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

Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition
Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition
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.
8756-3282
70-78
Casanova, Michele
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Herelle, Janelle
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Thomas, Marcel
fa2f2450-5f3c-47f2-8ba5-0f640a65cdb4
Softley, Rowan
62e65480-c269-4f44-ab6e-8f8e379fb358
Schindeler, Aaron
8d1eff15-dc0d-4fd7-ba28-06c2d41cd5cb
Little, David
cb88e4ce-b97b-45ee-a016-dc1c9fc00373
Schneider, Philipp
a810f925-4808-44e4-8a4a-a51586f9d7ad
Müller, Ralph
f881853a-540f-48f1-bb6d-e0cf1894e036
Casanova, Michele
6fece42d-9268-4e0f-9c14-1b1b4d74961e
Herelle, Janelle
4c1131b1-ac1b-4492-9b1b-72cd3dab0b9d
Thomas, Marcel
fa2f2450-5f3c-47f2-8ba5-0f640a65cdb4
Softley, Rowan
62e65480-c269-4f44-ab6e-8f8e379fb358
Schindeler, Aaron
8d1eff15-dc0d-4fd7-ba28-06c2d41cd5cb
Little, David
cb88e4ce-b97b-45ee-a016-dc1c9fc00373
Schneider, Philipp
a810f925-4808-44e4-8a4a-a51586f9d7ad
Müller, Ralph
f881853a-540f-48f1-bb6d-e0cf1894e036

Casanova, Michele, Herelle, Janelle, Thomas, Marcel, Softley, Rowan, Schindeler, Aaron, Little, David, Schneider, Philipp and Müller, Ralph (2016) Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition. Bone, 92, 70-78. (doi:10.1016/j.bone.2016.08.012).

Record type: Article

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.

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BONE-D-16-00258R2_Soton_ePrints.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 14 August 2016
e-pub ahead of print date: 16 August 2016
Published date: November 2016
Organisations: Bioengineering Group

Identifiers

Local EPrints ID: 405060
URI: https://eprints.soton.ac.uk/id/eprint/405060
ISSN: 8756-3282
PURE UUID: 8d43bb10-81b0-4996-9bfb-615c8c13a114
ORCID for Philipp Schneider: ORCID iD orcid.org/0000-0001-7499-3576

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Date deposited: 26 Jan 2017 14:06
Last modified: 19 Jul 2019 19:26

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