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Basic fibroblast growth factor forms new trabeculae that physically connect with pre-existing trabeculae, and this new bone is maintained with an anti-resorptive agent and enhanced with an anabolic agent in an osteopenic rat model

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Abstract

Osteoporosis is a disease of excess bone fragility that results from both the loss of bone mass and trabecular bone microarchitecture, thereby creating a very fragile skeleton. The purpose of this study was to determine whether treatment of ovariectomized (OVX) osteopenic rats with basic fibroblast growth factor (bFGF) would stimulate the production of new trabeculae, and whether the newly formed trabeculae would make physical connections with the pre-existing trabeculae after prolonged estrogen deficiency. Six-month-old Sprague Dawley rats were OVXed or sham-operated and were left untreated until day 60 post-OVX. A high resolution microscopic scan (XTM) of the right proximal tibia was performed on groups 1 and 2 on day 1 post-OVX, and was repeated in all animals on day 60 post-OVX. At day 60 groups 1 and 2 were treated with vehicle and groups 3 to 6 were injected with bFGF 200ug/kg/d intravenously for 15 days. At day 82, all animals obtained another in vivo XTM scan of the right tibia; then group 4 were treated with 17B estradiol 10ug/kg/3x a week, group 5 were treated with hPTH (1–34) at 80ug/kg/d for 35 days, group 6 were sacrificed, and groups 1 and 2 were treated with vehicle injections for 35 days. At day 110, all remaining animals were sacrificed, and repeat ex vivo XTM scans of the right proximal tibia were performed. Trabecular bone structural variables—including trabecular bone volume, connectivity, number, and thickness—were obtained from all XTM scans. Biochemical markers of bone turnover were also obtained 24 hours before each XTM scan (osteocalcin and deoxypyridinoline), and analyzed by ELISA. Animals OVXed and treated with vehicle had decreased trabecular bone volume, connectivity and number compared to sham-operated animals at both day 60 and day 110. Animals treated with bFGF from day 60–75 post-OVX had evidence of new trabeculae that physically connected with pre-existing trabeculae and also of increased trabecular bone volume seven days after the injections were discontinued. Biochemical markers of bone formation had a small and insignificant increase over baseline levels during the bFGF injections. Bone resorption markers were significantly reduced during the injection period, but returned to baseline levels after the injections were stopped. In addition, we also demonstrated that these newly formed trabecular connections could be maintained or added to with either estrogen or hPTH (1–34) treatments. Thirty-five days after ending the bFGF treatment, trabecular bone volume and connectivity was 25–80% higher in the estrogen and hPTH (1–34) treated animals compared to the untreated animals ( p <0.01). These results support continued development of bFGF as a potential treatment for severely osteoporotic individuals.

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Acknowledgements

The authors would like to acknowledge David Haupt for assistance in obtaining the XTM images. This work was supported by grants from the NIH 1R01AR43052, the Research Evaluation and Allocation Committee of UCSF and the Rosalind Russell Arthritis Research Center.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, University of California at San Francisco, Box 0868, 94143, San Francisco, California

    N. E. Lane

  2. Department of Medicine, University of California of California at San Francisco, 94143, San Francisco, California

    J. Kumer, W. Yao & G. Modin

  3. Department of Restorative Dentistry, School of Dentistry, University of California at San Francisco, 94143, San Francisco, California

    T. Breunig & J. H. Kinney

  4. Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, 32610, Gainsville, Florida

    T. Wronski

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  1. N. E. Lane
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Correspondence to N. E. Lane.

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Lane, N.E., Kumer, J., Yao, W. et al. Basic fibroblast growth factor forms new trabeculae that physically connect with pre-existing trabeculae, and this new bone is maintained with an anti-resorptive agent and enhanced with an anabolic agent in an osteopenic rat model. Osteoporos Int 14, 374–382 (2003). https://doi.org/10.1007/s00198-003-1374-7

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