Estrogen deficiency in humans causes trabecular bone loss and structural deterioration, leading to an increased incidence of low trauma fractures (osteoporosis). Loss of bone is easily tracked in vivo by densitometry, but trabecular bone structural deterioration is difficult to follow because a technique that visualizes trabecular structure in vivo is not available. The degeneration of trabecular lattices can be quantitated on planar sections of specimens obtained at biopsy or necropsy as decreased trabecular number, increased trabecular spacing, increased free ends, decreased nodes, and increased marrow star volume. These indirect measures imply a loss of 3D connectivity that is believed to weaken the trabecular lattice. To prevent deterioration in trabecular bone microstructure, clinicians treat post-menopausal women with agents like estrogen that normalize the bone remodeling. Both clinical and pre-clinical data show that bone mass and structure are preserved best when estrogen treatment is begun early in the hypoestrogenemic state. The applicants hypothesize that the first change of consequences in trabecular bone after estrogen depletion is increased fenestration of longitudinal trabecular plates. They further hypothesize that the fenestrations of trabecular plates associated with hypoestrogenemia are irreversible and prevented with prompt estrogen replacement.
The specific aims of this proposal are to: (1) use XTM (x-ray tomographic microscopy), a new technique of high resolution 3-dimensional morphometry, to determine the post-surgical timecourse of trabecular plate fenestration in the ovariectomized rat; (2) determine the ability of timely estrogen replacement therapy to prevent new trabecular plate fenestration; (3) determine the usefulness of biochemical bone resorptive markers for predicting deterioration of trabecular architecture; and (4) compare the trabecular structure changes seen by XTM in vertebral body trabecular bone to the structural properties of the vertebral body. To accomplish these specific aims the investigators plan will do two experiments using the ovariectomized rat, taking serial XTM scans of the proximal tibial metaphysis at 0-50 days post-ovariectomy. In the first, they will scan live rats at 4, 8, 12, 18, 24, 30, 40, and 50 days after ovariectomy. Conventional histomorphometry, densitometry, and crosslink collections will be done at times corresponding to the XTM scans. In the second, they will XTM scan live rats at 0-50 days post- ovariectomy that have begun estrogen-replacement therapy at 0, 8, 12 or 18 days post- ovariectomy. They will also test vertebral body strength and XTM- revealed structure at 120 days post-ovariectomy. The deterioration of trabecular structure during the evolution of hypoestrogenemia has never been visualized directly and sequentially because an in vivo three dimensional technique that reveals structure with suitable resolution has never been available. XTM is such a technique and is suitable for in vivo application. Visualizing these changes with the backing of a serial sacrifice study (and conventional analyses) can enable a new level of understanding of trabecular bone structure deterioration that can currently be approached only indirectly by two-dimensional techniques. It will be known not only when trabecular fenestrations become irreversible, but also the rate of enlargement, and the time for which estrogen replacement may be delayed without undue trabecular structure deterioration.
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