Method of Treating Alvelor Bone Loss Through The Use of Anti-Sclerostin Antibodies

Abstract

The invention provides a method of treating alveolar bone loss involving administration of a sclerostin inhibitor to a subject in need thereof.

What is claimed is: 
     
         1 . A method for treating alveolar bone loss in a subject comprising administering to the subject an anti-sclerostin antibody in an amount effective to decrease the distance between the cement-enamel junction and the alveolar bone crest, at a dose from about 5 mg to about 1,000 mg per week. 
     
     
         2 . The method of  claim 1 , wherein the distance between the cement-enamel junction and the alveolar bone crest is decreased by at least 10% compared to the pre-treatment distance by six weeks after initiation of treatment. 
     
     
         3 . The method of  claim 1 , wherein the alveolar bone height is increased by at least 10% compared to the pre-treatment alveolar bone height by six weeks after initiation of treatment. 
     
     
         4 . The method of  claim 1 , wherein the alveolar bone height of the subject is increased by at least 1 mm compared to pre-treatment alveolar bone height by six weeks after initiation of treatment. 
     
     
         5 . The method of  claim 1 , wherein the alveolar bone density of the subject is increased by at least 10% compared to pre-treatment alveolar bone density by six weeks after initiation of treatment. 
     
     
         6 . The method of  claim 1 , wherein the alveolar bone volume fraction is increased by at least 10% compared to pre-treatment bone volume fraction by six weeks after initiation of treatment. 
     
     
         7 . The method of  claim 1 , wherein the antibody is administered in an amount from about 120-270 mg. 
     
     
         8 . The method of  claim 1 , wherein the anti-sclerostin antibody is administered twice a week. 
     
     
         9 . The method of  claim 1 , wherein the anti-sclerostin antibody is administered locally to diseased gingival area or diseased periodontal pocket of the subject. 
     
     
         10 . The method of any one of  claims 1 - 9 , wherein the method comprises administering a standard of care therapeutic selected from the group consisting of Periostat® or chemically modified tetracycline-3 (CMT-3) prior to administering the anti-sclerostin antibody. 
     
     
         11 . The method of any one of  claims 1 - 10 , further comprising administering a second bone-enhancing therapeutic selected from the group consisting of parathyroid hormone, teriparatide, a bisphosphonate, a RANKL antibody and a DKK-1 antibody. 
     
     
         12 . The method of  claim 10 , wherein the second bone-enhancing therapeutic is administered after the treatment period with the anti-sclerostin antibody has ended. 
     
     
         13 . The method of  claim 1 , optionally comprising administering the anti-sclerostin antibody for a second period of time in an amount sufficient to maintain alveolar bone. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the anti-sclerostin antibody is an immunoglobulin comprising a heavy chain and a light chain. 
     
     
         15 . The method of any one of  claims 1 - 13 , wherein the anti-sclerostin antibody is an antibody or fragment thereof that demonstrates a binding affinity for sclerostin of SEQ ID NO: 1 of less than or equal to 1×10 −9  M. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein the anti-sclerostin antibody neutralizes human sclerostin in a MC3T3 cell-based mineralization assay when there is less than a six-fold excess of moles of sclerostin binding sites per well as compared to the number of moles of sclerostin per well. 
     
     
         17 . The method of any one of  claims 1 - 13 , where the anti-sclerostin antibody cross-blocks the binding of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin and/or is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24. 
     
     
         18 . The method of any one of  claims 1 - 13 , wherein the anti-sclerostin antibody comprises a CDR-H1 of SEQ ID NO:245, a CDR-H2 of SEQ ID NO:246, a CDR-H3 of SEQ ID NO:247, a CDR-L1 of SEQ ID NO:78, a CDR-L2 of SEQ ID NO:79, and a CDR-L3 of SEQ ID NO:80. 
     
     
         19 . The method of  claim 18 , wherein anti-sclerostin antibody comprises heavy chains comprising SEQ ID NO: 378 and light chains comprising SEQ ID NO 376. 
     
     
         20 . A dental implant comprising an anti-sclerostin antibody that binds to a sclerostin polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein said anti-sclerostin antibody demonstrates a binding affinity for sclerostin of SEQ ID NO: 1 of less than or equal to 1×10 −9  M. 
     
     
         21 . A gel or matrix comprising an anti-sclerostin antibody that binds to a sclerostin polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein said anti-sclerostin antibody demonstrates a binding affinity for sclerostin of SEQ ID NO: 1 of less than or equal to 1×10 −9  M. 
     
     
         22 . An anti-sclerostin antibody for use in a method of treating alveolar bone loss in a subject, the method comprising administering an anti-sclerostin antibody in an amount effective to decrease the distance between the cement-enamel junction and the alveolar bone crest, optionally at a dose from about 5 mg to about 1,000 mg per week. 
     
     
         23 . The anti-sclerostin antibody according to  claim 22 , wherein the method of treating alveolar bone loss further comprises administering a second bone-enhancing therapeutic selected from the group consisting of parathyroid hormone, teriparatide, a bisphosphonate, a RANKL antibody and a DKK-1 antibody. 
     
     
         24 . The anti-sclerostin antibody according to  claim 23 , wherein the second bone-enhancing therapeutic is administered after the treatment period with the anti-sclerostin antibody has ended. 
     
     
         25 . The anti-sclerostin antibody according to  claim 22 , wherein the method of treating alveolar bone loss optionally further comprises administering the anti-sclerostin antibody for a second period of time in an amount sufficient to maintain alveolar bone. 
     
     
         26 . The anti-sclerostin antibody of any one of  claims 22 - 25 , wherein the anti-sclerostin antibody is an immunoglobulin comprising a heavy chain and a light chain. 
     
     
         27 . The anti-sclerostin antibody of any one of  claims 22 - 26 , wherein the anti-sclerostin antibody is an antibody or fragment thereof that demonstrates a binding affinity for sclerostin of SEQ ID NO: 1 of less than or equal to 1×10-9 M. 
     
     
         28 . The anti-sclerostin antibody of any one of  claims 22 - 27 , wherein the anti-sclerostin antibody neutralizes human sclerostin in a MC3T3 cell-based mineralization assay when there is less than a six-fold excess of moles of sclerostin binding sites per well as compared to the number of moles of sclerostin per well. 
     
     
         29 . The anti-sclerostin antibody of any one of  claims 22 - 28 , where the anti-sclerostin antibody cross-blocks the binding of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin and/or is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24. 
     
     
         30 . The anti-sclerostin antibody of any one of  claims 22 - 29 , wherein the anti-sclerostin antibody comprises a CDR-H1 of SEQ ID NO:245, a CDR-H2 of SEQ ID NO:246, a CDR-H3 of SEQ ID NO:247, a CDR-L1 of SEQ ID NO:78, a CDR-L2 of SEQ ID NO:79, and a CDR-L3 of SEQ ID NO:80. 
     
     
         31 . The anti-sclerostin antibody of  claim 30 , wherein anti-sclerostin antibody comprises heavy chains comprising SEQ ID NO: 378 and light chains comprising SEQ ID NO 376. 
     
     
         32 . Use of an anti-sclerostin antibody in preparation of a medicament for treating alveolar bone loss in a subject in an amount effective to decrease the distance between the cement-enamel junction and the alveolar bone crest, wherein the anti-sclerostin antibody is optionally at a dose from about 5 mg to about 1,000 mg per week.