiographic indicators, bone histomo ⁇ hometry or density, the biochemical indicators, namely, serum alkaline phosphate (SAP) activity and level or urinary hydroxyproline (UHP) excretion.
  • SAP serum alkaline phosphate
  • UHP urinary hydroxyproline
  • SAP activity and UHP levels are suggestive of osteoblast and osteoclast activity, respectively.
  • An alternative indicator of osteoclast activity is the urinary level of n- telopeptide (NTX); this measure is more sensitive than UHP.
  • the key to the success of local delivery of bisphosphonates to the bone surrounding prosthetic implants is the duration of the remission of bone reso ⁇ tion following the elution of the bisphosphonates from the bone cement mantle to the adjacent bone.
  • the duration of the effect of pamidronate disodium can be inferred from published clinical trials using the drug for chronic bone diseases or conditions, e.g., Paget's disease, osteoporosis, or hypercalcemia of malignancy. Harnick et al.
  • the bone cement or the bone graft of the invention may further comprise one or more chemotherapeutic agents.
  • chemotherapeutic agent means any substance that can used to treat cancer in an animal, preferably a mammal, more preferable a human.
  • the anti-reso ⁇ tive agent and the chemotherapeutic agent can be associated via a chemical bond or as a salt complex or they may be present individually in the bone cement or the bone graft.
  • the chemotherapeutic agent and the bisphosphonate are associated via a chemical bond or as a salt complex, the resultant compound or material is referred to herein as a "bisphosphonate-chemotherapeutic agent conjugate".
  • the chemotherapeutic agent and the bisphosphonate are in the form of such a bisphosphonate- chemotherapeutic agent conjugate.
  • the bisphosphonate may be any bisphosphonate, for example, one of those described above.
  • suitable chemotherapeutic agents include, but are not limited to, daunorubicin, dactinomycin, doxorubicin, bleomycin, mitomycin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide,
  • chemotherapeutic agents for other suitable chemotherapeutic agents see, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al, eds., 1987, Rahway, N.J., pages 1206-1228, all of which compounds are inco ⁇ orated by reference herein).
  • the chemotherapeutic agent is doxorubicin or methotrexate and the anti- reso ⁇ tive agent is pamidronate.
  • the preferred bisphosphonate-chemotherapeutic agent conjugate s are pamidronate/doxorubicin or pamidronate/methotrexate conjugates.
  • the bisphosphonate-chemotherapeutic agent conjugate may be prepared by forming a bisphophonic acid/chemotherapeutic amine salt complex by quenching an acidic bisphosphonate with the amine.
  • the amino function of doxorubicin may be quenched with the acid function of pamidronate to give the pamidronate/doxorubicin bisphosphonate-chemotherapeutic agent conjugate as a salt complex.
  • the chemotherapeutic agent has an acidic moiety, it can be condensed with a basic group on the bisphosphonate, for example, the amino group of alendronate.
  • the bisphosphonate may be chemically coupled to the chemotherapeutic agent via any functional group suitable for forming a chemical bond to a suitable functional group on the chemotherapeutic agent.
  • any functional group suitable for forming a chemical bond to a suitable functional group on the chemotherapeutic agent Such functional groups and methods for their coupling are well within the purview of one skilled in the art.
  • the bisphosphonate is chemically bonded to the chemotherapeutic agent through one or more of its hydroxyl or amino groups.
  • the bisphosphonate-chemotherapeutic agent conjugates can be prepared by well-known chemical coupling of either an alcohol, a carboxylic acid, or an amine moiety present on the chemotherapeutic agent with the acid functionality of the bisphosphonate (e.g., see the procedures described in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. p. 393-396; 401-402; and 419-421, inco ⁇ orated herein by reference).
  • these chemotherapeutic agent-bisphosphonate drug combinations are especially useful when using the bone cement to reduce, preferably fill bone voids resulting from removal of a bony metathesis lesion, by functioning as a therapeutic support structure to deliver the chemotherapeutic agent to kill remaining tumor cells and the bisphosphonate to prevent bone reso ⁇ tion.
