Skeletal removal of bisphosphonates
Disclosed herein are methods and compositions for removing or displacing bisphosphonates in skeletal tissue.
1. A method of removing or displacing an active bisphosphonate in a skeletal tissue, which comprises administering to the skeletal tissue one or more inactive bisphosphonates, wherein the one or more inactive bisphosphonates has a molecular scaffold that (a) lacks an α-hydroxy group, (b) has a pyridyl side chain that is para-substituted, or (c) lacks an α-hydroxy group and has a pyridyl side chain that is para-substituted.
2. The method according to claim 1 , wherein the one or more inactive bisphosphonates has a detectable label attached thereto.
3. The method according to claim 1 , wherein the one or more inactive bisphosphonates comprises a bisphosphonate conjugated to a fluorescent compound.
4. The method according to claim 3 , wherein the fluorescent compound is selected from the group consisting of: ROX, FAM, AF647, ICG, ICG analogs, Cy5, Sulfo-Cy5, Cy7, and IRDye 800CW.
5. The method according to claim 3 , wherein the one or more inactive bisphosphonates is selected from the group consisting of: 5-FAM-dRIS, 5(6)-FAM-dRIS, 5(6)-RhR-dRIS, and ICG-p-pyrEBP.
6. The method according to claim 3 , wherein the one or more inactive bisphosphonates is ICG-A-p-PyrEBP, ICG-B-p-PyrEBP, ICG-C-p-PyrEBP, ICG-D-p-PyrEBP, ICG-A-p-RIS, ICG-C-p-RIS, or ICG-D-p-RIS.
7. The method according to claim 1 , wherein the active bisphosphonate is an active nitrogen-containing bisphosphonate.
8. The method according to claim 7 , wherein the active nitrogen-containing bisphosphonate is alendronate, ibandronate, minodronate, pamidronate, risedronate, or zoledronate.
9. The method according to claim 1 , wherein the active bisphosphonate in the skeletal tissue is removed or displaced in vivo in a subject.
10. The method according to claim 9 , wherein the one or more inactive bisphosphonates is locally administered to the subject.
11. The method according to claim 9 , wherein the one or more inactive bisphosphonates is administered orally to the subject.
12. The method according to claim 9 , wherein the one or more inactive bisphosphonates is administered to a gingival tissue and/or a palatal tissue of the subject.
13. The method according to claim 9 , wherein the one or more inactive bisphosphonates is administered by intraoral application to a site of a dentoalveolar procedure.
14. The method according to claim 13 , wherein the one or more inactive bisphosphonates is administered before, during, and/or after the dentoalveolar procedure.
15. The method according to claim 1 , wherein an effective amount of the one or more inactive bisphosphonates is administered.
16. The method according to claim 1 , wherein the one or more inactive bisphosphonates is administered in the form of a liposomal formulation or a nanovesicle formulation, preferably a deformable nanovesicle formulation.
17. A method of treating, reducing, preventing, or inhibiting Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ) or a bisphosphonate-related symptom in a subject, which comprises administering to the subject a therapeutically effective amount of one or more inactive bisphosphonates, wherein the one or more inactive bisphosphonates has a molecular scaffold that (a) lacks an α-hydroxy group, (b) has a pyridyl side chain that is para-substituted, or (c) lacks an α-hydroxy group and has a pyridyl side chain that is para-substituted.
18. The method according to claim 17 , wherein the subject has been or is being treated with an active bisphosphonate.
19. The method according to claim 17 , wherein the one or more inactive bisphosphonates are selected from the group consisting of: 5(6)-FAM-dRIS, 5(6)-RhR-dRIS, 5-FAM-dRIS, 5-FAM-p-RIS, 800CW-p-pyrEBP, 800CW-p-RIS, AF647-p-RIS, clodronate, ICG-A-p-pyrEBP, ICG-A-p-RIS, ICG-B-p-pyrEBP, ICG-B-p-RIS, ICG-C-p-pyrEBP, ICG-C-p-RIS, ICG-D-p-pyrEBP, ICG-D-p-RIS, ICG-p-pyrEBP, MBP, p-PyrEBP, p-PyrEBP, p-RIS, ROX-p-RIS, and tiludronate.
20. The method according to claim 1 , wherein the one or more inactive bisphosphonates is selected from the group consisting of: 5-FAM-p-RIS, 800CW-p-pyrEBP, 800CW-p-RIS, AF647-p-RIS, clodronate, MBP, p-PyrEBP, p-PyrEBP, p-RIS, ROX-p-RIS, and tiludronate.