PMID- 26608966 OWN - NLM STAT- MEDLINE DCOM- 20160808 LR - 20220318 IS - 1528-1132 (Electronic) IS - 0009-921X (Print) IS - 0009-921X (Linking) VI - 474 IP - 5 DP - 2016 May TI - Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model? PG - 1294-302 LID - 10.1007/s11999-015-4640-z [doi] AB - BACKGROUND: Sclerostin is a secreted glycoprotein that inhibits the intracellular Wnt signaling pathway, which, when inactivated, stimulates bone formation. This has been seen in fracture studies, which have shown larger and stronger calluses with accelerated fracture healing in sclerostin knockout and sclerostin antibody injection models. However, the effects of these two mechanisms have not been compared in the context of fracture healing. QUESTIONS/PURPOSES: We sought to determine the degree to which sclerostin inhibition (Scl-Ab injection) and complete sclerostin depletion inhibit fracture healing in a mouse model as evaluated by (1) morphometric trabecular bone measures at the fracture site, and (2) fracture site structural strength. METHODS: Ten-week-old male sclerostin knockout (n = 20) and wild type (n = 40) mice underwent insertion of a tibial intramedullary pin after which a midshaft tibial osteotomy was performed. The mice were divided in three groups: sclerostin knockout (n = 20), wild type with sclerostin antibody injection (intravenous dose of 100 mg/kg weekly) (n = 20), and wild type with saline injection (n = 20). The mice for each group where subdivided and euthanized at 14, 21, 28, and 35 days after surgery, at which time the fractured tibias were assessed with microCT (to assess morphometric trabecular bone measures: bone volume to total volume (BV/TV), trabecular thickness, trabecular number, and structural model index at the fracture site. Biomechanical testing in the form of three-point bending also was done to assess fracture site structural strength. A difference greater than 3.7% in our primary outcome (BV/TV) would be required to detect a difference between groups with a power of 80%, as per our power analysis. RESULTS: The wild type with sclerostin antibody and the sclerostin knockout groups showed increased trabecular BV/TV at the fracture site compared with the wild type group with saline at all times, however no difference was seen between the treatment groups with the numbers available, except at 28 days postoperatively when the sclerostin knockout group showed greater BV/TV than the wild type sclerostin antibody group (47.0 +/- 3.5 vs 40.1 +/- 2.1; p < 0.05). On biomechanical testing the wild type sclerostin antibody showed increased stiffness at Days 14 and 28 compared with the wild type with saline group (70.9 +/- 6.4 vs 14.8 +/- 8.1; p = 0.001), (106.8 +/- 24.3 vs 74.9 +/- 16.0; p = 0.004); respectively. However, with the numbers available, no differences were detected between the wild type with sclerostin antibody and the sclerostin knockout groups in terms of whole-bone structural strength. CONCLUSIONS: Sclerostin antibody injections showed promising results, which were not different with the numbers available, from results achieved with complete depletion of sclerostin, especially at earlier stages of the healing process, and therefore completed the healing process at an earlier time. CLINICAL RELEVANCE: Sclerostin antibody injections appear to enhance fracture healing to a degree that is not different than complete sclerostin depletion, but larger animal studies are required to assess the accurate dosage and timing of administration in the fracture healing process to further evaluate its potential clinical utility to enhance fracture healing. FAU - Alzahrani, Mohammad M AU - Alzahrani MM AD - Shriners Hospital for Children, Montreal Children's Hospital, Montreal, QC, Canada. mohammad.alzahrani2@mail.mcgill.ca. AD - Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada. mohammad.alzahrani2@mail.mcgill.ca. AD - Department of Orthopaedic Surgery, University of Dammam, Dammam, Saudi Arabia. mohammad.alzahrani2@mail.mcgill.ca. AD - , 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada. mohammad.alzahrani2@mail.mcgill.ca. FAU - Rauch, Frank AU - Rauch F AD - Shriners Hospital for Children, Montreal Children's Hospital, Montreal, QC, Canada. FAU - Hamdy, Reggie C AU - Hamdy RC AD - Shriners Hospital for Children, Montreal Children's Hospital, Montreal, QC, Canada. AD - Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada. LA - eng PT - Journal Article DEP - 20151125 PL - United States TA - Clin Orthop Relat Res JT - Clinical orthopaedics and related research JID - 0075674 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antibodies) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Sost protein, mouse) SB - IM CIN - Clin Orthop Relat Res. 2016 May;474(5):1303-6. PMID: 26758443 MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Antibodies/administration & dosage MH - Biomechanical Phenomena MH - *Bone Remodeling/drug effects/genetics MH - Disease Models, Animal MH - *Fracture Healing/drug effects/genetics MH - Genotype MH - Glycoproteins/antagonists & inhibitors/*deficiency/genetics/immunology MH - Intercellular Signaling Peptides and Proteins MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Phenotype MH - Tibia/diagnostic imaging/drug effects/*metabolism/physiopathology/surgery MH - Tibial Fractures/genetics/*metabolism/physiopathology MH - Time Factors MH - X-Ray Microtomography PMC - PMC4814400 EDAT- 2015/11/27 06:00 MHDA- 2016/08/09 06:00 PMCR- 2017/05/01 CRDT- 2015/11/27 06:00 PHST- 2015/08/06 00:00 [received] PHST- 2015/11/13 00:00 [accepted] PHST- 2015/11/27 06:00 [entrez] PHST- 2015/11/27 06:00 [pubmed] PHST- 2016/08/09 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - 10.1007/s11999-015-4640-z [pii] AID - 4640 [pii] AID - 10.1007/s11999-015-4640-z [doi] PST - ppublish SO - Clin Orthop Relat Res. 2016 May;474(5):1294-302. doi: 10.1007/s11999-015-4640-z. Epub 2015 Nov 25.