  • Such bone cement is especially useful for reducing and patching bone voids in the vertebra after removal of tumors adjacent to the spine. Complete removal of metathesistic lesions from the spine is difficult because of the spinal cord's proximate location; thus, often, a significant portion of the tumor is left behind.
  • drugs such as estrogen (to provide specificity of action) to a small peptide (as a vehicle to provide specificity of location) that to localize on hydroxyapatite or a matrix protein such as osteocalcin conferring specificity to bone.
  • a protype is an (Asp) 6 conjugate with estrogen.
  • the function of the anti-reso ⁇ tive agent with respect to grafts and bone cements is different.
  • the function of the anti-reso ⁇ tive agent in grafts is to provide chemical bonding preferably permanent chemical bonding, of the anti-reso ⁇ tive agent to the graft.
  • an anti-reso ⁇ tive agent when used with bone cements, there is a physical entrapment (e.g., impregnation) of the anti-reso ⁇ tive agent in the bone cement, rather than a chemical bonding.
  • the anti-reso ⁇ tive agent is released by a leaching process or a passive diffusion process (generically “elution") so as to provide an in vivo local delivery of the anti-reso ⁇ tive agent to the bone.
  • the bone cements and bone grafts of the invention may further comprise one or more other biologically active substances.
  • other biologically active substances are selected from the group consisting of adrenal hormones and corticosteroids such as teracosactrin, alsactide, cortisone, cortisoneacetate, hydrocortisone, hydrocortisone alcohol, hydrocortisone acetate, hydrocortisone hemisuccinate, prednisolone, prednisoloneterbutate, 9-alphafluoroprednisolone, triamcinolone acetonide, dexamethasone phosphate, flunisolide, budesonide, toxicorol pivalate, and the like; amino acids; anorectics such as benzphetamine HC1, chlo ⁇ hentermine HC1, and the like; antibiotics such as tetracycline HC1, tyrothricin, cephalosporine, aminoglycosides, streptomycin, gentamycin, leucomycin, penicillin and derivatives; erythromycin; anti-
  • enzymes such as lysozyme chloride, dextranase, and the like; gastrointenstinal hormones and derivatives such as secretin, substance P, and the like; hypothalamus hormones and derivatives such as nafarelin, buserelin, zolidex, and the like, enkephalins such as metkephamid, leucine enkephalin, TRH (thyrotropin releasing hormone), and the like; local aesthetics such as benzocain, procaine, lidocaine, tetracaine, and the like; migraine treatment substances such as dihydroergotamine, ergometrine, ergotamine, pizotizin, and the like; narcotics, antagonists and analgesics such as bupreno ⁇ hine, naloxone and the like; pancreatic hormones and derivatives such as insulin (hexameric/dimeric/monomeric forms), glucagon, and the like; para
  • vasopressin and analogues such as aprotinin citrate and the like
  • protease inhibitors such as aprotinin citrate and the like
  • sedatives such as alprazolam, bromazepam, brotizolam, camazepam, chlordiazepeoxide, clobazam, chlorazepic acid, clonazepam, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, ethyl loflazepate, fludiazepam, flunitrazepam, flurazepam, flutazolam, halazepam, haloxazolam, ketazolam, lorazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam,
  • the present invention thus involves the treatment, e.g., impregnation, of bone cement or allografts (particulate and large segments) with one or more anti-reso ⁇ tive agents, such a bisphosphonate or a gallium salt prior to implantation to locally minimize the osteolytic processes that frequently occur following implantation of prosthetic devices or allografts as part of limb reconstructive surgery.
  • An embodiment of the present invention thus serves to deliver an anti-reso ⁇ tive agent, such as a bisphosphonate, in vivo during and following implantation.
  • the anti-reso ⁇ tive agent serves to block bone reso ⁇ tion to prevent osteolysis and prosthetic failure.
  • Bone cement impregnated with anti-reso ⁇ tive agents can be used not only for implant fixation, but also as a local drug depot, delivering significantly levels of the anti-reso ⁇ tive agent than those obtainable upon systemic administration.
