Authors: Mohammad M Alzahrani Frank Rauch Reggie C Hamdy
Publish Date: 2015/11/25
Volume: 474, Issue: 5, Pages: 1294-1302
Abstract
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 healingWe sought to determine the degree to which sclerostin inhibition SclAb 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 strengthTenweekold 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 threepoint bending also was done to assess fracture site structural strength A difference greater than 37 in our primary outcome BV/TV would be required to detect a difference between groups with a power of 80 as per our power analysisThe 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 470 ± 35 vs 401 ± 21 p 005 On biomechanical testing the wild type sclerostin antibody showed increased stiffness at Days 14 and 28 compared with the wild type with saline group 709 ± 64 vs 148 ± 81 p = 0001 1068 ± 243 vs 749 ± 160 p = 0004 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 wholebone structural strengthSclerostin 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 timeSclerostin 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 healingEach author certifies that he or she or a member of his or her immediate family has no funding or commercial associations eg consultancies stock ownership equity interest patent/licensing arrangements etc that might pose a conflict of interest in connection with the submitted article
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