Insulin-mimetics as therapeutic adjuncts for bone regeneration

Abstract

Methods of promoting bone healing or regeneration by locally administering insulin mimetic agents to patients in need thereof and new uses of insulin-mimetic compounds for accelerating bone-healing processes are disclosed. Bone injury treatment and void filler devices, products and kit suitable for local administration of insulin-mimetic agents or compositions thereof to patients in need of such treatment are also disclosed.

What is claimed is: 
     
         1 . A method of promoting bone healing or regeneration in a patient inflicted with a bone condition, comprising locally administering to said patient a therapeutically effective amount of an insulin-mimetic agent. 
     
     
         2 . The method of  claim 1 , wherein said insulin-mimetic agent is an insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, or manganese compound. 
     
     
         3 . The method of  claim 2 , wherein said insulin-mimetic agent is a zinc, vanadium, or manganese compound. 
     
     
         4 . The method according to any of  claims 1 - 3 , wherein said insulin-mimetic agent is administered to the bone injury site. 
     
     
         5 . The method according to any of  claims 1 - 4 , wherein said bone condition is selected from the group consisting of bone fracture, bone trauma, arthrodesis, including spinal arthrodesis, extremity arthrodesis and the like, and a bone deficit condition associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-plastic bone surgery, post-dental surgery, bone chemotherapy treatment, congenital bone loss, post traumatic bone loss, post surgical bone loss, post infectious bone loss, allograft incorporation or bone radiotherapy treatment. 
     
     
         6 . The method according to any of  claims 1 - 4 , wherein said bone condition is selected from bone fractures, osseous defects, and delayed unions and non-unions. 
     
     
         7 . The method according to any of  claims 1 - 6 , wherein the method is used in combination with a second method for promoting bone regeneration, selected from bone autograft methods, bone allograft methods, autologous stem cell treatment methods, methods using autologous growth factor concentrates, allogeneic stem cell treatment methods, chemical stimulation methods, electrical stimulation methods, low-intensity pulse ultrasound (LIPUS) methods, internal fixation methods, and external fixation methods. 
     
     
         8 . The method according to any of  claims 1 - 6 , wherein the method is used in combination with an allograft method, autograft method, xenograft method, alloplastic graft method, or orthopedic biocomposite method. 
     
     
         9 . The method according to any of  claims 1 - 6 , wherein said method comprises co-administering a cytotoxic agent, cytokine or growth inhibitory agent with said insulin-mimetic agent. 
     
     
         10 . The method according to any of  claims 1 - 6 , wherein the method is used in conjunction with an external bone growth stimulator. 
     
     
         11 . The method according to any of  claims 1 - 6 , wherein the method comprises co-administering a bioactive bone agent with said insulin-mimetic agent. 
     
     
         12 . The method of  claim 11 , wherein said bioactive bone agent is selected from the group consisting of peptide growth factors, anti-inflammatory factors, pro-inflammatory factors, inhibitors of apoptosis, MMP inhibitors, and bone catabolic antagonists. 
     
     
         13 . The method of  claim 12 , wherein said peptide growth factor is selected from the group consisting of IGF (1,2), PDGF (AA, AB, BB), BMPs, FGF (1-20), TGF-beta (1-3), aFGF, bFGF, EGF, VEGF, parathyroid hormone (PTH), and parathyroid hormone-related protein (PTHrP). 
     
     
         14 . The method of  claim 12 , wherein said anti-inflammatory factor is selected from the group consisting of anti-TNFa, soluble TNF receptors, ILlra, soluble IL1 receptors, IL4, IL-10, and IL-13. 
     
     
         15 . The method of  claim 12 , wherein said bone catabolic antagonist is selected from the group consisting of bisphosphonates, osteoprotegerin, and statins. 
     
     
         16 . Use of an insulin-mimetic agent for manufacture of a medicament for accelerating bone healing or regeneration in a patient in need thereof characterized by local administration of said medicament. 
     
     
         17 . A bone injury treatment kit comprising a therapeutically effective amount of an insulin-mimetic agent formulated for localized administration to a patient inflicted with a bone condition in need of healing or bone regeneration. 
     
     
         18 . A bone regeneration material for bone fusion or void filling, comprising an osteoconductive carrier and an insulin-mimetic agent. 
     
     
         19 . The material of  claim 18 , wherein said insulin-mimetic agent is an insulin pathway stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, or manganese compound. 
     
     
         20 . The material of  claim 19 , wherein said insulin-mimetic agent is a vanadium or zinc compound. 
     
     
         21 . The material according to any of  claims 18 - 20 , wherein said osteoconductive carrier is selected from the group consisting of autograft material, allograft material, calcium phosphate, calcium sulfate, xenograft materials, alloplastic graft biomaterials, and orthopedic biocomposites. 
     
     
         22 . An orthopedic or spinal implant, comprising at least one bone-contacting surface incorporating an insulin-mimetic compound or composition thereof 
     
     
         23 . The orthopedic or spinal implant of  claim 22 , wherein the orthopedic implant is selected from the group consisting of screws, plates, rods, k-wires, pins, hooks, anchors, intramedullary devices, pedicle screws, pedicle hooks, spinal fusion cages, spinal fusion plates, prostheses, and porous metal implants (such as trabecular metal implants). 
     
     
         24 . The orthopedic or spinal implant of  claim 22  or  23 , made from a metal selected from the group consisting of titanium, alloys thereof, tantalum, alloys thereof, cobalt chrome alloys, steel alloys, and combinations thereof. 
     