  • Anti-reso ⁇ tive agents elute from the cement and bind to the adjacent bone matrix. The bound anti-reso ⁇ tive agents inhibit regional osteoclast activity and minimize the local osteolytic processes responsible for prosthetic failure.
  • Anti-reso ⁇ tive agents such as bisphosphonates or salts of Group IIIA elements, such as gallium salts, for inco ⁇ oration into bone-cement dough (such as PMMA bone- cement dough or hydroxyapatite bone-cement dough) or into grafts, such as allogeneic bone grafts, offer the following advantages:
  • Anti-reso ⁇ tive agents impregnated organic, particularly an acrylic, bone cement can serve as a slow-release depot for the drug (e.g., bisphosphonate) to adjacent bone regions.
  • drug e.g., bisphosphonate
  • Anti-reso ⁇ tive agent impregnated organic, particularly an acrylic, bone cement used in hip arthroplasty procedures significantly extend (a) the time when prosthetic loosening begins, and (b) the duration of normal levels of the bone biochemical markers serum alkaline phosphatase, N-telopeptidem, and calcium.
  • the anti-reso ⁇ tive agent elutes out from the matrix, it binds to local bone and inhibits osteoclast activity. This in turn may reduce the need for revision surgery to correct problems associated with bone reso ⁇ tion.
  • the present invention provides an effective system that retards or prevents the rapid bone reso ⁇ tion that leads to failure of particulate allografts from lack of bone union or reso ⁇ tion and to fracture of healed, large segment grafts. This may also prevent the previously described reso ⁇ tion of the host bone that is induced by allograft transplants.
  • the local delivery of the anti-reso ⁇ tive agent will induce greater bone formation stimulated from the host bone bed. Potentially, each of the 200,000 grafts performed in the United States each year
  • each graft costs approximately $250-$5,000
  • an anti-reso ⁇ tive agent by the merchant bone bank or the skilled artisan using the bone product.
  • the present invention also provides an improved orthopaedic implant by reducing reso ⁇ tion (preventing or reducing the gap between the allograft bone and the normal bone) and preventing the loss of mechanical properties, which often results in fractures.
  • the present invention also provides a relatively easy and inexpensive means to enhance the efficacy of allogeneic bone grafting procedures for various orthopaedic indications.
  • the dosage of the anti-reso ⁇ tive agent can be adjusted based on local requirements, creating flexibility for the skilled artisan, e.g., a surgeon. Local effects 5 should be maximized and systemic toxicity of the anti-reso ⁇ tive agents minimized.
  • the graft Since the graft is not vascularized, there is no oral or intravenous delivery of the anti-reso ⁇ tive agent, such as a bisphosphonate, to the graft. In vitro adso ⁇ tion of the anti-reso ⁇ tive agent overcomes this obstacle.
  • the anti-reso ⁇ tive agent such as a bisphosphonate
  • the anti-reso ⁇ tive agent such as a bisphosphonate, may be permanently adsorbed 10 to the adjacent bone, and its effect may therefore be exerted on an ongoing basis.
  • FIGs. 1 and 2 summarize the results of compression tests on the PMMA impregnated with each of
  • the PMMA powder (basis: 40 grams) was blended with the bisphosphonate drug using a rotary tumbler mixer for 30 minutes.
  • Drug levels that were selected for these tests e.g., 0.5, 1.0, 1.5, 2.0 gram/40 grams PMMA, are similar to published antibiotic drug levels (Duncan, et al, supra).
  • the final determination of the drug level will depend upon the elution profile of the drug from the polymerized drug-cement matrix.
  • the blend should be such that mean elution drug levels during the initial 1 to 2 weeks of elution will approximate plasma levels following a 10-day intravenous administration of the drug. For pamidronate disodium, this level is 90 mg/70-kg patient (Fitton and McTavish, supra).
