When examining many musculoskeletal problems associated with growing older, such as decreased bone density and possible osteoporosis a good animal model for old human bone is essential. It is the broad objective of this proposal to explore the use of the ovariectomized (OVX) sheep as a large animal model for osteoporotic human bone. This model would allow researchers to more realistically investigate problems in older adults that are associated with low bone mass and osteoporotic conditions, including response of the osteogenic skeleton to various therapeutic regimens such as exercise, hormone, and diet therapy. To investigate the use of the female sheep as a model for postmenopausal bone loss, there will be two groups of twelve sheep with six OVX and six control animals in each group. The groups will be followed for 110 and 365 days. During the experimental period blood samples will be drawn every 50 days and subjected to analysis to determine circulating estrogen levels. Paired (right and left) rib and transiliac bone biopsies will be taken after double fluorochrome labeling to quantitate static and dynamic bone remodeling parameters before and after OVX histomorphological techniques. It is hypothesized that the OVX sheep will experience accelerated bone loss as compared to the controls and that they will experience an acute period of bone loss immediately following OVX, characterized by not only an increase in the activation of the remodeling units but also a transient synchronization of these units. This speculated synchronization may cause an acute loss of trabecular mass and integrity because the synchronized resorption action will increase the probability that trabecular plates and elements will become perforated. After the initial synchronization the cycle times should return to a random distribution in a period of months as that future loss is more gradual. This process should yield an experimental animal with reduced bone mass, and by carefully examining the transient process a better understanding of some of the observed features of postmenopausal osteoporosis should result. The bone parameters for the OVX group will also be used in developing a mathematical model to simulate the initial activation response of bone remodeling units of trabecular bone to decreased estrogen. This study should not only provide an attractive alternative to previous OVX animal models, but also should provide valuable bone histomorphological data on the sheep, an animal which is being used more frequently in orthopaedic studies.
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