     
         25 . The orthopedic or spinal implant of  claim 24 , wherein said steel alloy is a stainless steel. 
     
     
         26 . The orthopedic or spinal implant of  claim 22  or  23 , made from a polymeric material. 
     
     
         27 . The orthopedic or spinal implant of  claim 26 , wherein said polymeric material comprises a polymer selected from polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyether ether ketone (PEEK), polyethylene terephthalate (PET), polypropylene (PP), polycarbonates (PC), poly(ortho esters) (POEs), and combinations thereof. 
     
     
         28 . The orthopedic or spinal implant according to any of  claims 22 - 27 , wherein said insulin-mimetic agent is selected from the group consisting of insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, and manganese compounds, and combinations thereof. 
     
     
         29 . The orthopedic or spinal implant of  claim 28 , wherein said insulin-mimetic agent is a zinc, vanadium, or manganese compound. 
     
     
         30 . A method of enhancing spinal fusion in a spinal fusion surgical procedure, the method comprising the steps of:
 exposing a portion of each of adjacent vertebrae; and   placing supplementary bone tissue material and an insulin-mimetic agent within an area between the exposed portions of the adjacent vertebrae and in contact with the exposed portions of both vertebrae;   wherein the insulin-mimetic agent is provided in an amount effective to increase the rate of fusion of the two vertebrae with the bone tissue material.   
     
     
         31 . The method of  claim 30 , wherein the insulin-mimetic agent is an insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, or manganese compound. 
     
     
         32 . The method of  claim 31 , wherein the insulin-mimetic agent is a zinc or vanadium compound. 
     
     
         33 . The method according to any of  claims 30 - 32 , wherein the insulin-mimetic agent is added to the fusion site. 
     
     
         34 . The method according to any of  claims 30 - 32 , wherein the insulin-mimetic agent is added in a form of bone tissue material formulated to be suitable for implantation. 
     
     
         35 . The method according to any of  claims 30 - 32 , wherein the insulin-mimetic agent is added as a composition further comprising a surgically acceptable carrier. 
     
     
         36 . The method of  claim 35 , wherein the composition is calcium sulfate pellet comprising said insulin-mimetic agent. 
     
     
         37 . The method according to any of  claims 30 - 32  in combination with transplantation of an autograft bone, allograft bone, xenograft bone, orthopedic biocomposite, or synthetic bone void filler. 
     
     
         38 . The method of  claim 37 , wherein the synthetic bone void filler is a ceramic bone-graft substitute. 
     
     
         39 . The method of  claim 37 , wherein the method is posterior fusion, comprising decortication of the native host bone of the lamina or lateral masses to form a prepared area, and packing of a bone grafting mixture comprising the insulin-mimetic compound over the prepared area to induce segmental fusion. 
     
     
         40 . The method of  claim 37 , wherein the method is posterolateral fusion, comprising decortication of the side of the facet joints, one or more transverse processes to form a prepared area, and packing of bone grafting mixture comprising the insulin-mimetic compound over the prepared area to induce segmental fusion. 
     
     
         41 . The method according to any of  claims 30 - 32  in combination with implantation of an interbody device. 
     
     
         42 . The method according to any of  claims 30 - 32  in combination with autograft, allograft, or synthetic (e.g., ceramic) bone void filler in the central chamber of an interbody device to enhance fusion between the vertebral bodies of the anterior column of the spine (anterior interbody spinal fusion). 
     
     
         43 . The method of  claim 42 , performed after anterior discectomies and decompressions as well as after anterior corpectomies when the vertebral body is removed for purposes of decompression or to address trauma, tumor or infection involving the vertebral body. 
     
     
         44 . A bone tissue kit for facilitating fusion of vertebrae in a spinal fusion surgical procedure, comprising a composition formulated for facile application in a spinal fusion procedure comprising an insulin-mimetic agent and a pharmaceutically acceptable carrier. 
     
     
         45 . The bone tissue kit of  claim 44 , further comprising allograft bone tissue material and/or ceramic bone-graft substitute. 
     
     
         46 . The hone tissue kit of  claim 45 , wherein the insulin-mimetic agent and the allograft bone tissue material or ceramic bone-graft substitute are provided in a mixture. 
     
     
         47 . The bone tissue kit of  claim 45 , wherein the insulin-mimetic agent and allograft bone tissue material or ceramic bone-graft substitute are provided for subsequent mixing. 
     
     
         48 . The bone tissue kit of  claim 44  wherein said insulin-mimetic agent is selected from the group consisting of insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, or manganese compounds, and combinations thereof. 
     
     
         49 . A composition for enhancing spinal fusion in a spinal fusion surgical procedure comprising an insulin-mimetic agent and a pharmaceutically acceptable carrier. 
     
     
         50 . The composition of  claim 49 , wherein said insulin-mimetic agent is selected from the group consisting of insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, and manganese compounds, and combinations thereof. 
     
     
         51 . An implantable device for enhancing spinal fusion, comprising a prosthetic implant configured to stabilize and promote the fusion of two adjacent vertebrae, wherein the bone tissue contacting surfaces of the prosthetic implant are coated with a composition comprising an insulin-mimetic agent. 
     
     
         52 . The implantable device of  claim 51 , wherein said insulin-mimetic agent is selected from the group consisting of insulin pathway-stimulating zinc, vanadium, tungsten, molybdenum, niobium, selenium, and manganese compounds, and combinations thereof. 
     
     
         53 . The implantable device of  claim 52 , wherein said insulin-mimetic agent is a zinc, vanadium, or manganese compound.