  • Figs. 1 and 2 The compression and tension data shown in Figs. 1 and 2 indicate that PMMA impregnated with etidronate disodium and pamidronate disodium do not compromise the strength of the cement. These drugs are eluted out at levels that are therapeutically effective. In addition, the local delivery of anti-reso ⁇ tive agents to the bone region surrounding an implant reduces the incidence of loosening, and prolong implant longevity.
  • Drug level analysis can be performed by the following techniques: capillary electrophoresis, HPLC and fluorescence spectrophotometry.
  • a method of analysis for pamidronate disodium and etidronate disodium samples from cement, bone and fluid samples using capillary electrophoresis (“CE”) technology is employed (Leveque, D., Gallion, C, Tarral, Monteil H., Jehl, F., "Determination of fosfomycin in biological fluids by capillary electrophoresis", J. of Chromatography B., 655. 320-324, (1994); Olmstead, M ., “Canine cemented total hip replacements: State of the art", J.
  • Pamidronate disodium and etidronate disodium do not possess any chromaphores, and thus present a problem for routine HPLC analytical methods.
  • Pamidronate disodium has a primary amine group that can be easily derivatized for high-pressure liquid chromatograph ("HPLC") analysis (King, L.E., Veith, R., "Extraction and Measurement of Pamidronate disodium from Bone Samples Using Automated Pre-Column Derivatization, High Performance Liquid Chromatography and Fluorescence Detection", Journal of Chromatography B., 678. 325-330, (1996)), however etidronate disodium does not.
  • HPLC high-pressure liquid chromatograph
  • the detection limit of the King and Veith method is 0.1 microgram/milliliters.
  • the HPLC technique is approximately ten times more sensitive than micro-electrophoresis and is used to measure pamidronate disodium levels after micro-electrophoresis detection limits are reached (this method does not work with etidronate disodium).
  • CE bisphosphonate analysis from biological samples, such as plasma or bone, requires preparation prior to analysis; the approach used for the HPLC method for pamidronate disodium (King and Veith, supra) will be adopted.
  • Bisphosphonates can be highly water-soluble and can have two ionized phosphate groups.
  • CE a new analytical technique, performs separation by the electrical charge of the molecule.
  • the separation is performed on a Hewlett Packard microelectrophoresis with sensitive flow cell using a 75 micrometers x 50 centimeters bare silica capillary at -lOkv and monitored at 254 nm.
  • the buffer consists of 1.5 mM sodium dihydrogen phosphate, 15.4 mM sodium 4-hydroxybenzoate (for indirect detection), 13 mM centrimide, 25 mM lithium hydroxide and 2.5 percent methanol.
  • the retention time for etidronate disodium and pamidronate disodium are 4.7 and 5.6 minutes, respectively, and each drug can serve as the internal standard for the other.
  • Cement drug levels of etidronate disodium or pamidronate disodium were measured from representative samples of each drug-PMMA blend after the dough was polymerized for 24 hours. The intent of this analysis was to determine whether the drug blending technique produced a uniformly mixed powder and to determine whether the temperatures generated during the polymerization changed the chemical nature of the drug.
  • the bisphosphonate/bone containing samples were first pulverized using an SPEX Freezer Mill Model 6700.
  • the bisphosphonates were then extracted from the powder by aqueous extraction and analyzed.
  • the results of the analysis determined that the polymerization does not alter the structure of either bisphosphonate.
  • the electrophorograms of the drug standard, and the drug eluted from pulverized polymerized drug-cement samples were essentially the same. Changes such as additional peaks or retention time differences, strongly suggestive of chemical changes, were not observed. Further, the analysis performed on several specimens of the drug-cement matrix demonstrated that the cement and drug were uniformly blended because the expected concentration was realized and the variance was small. Fig.
  • the model parameters are used with a subsequent mathematical model of the diffusion-adso ⁇ tion process that describes the elution of drug from cement and adsorbs onto bone.
  • These mathematical analyses e.g., parameter estimation and simulation, are performed using the Macsyma/PDEase software package.

