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The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.
Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden; Department of Oral and Maxillofacial Surgery, Örebro University Hospital, Örebro, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg, Sweden.
Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg, Sweden.
Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg, Sweden.
Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg, Sweden; Department of Oral and Maxillofacial Surgery, Institute of Odontology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
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2013 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 5, 1546-1561 p.Article in journal (Refereed) Published
Abstract [en]

Bisphosphonates reverse the negative effects of ovariectomy on bone, but they have also been associated with adverse processes in human jawbone. The molecular events determining bone regeneration and implant integration in osteoporotic conditions, with and without bisphosphonate treatment, are unclear. In this study, ovariectomised rats, to which a single dose of saline (NaCl) or zoledronic acid (Zol) was administered, received titanium alloy implants in their tibiae and mandibles. An enzyme-linked immunosorbent assay, gene expression analysis and histomorphometry were performed. The results show that ovariectomy, per se, upregulated the expression of genes denoting bone formation in the tibia, bone remodelling in the mandible and apoptosis in the tibia and mandible. Zoledronic acid administration resulted in lower levels of a remodelling marker in serum and downregulated gene expression for inflammation, bone formation, angiogenesis and apoptosis, mainly in the mandible, after 28 d of healing. Histomorphometry revealed improved bone-to-implant contact in the tibia, while the opposite was observed in the mandible. The present data show that a systemic single dose of zoledronic acid, in ovariectomised animals, results in site-specific differences in the regulation of genes involved in bone healing and regeneration in association with implant installation. These events occur in parallel with site-specific differences in the rate of osseointegration, indicating diverse tissue responses in the tibia and mandible after zoledronic acid treatment. The zoledronic acid effect on gene expression, during the late phase of healing in the mandible, suggests negative effects by the anti-resorptive agent on osseointegration at that particular site.

Place, publisher, year, edition, pages
2013. Vol. 34, no 5, 1546-1561 p.
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:liu:diva-135755DOI: 10.1016/j.biomaterials.2012.11.003PubMedID: 23182921OAI: oai:DiVA.org:liu-135755DiVA: diva2:1083325
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-28
In thesis
1. Effects of antiresorptive agents on inflammation and bone regeneration in different osseous sites - experimental and clinical studies
Open this publication in new window or tab >>Effects of antiresorptive agents on inflammation and bone regeneration in different osseous sites - experimental and clinical studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The biological mechanisms involved in bone regeneration in osteoporotic bone and the effect of antiresorptive drugs in relation to surgically inserted biomaterials are not fully understood. Improved osseointegration of titanium implants but also adverse effects of antiresorptive therapies, such as osteonecrotic jaw have been described in the literature. The aims of this research project were, firstly, to investigate and to understand the biological events determining bone regeneration and implant integration, after administration of antiresorptive agents; secondly, to determine the cellular and molecular patterns of bone regeneration at implants and synthetic bone substitutes under osteoporotic conditions and, thirdly, to determine how different skeletal sites are affected. The present research included a study of jawbone morphology and gene expression in patients treated with systemic bisphosphonates. When compared to controls, higher gene expression levels of IL-1β was observed in bisphosphonate treated patients with osteonecrosis while bisphosphonate treated patients without necrosis showed lower expression levels of caspase 8, an apoptosis marker involved in the immune response. In ovariectomised rats, zoledronic acid resulted in site-specific differences in the rate of osseointegration and also of gene expression involved in bone healing and regeneration. Strontium-doped calcium phosphate inserted in the rat femur induced lower expression of osteoclastic markers compared to hydroxyapatite and higher bone formation in the periphery of the defects. Whereas major structural changes were demonstrated in the long bones of the ovariectomised rat, less structural alterations were shown in the mandible. However, ovariectomy resulted in lower expression of genes coding for bone formation and angiogenesis in the mandible. In conclusion, the present study shows that the mandible is differently affected by experimentally induced estrogen deficiency than the long bones. Bisphosphonates, administered systemically to estrogen deficient animals, impair osseointegration in the mandible, at least partly related to a downregulation of genes important for the osteogenic process. These observations may have implications for understanding the mechanisms involved in the deranged bone healing observed in the jawbone of bisphosphonate treated patients.

Place, publisher, year, edition, pages
Göteborg: Göteborgs universitet, 2014. 87 p.
Keyword
Qntiresorptive agents, ovariectomised rat, osteoporosis, skeletal site, differences osteonecrosis of the jaw, osseointegration, bone substitute, inflammation, bone regeneration, gene expression, histomorphometry, Micro-CT
National Category
Biomaterials Science Medical Biotechnology Cell and Molecular Biology Genetics
Identifiers
urn:nbn:se:liu:diva-136114 (URN)9789162891084 (ISBN)9789162891121 (ISBN)
Public defence
2014-10-17, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg, 13:00 (English)
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Available from: 2017-03-30 Created: 2017-03-28 Last updated: 2017-03-30Bibliographically approved

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