Osteoporosis is a syndrome of excessive skeletal fragility resulting from estrogen deficiency. Estrogen loss tends to a reduction of trabecular bone mass and an irreversible alteration of the trabecular bone structure. Currently available treatments for osteoporosis can maintain or modestly increase bone mass in individuals with an adequate number of pre-existing trabeculae, however, they cannot stimulate the production of new trabecular elements or reestablish trabecular connectivity. To reverse skeletal fragility in severely osteoporotic individuals, we first need to establish a scaffold of new trabeculae. Recently, it was found that uncommitted bone marrow stromal cells can be stimulated by specific growth factors (specifically, basic fibroblast growth factor, bFGF) to differentiate into osteoblasts and form new trabecular bone spicules. Also, systemic treatment of osteopenic female rats with bFGF for 14 days resulted in growth of new trabecular spicules in the secondary spongiosa of the proximal tibia. Based on these observations, we hypothesize that systemic bFGH treatment will stimulate the formation of new bone trabeculae beginning from both existing bone surfaces and de novo from within bone marrow cavity. We further hypothesize that these new trabeculae will reconnect with the established trabecular scaffolding, thereby increasing trabecular bone connectivity and strength. Lastly, we hypothesize that this newly formed bone will disappear through remodeling unless it is maintained with anti-resorptive treatment. To test these hypotheses we propose the following specific aims. 1. To determine the ability of bFGF to stimulate new trabecular bone and increase connectivity in the ostteopenic rat. 2. To determine how the new trabeculae are maintained after bFGF is discontinued. 3. To determine if treatment with an anti-resorptive agent (estrogen or a bisphosphonate) will maintain the newly formed trabecular bone. 4. To determine the usefulness of biochemical markers of bone turnover to assess the changes in trabecular bone mass and structure with bFGF and antiresorptive treatment. 5. To determine the effects of bFGF treatment on the strength of trabecular bone regions and cortical bone. To accomplish these specific aims serial XTM scans of the proximal rat tibia conventional histomorphometry densitometry, biochemical markers of bone turnover, and biomechanical tests will be perfomed. It is expected that this research will further our ability to reverse severe osteoporosis.
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