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Abstract

Cette invention se rapporte à des ciments osseux anti-résorption, qui comprennent une quantité anti-résorption d'un ou plusieurs agents anti-résorption, cet agent étant constitué de préférence par un bisphosphonate. Ces ciments osseux anti-résorption servent à réduire les vides osseux et à fixer des prothèses à l'os. Cette invention se rapporte également à des implants osseux allogènes, autogreffés et xénogreffés, qui contiennent une quantité anti-résorption d'un agent anti-résorption, tel qu'un bisphophonate. Ces greffes osseuses anti-résorption sont utiles pour la chirurgie osseuse reconstructive.
PCT/US2000/003285 1999-02-09 2000-02-09 Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes WO2000047214A1 (fr)

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EP00911738A EP1150684A4 (fr) 1999-02-09 2000-02-09 Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes
AU33588/00A AU776555B2 (en) 1999-02-09 2000-02-09 Anti-resorptive bone cements and allogeneic, autografic, and xenografic bone grafts
CA002360319A CA2360319A1 (fr) 1999-02-09 2000-02-09 Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes
JP2000598166A JP2002536123A (ja) 1999-02-09 2000-02-09 抗吸収性骨セメントならびに同種、自家、および異種骨移植片

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FR2836681A1 (fr) * 2002-03-04 2003-09-05 Centre Nat Rech Scient Compose phosphocalcique modifie, composition injectable le contenant
US6632447B1 (en) 1998-05-07 2003-10-14 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer
EP1383509A1 (fr) * 2001-04-03 2004-01-28 The Royal Alexandra Hospital for Children Medicament a utiliser en matiere de greffe osseuse
JP2006521859A (ja) * 2003-04-04 2006-09-28 ティーエー コントラスト エービー 骨セメント組成物
WO2006123589A1 (fr) * 2005-05-16 2006-11-23 Tokyo Medical And Dental University Materiau destine a un usage medical
EP1958649A1 (fr) * 2007-02-14 2008-08-20 Graftys Ciment calcium-phosphate injectable libérant un inhibiteur de la résorption osseuse
WO2009006921A1 (fr) * 2007-07-10 2009-01-15 Barrera Jose Bouza Substance microporeuse pour implant chirurgical
WO2009134856A2 (fr) * 2008-04-30 2009-11-05 Genta Incorporated Compositions pharmaceutiques à base de gallium et procédés associés
US7887831B2 (en) 2002-12-26 2011-02-15 Hepacore Ltd. Bone enhancing composite
WO2013043529A1 (fr) * 2011-09-19 2013-03-28 Emory University Activation de la voie de la protéine morphogénétique osseuse, compositions pour ossification et méthodes associées
US9539367B2 (en) 2003-12-04 2017-01-10 University Of Iowa Research Foundation Gallium inhibits biofilm formation
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
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CN109010334A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合辛伐他汀骨水泥用于制备假体周围骨溶解和炎症反应的药物中的应用
CN109010909A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合红霉素骨水泥用于防治假体周围骨溶解和炎症反应的应用
CN111321403A (zh) * 2020-03-10 2020-06-23 河北北方学院 一种基于多巴胺的锌表面载镓-氧化石墨烯复合涂层的制备方法
CN113181425A (zh) * 2021-04-28 2021-07-30 北京邦塞科技有限公司 骨水泥固相粉料、骨水泥及其制备方法和应用
CN114984310A (zh) * 2022-06-30 2022-09-02 西安理工大学 一种抗溃散吸水膨胀有机-无机复合骨水泥及其制备方法

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AU2002244520B2 (en) * 2001-04-03 2007-05-24 The Royal Alexandra Hospital For Children A drug for use in bone grafting
EP1383509A1 (fr) * 2001-04-03 2004-01-28 The Royal Alexandra Hospital for Children Medicament a utiliser en matiere de greffe osseuse
