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Pharmacological manipulation of fracture healing and bone remodeling

Harding, Anna Kajsa LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:56.
Abstract
Drug treatment has been and will continue to be a successful method in modern medicine that can change the course of a disease. However, it is surprisingly seldom used in the more technically oriented orthopedic surgery. Bone healing and physiological skeletal remodeling involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. Pharmaceutical substances, both anabolic drugs increasing bone formation and anti-catabolic drugs decreasing bone resorption, can be used to modulate fracture healing.

In the experimental studies, we used bone grafts placed in bone chambers in rats. In the first study the grafts were untreated and... (More)
Drug treatment has been and will continue to be a successful method in modern medicine that can change the course of a disease. However, it is surprisingly seldom used in the more technically oriented orthopedic surgery. Bone healing and physiological skeletal remodeling involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. Pharmaceutical substances, both anabolic drugs increasing bone formation and anti-catabolic drugs decreasing bone resorption, can be used to modulate fracture healing.

In the experimental studies, we used bone grafts placed in bone chambers in rats. In the first study the grafts were untreated and the animals received weekly injections with zoledronate, an anti-resorptive drug, or saline as control. In the second study the grafts were either pretreated with a bone inducing protein, BMP-7 or saline before surgery. As BMP-7 also induces resorption, the rats received either an injection of zoledronate or saline after two weeks. We saw that weekly injections of zoledronate decreased the resorption of both old graft and new-formed bone during bone graft remodeling. The combination of local BMP-7 and a single injection of zoledronate increased the bone formation substantially and at the same time protected the graft against premature catabolism.

In the clinical studies, we used high tibial osteotomies as a clinical model to study the effect of a bisphosphonate in fracture healing and pin fixation. Forty-eight patients were randomized to either an infusion of 4 mg zoledronate or saline after four weeks. Zoledronate almost doubled the fixation of the non-coated pins in the diaphyseal bone. The healing time was not affected.

In conclusion, bisphosphonates in experimental models delay the resorption of remodeling bone without disturbing the formation. BMP can be used to stimulate bone formation and can be combined with a bisphosphonate to control the simultaneously induced bone resorption. In humans single infusion of zoledronate almost doubled the pin-fixation in cortical diaphyseal bone. (Less)
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author
supervisor
opponent
  • Professor Larsson, Sune, Uppsala University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
pin-fixation, fracture healing, bone remodeling, bone graft, Bisphosphonate, BMP
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:56
pages
94 pages
publisher
Department of Orthopaedics, Lund University
defense location
Föreläsningssal F1, Centralblocket, Skånes Universitetssjukhuset i Lund
defense date
2010-05-20 13:00
ISSN
1652-8220
ISBN
978-91-86443-71-9
language
English
LU publication?
yes
id
ace28012-7997-4423-9c50-49af80a34ae3 (old id 1593175)
date added to LUP
2010-04-29 11:10:41
date last changed
2018-05-29 11:36:54
@phdthesis{ace28012-7997-4423-9c50-49af80a34ae3,
  abstract     = {Drug treatment has been and will continue to be a successful method in modern medicine that can change the course of a disease. However, it is surprisingly seldom used in the more technically oriented orthopedic surgery. Bone healing and physiological skeletal remodeling involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. Pharmaceutical substances, both anabolic drugs increasing bone formation and anti-catabolic drugs decreasing bone resorption, can be used to modulate fracture healing. <br/><br>
In the experimental studies, we used bone grafts placed in bone chambers in rats. In the first study the grafts were untreated and the animals received weekly injections with zoledronate, an anti-resorptive drug, or saline as control. In the second study the grafts were either pretreated with a bone inducing protein, BMP-7 or saline before surgery. As BMP-7 also induces resorption, the rats received either an injection of zoledronate or saline after two weeks. We saw that weekly injections of zoledronate decreased the resorption of both old graft and new-formed bone during bone graft remodeling. The combination of local BMP-7 and a single injection of zoledronate increased the bone formation substantially and at the same time protected the graft against premature catabolism.<br/><br>
In the clinical studies, we used high tibial osteotomies as a clinical model to study the effect of a bisphosphonate in fracture healing and pin fixation. Forty-eight patients were randomized to either an infusion of 4 mg zoledronate or saline after four weeks. Zoledronate almost doubled the fixation of the non-coated pins in the diaphyseal bone. The healing time was not affected.<br/><br>
In conclusion, bisphosphonates in experimental models delay the resorption of remodeling bone without disturbing the formation. BMP can be used to stimulate bone formation and can be combined with a bisphosphonate to control the simultaneously induced bone resorption. In humans single infusion of zoledronate almost doubled the pin-fixation in cortical diaphyseal bone.},
  author       = {Harding, Anna Kajsa},
  isbn         = {978-91-86443-71-9},
  issn         = {1652-8220},
  keyword      = {pin-fixation,fracture healing,bone remodeling,bone graft,Bisphosphonate,BMP},
  language     = {eng},
  pages        = {94},
  publisher    = {Department of Orthopaedics, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Pharmacological manipulation of fracture healing and bone remodeling},
  volume       = {2010:56},
  year         = {2010},
}