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Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition.

Abstract：

:In recent years, great interest in combined treatment of parathyroid hormone (PTH) with anti-resorptive therapy has emerged. PTH has been suggested to aid bridging of atrophic fractures and improve strength in closed fracture models. Bisphosphonate treatments typically result in a larger woven bone callus that is slower to remodel. The combination of both drugs has been demonstrated to be effective for the treatment of osteoporotic bone loss in many preclinical studies. However, the effect of combined treatment on fracture repair is still largely unexplored. In this study, we aimed to compare these drugs as single-agent and in combination in a murine closed fracture model. We wanted to assess potential differences in material properties, morphometry and in the development of the lacuno-canalicular network. A total of 40 female, 11-week-old wild type mice underwent a closed fracture on the midshaft of the tibia and were assigned to four groups (n=8-10 per group). Beginning on post-operative day 8, animals received different subcutaneous injections. Group 1 received a single injection of saline solution and Group 2 of zoledronic acid (ZA). Group 3 received daily dosing of PTH. Group 4 received a dual treatment, starting with a single dose of ZA followed by daily injection of PTH. Three weeks after fracture, all animals were euthanized and tibiae were assessed using micro-computed tomography (micro-CT), high-resolution micro-CT (HR micro-CT), Raman spectroscopy, quantitative histomorphometry, and deconvolution microscopy (DV microscopy). Combined treatment showed a significant increase of 41% in bone volume fraction and a significant decrease of 61% in the standard deviation of the trabecular spacing compared to vehicle, both known to be strong predictors of callus strength. An analysis via HR micro-CT showed similar results on all groups for lacunar numerical density, whereas mean lacuna volume was found to be higher compared to vehicle in treated groups, but only PTH mono-treatment showed a significant increase compared to vehicle (+45%). Raman spectroscopy did not reveal detectable changes in material properties of the bone calluses. Sclerostin staining, tartrate resistant acid phosphatase (TRAP) staining and canalicular analysis with DV microscopy on a subset of samples did not display distinctive difference in any of the treatments. We therefore consider PTH+ZA treatment beneficial for bone healing. No clear negative effect on bone quality was detected during this study.

journal_name

Bone

journal_title

Bone

authors

Casanova M,Herelle J,Thomas M,Softley R,Schindeler A,Little D,Schneider P,Müller R

doi

10.1016/j.bone.2016.08.012

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

70-78

eissn

8756-3282

issn

1873-2763

pii

S8756-3282(16)30231-9

journal_volume

92

pub_type

杂志文章

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