EP1383509A4 (fr) * 2001-04-03 2005-10-26 Royal Alexandra Hosp Children Medicament a utiliser en matiere de greffe osseuse
WO2003045454A3 (fr) * 2001-11-29 2003-08-07 Kathy Rzeszutek Implants osseux a resorption regulee
WO2003045454A2 (fr) * 2001-11-29 2003-06-05 Kathy Rzeszutek Implants osseux a resorption regulee
FR2836681A1 (fr) * 2002-03-04 2003-09-05 Centre Nat Rech Scient Compose phosphocalcique modifie, composition injectable le contenant
WO2003074098A1 (fr) * 2002-03-04 2003-09-12 Centre National De La Recherche Scientifique Compose phosphocalcique modifie, composition injectable le contenant
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US7521436B2 (en) 2002-03-04 2009-04-21 Centre National De La Recherche Scientifique Modified phosphocalcic compound, injectable composition containing same
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JP2006521859A (ja) * 2003-04-04 2006-09-28 ティーエー コントラスト エービー 骨セメント組成物
US9539367B2 (en) 2003-12-04 2017-01-10 University Of Iowa Research Foundation Gallium inhibits biofilm formation
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WO2008098959A1 (fr) * 2007-02-14 2008-08-21 Graftys Ciment de phosphate de calcium injectable libérant un inhibiteur de la résorption osseuse
EP1958649A1 (fr) * 2007-02-14 2008-08-20 Graftys Ciment calcium-phosphate injectable libérant un inhibiteur de la résorption osseuse
RU2465922C2 (ru) * 2007-02-14 2012-11-10 Графтис Инъецируемый кальций-фосфатный цемент в форме апатита, высвобождающий ингибитор резорбции костной ткани
EP2117612B1 (fr) 2007-02-14 2015-07-29 Graftys Ciment de phosphate de calcium injectable libérant un inhibiteur de la résorption osseuse
US8889165B2 (en) 2007-02-14 2014-11-18 Graftys Injectable calcium-phosphate cement releasing a bone resorption inhibitor
WO2009006921A1 (fr) * 2007-07-10 2009-01-15 Barrera Jose Bouza Substance microporeuse pour implant chirurgical
WO2009134856A3 (fr) * 2008-04-30 2010-01-28 Genta Incorporated Compositions pharmaceutiques à base de gallium et procédés associés
WO2009134856A2 (fr) * 2008-04-30 2009-11-05 Genta Incorporated Compositions pharmaceutiques à base de gallium et procédés associés
WO2013043529A1 (fr) * 2011-09-19 2013-03-28 Emory University Activation de la voie de la protéine morphogénétique osseuse, compositions pour ossification et méthodes associées
US10286113B2 (en) 2011-09-19 2019-05-14 Emory University Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto
US11179501B2 (en) 2011-09-19 2021-11-23 Emory University Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US11555172B2 (en) 2014-12-02 2023-01-17 Ocugen, Inc. Cell and tissue culture container
CN109010334A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合辛伐他汀骨水泥用于制备假体周围骨溶解和炎症反应的药物中的应用
CN109010909A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合红霉素骨水泥用于防治假体周围骨溶解和炎症反应的应用
CN111321403A (zh) * 2020-03-10 2020-06-23 河北北方学院 一种基于多巴胺的锌表面载镓-氧化石墨烯复合涂层的制备方法
CN113181425A (zh) * 2021-04-28 2021-07-30 北京邦塞科技有限公司 骨水泥固相粉料、骨水泥及其制备方法和应用
CN114984310A (zh) * 2022-06-30 2022-09-02 西安理工大学 一种抗溃散吸水膨胀有机-无机复合骨水泥及其制备方法
CN114984310B (zh) * 2022-06-30 2023-09-08 西安理工大学 一种抗溃散吸水膨胀有机-无机复合骨水泥及其制备方法

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AU3358800A (en) 2000-08-29
EP1150684A4 (fr) 2005-06-15
AU776555B2 (en) 2004-09-16
EP1150684A1 (fr) 2001-11-07
JP2002536123A (ja) 2002-10-29
CA2360319A1 (fr) 2000-08-17
WO2000047214A9 (fr) 2002-04-11

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