The healing of osteoporotic bone defects

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Copyright: Francisco, Joy Irene
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Abstract
Estrogen deficiency represents a common cause of osteoporosis in women. Previous works have established a link between estrogen deficiency and impaired bone healing. However, the mechanism behind it is not fully understood and the effect of estrogen status on cancellous bone healing is undetermined. The ovariectomised (OVX) rat is the most widely used animal model in osteoporosis research, but there is no standard in terms of rat age, skeletal site and time post-OVX. Phase I examined how combinations of rat age (12, 24 and 44 weeks old), skeletal site (proximal tibia, spine, distal femur and proximal femur) and time post-OVX (2, 5, 10, 15, 20, 25 and 30 weeks) affect bone mineral and microarchitecture. Overall, the proximal tibia showed the earliest and greatest response to OVX, while the 24 week old group showed the best osteoporotic response. Rat age also induced site specific responses. Phase II involved: 1) Establishing an in vivo model of osteoporotic bone healing using a contained bone defect, 2) Examining the effect of estrogen deficiency on cancellous bone defect healing, and 3) Assessing osteoporotic autografts for augmenting bone healing. Based on Phase I, bilateral distal femur condylar defects were created in rats (24 weeks at OVX) at 20 weeks post-OVX. One defect remained empty and the other treated with iliac crest autograft. Healing was assessed after 1, 2 and 4 weeks. Estrogen deprivation resulted in inferior healing. OVX defects showed compositional differences (less new bone, higher osteoclast numbers and cathepsin-K expression) suggesting that increased catabolic activity upon estrogen deficiency contribute to its impaired healing. Osteoporotic autografts aided healing, but not as well as healthy bone, indicating that osteoporotic bone maintains some regenerative capacity. In summary, Phase I led to the development of a clinically relevant animal model of osteoporosis and yielded data that facilitates comparison between different studies. An in vivo model of osteoporotic cancellous bone healing was developed in Phase II, where the defects created was the first to be used in OVX rats. Estrogen deficiency was shown to impair cancellous bone healing due to up-regulated catabolic action, where osteoporotic bone has less regenerative capacity than healthy bone. Combination of grafting with anabolic and/or anti-catabolic agents (e.g. cathepsin-K inhibitors) may represent alternative strategies for treating osteoporotic bone defect healing.
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Author(s)
Francisco, Joy Irene
Supervisor(s)
Yu, Yan
Oliver, Rema
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Publication Year
2010
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Thesis
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PhD Doctorate
UNSW Faculty
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