Although
basic fibroblast growth factor (bFGF) is a potent stimulator of bone formation when administered intravenously, less is known regarding the effects of this
peptide on bone following subcutaneous (s.c.) administration. In addition, it is unknown whether coadministration of
estrogen enhances the bone response to treatment with bFGF. Therefore, the purpose of this study was (1) to characterize the skeletal response to s.c. injection of a high dose of bFGF, and (2) to determine whether concurrent administration of
estrogen affects the skeletal response to bFGF treatment. Female Sprague-Dawley rats were ovariectomized (ovx) or
sham-operated (
sham) at 3 months of age and left untreated for 2 months to establish cancellous
osteopenia in the ovx group. The
sham rats (n=10) and one group of ovx rats (n=9) were then injected s.c. with vehicle alone for 3 weeks. Two additional groups of ovx rats were injected s.c. with bFGF (n=10) or with bFGF +
estrogen (n=10) for 3 weeks. bFGF was administered s.c. at a daily dose of 1 mg/kg/day and
estrogen was administered s.c. 4 days per week at a dose of 10 microg/kg for the 3-week
duration of treatment. Lumbar vertebrae were collected and processed undecalcified for quantitative bone histomorphometry. Cancellous bone volume was lower and cancellous bone turnover was higher in vehicle-treated ovx rats than in vehicle-treated
sham rats. Subcutaneous treatment of ovx rats with bFGF for 3 weeks resulted in a 4-fold increase in osteoblast surface and an 8-fold increase in osteoid surface in comparison to vehicle treatment of ovx rats. Osteoid volume was also markedly increased in the bFGF-treated ovx rats (7 +/- 4%) in comparison to vehicle-treated ovx rats (<0.1%). Osteoblast surface, osteoid surface, and osteoid volume were nearly identical in ovx rats treated with bFGF alone and with bFGF +
estrogen. Although the majority of the osteoid in bFGF- and bFGF +
estrogen-treated animals was deposited along mineralized bone surfaces, osteoid spicules without any connections to preexisting bone surfaces were also detected, providing definitive proof for bone formation within bone marrow in response to bFGF administration. Osteoclast surface, an index of
bone resorption, was not affected by bFGF treatment. However, cotreatment of ovx rats with bFGF +
estrogen resulted in lower osteoclast surface in comparison to treatment of ovx rats with either vehicle or bFGF alone. In summary, these findings indicate that administration of a high dose of bFGF via s.c. injection markedly increases bone formation and may be a useful treatment for cancellous
osteopenia in the
estrogen-deplete skeleton. The
anabolic effects of bFGF on bone are not enhanced by concurrent treatment with
estrogen at the replacement dose used in this study.