Methods of treating osteonecrosis with llp2a-bisphosphonate compounds

Abstract

Methods of treating osteonecrosis in a subject are provided. In some embodiments, the method comprises administering to a subject having or suspected of having osteonecrosis a pharmaceutical composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug. In some embodiments, the pharmaceutical composition comprises a conjugate of LLP2A and alendronate (LLP2A-Ale). In some embodiments, the method further comprises administering exogenous mesenchymal stem cells.

1 . A method of treating osteonecrosis in a subject, the method comprising:
 administering to the subject a pharmaceutical composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug.   
     
     
         2 . The method of  claim 1 , wherein the pharmaceutical composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”) having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein prior to the administering step, the method further comprises identifying a subject having at least one osteonecrotic lesion in at least one bone. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 3 , wherein the identifying step comprises detecting at least one osteonecrotic lesion having a size of at least 3.5 cm 2 . 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the osteonecrosis is traumatic osteonecrosis. 
     
     
         10 . The method of  claim 1 , wherein the osteonecrosis is glucocorticoid-induced osteonecrosis or alcohol-induced osteonecrosis. 
     
     
         11 . The method of  claim 1 , wherein the method further comprises administering exogenous mesenchymal stem cells. 
     
     
         12 . The method of  claim 11 , wherein the pharmaceutical composition and the exogenous mesenchymal stem cells are administered concurrently. 
     
     
         13 . The method of  claim 11 , wherein the pharmaceutical composition and the exogenous mesenchymal stem cells are administered sequentially. 
     
     
         14 . The method of  claim 1 , wherein the pharmaceutical composition is administered systemically. 
     
     
         15 . The method of  claim 1 , wherein the pharmaceutical composition is administered locally. 
     
     
         16 . The method of  claim 15 , wherein the pharmaceutical composition is administered locally at the site of the at least one osteonecrotic lesion. 
     
     
         17 . The method of  claim 1 , wherein the pharmaceutical composition is administered intravenously. 
     
     
         18 . The method of  claim 1 , wherein the pharmaceutical composition is administered by injection. 
     
     
         19 . A method of increasing vascular density in an osteonecrotic tissue, the method comprising:
 administering to the subject a pharmaceutical composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug.   
     
     
         20 . The method of  claim 19 , wherein the pharmaceutical composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”) having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         21 - 27 . (canceled) 
     
     
         28 . The method of  claim 19 , wherein the method further comprises administering exogenous mesenchymal stem cells. 
     
     
         29 - 35 . (canceled) 
     
     
         36 . A method of preventing or reducing cell death in an osteonecrotic tissue, the method comprising:
 administering to the subject a pharmaceutical composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug.   
     
     
         37 . The method of  claim 36 , wherein the pharmaceutical composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”) having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 - 44 . (canceled) 
     
     
         45 . The method of  claim 36 , wherein the method further comprises administering exogenous mesenchymal stem cells. 
     
     
         46 - 52 . (canceled)