The dose-related effects of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 were monitored in the osteopenic rat skeleton at three different sites with cancellous bone: distal femoral metaphysis, epiphysis, and lumbar vertebral bodies. At the age of 16 weeks, rats were bilaterally ovariectomized (OVX) or sham operated (sham) and 8 weeks later divided into the control groups (sham OVX), and OVX groups treated with different doses of rhIGF-I or rhIGF-I/IGFBP-3 for 8 weeks. Fluorescent bone markers were given 9 and 2 days before necropsy. In addition, changes in designated bone sites as a result of ovariectomy alone were evaluated 8 and 16 weeks after surgery. High bone resorption, which dominates the postovariectomy remodeling process, resulted in a loss of cancellous bone at all measured sites. The highest trabecular bone loss was measured in the metaphyses (40%), compared with 22% in the lumbar vertebrae and 16% in the epiphyses. After 8 weeks of treatment with 7.5 mg/kg of rhIGF-I/IGFBP-3, bone formation rates were increased at all sites measured. Increased trabecular thickness was observed at the epiphyses and in the lumbar vertebral bodies. Increased bone resorption was restricted to the metaphyses of the rats that received the highest dose of rhIGF-I or rhIGF-I/IGFBP-3. Both formulations of rhIGF-I increased longitudinal bone growth similarly. This experiment demonstrates site-specific differences in cancellous bone reactions following ovariectomy. Epyphyses showed some advantages for cancellous bone histomorphometry over metaphyses and lumbar vertebral bodies. The data presented confirm the potential of rhIGF-I/IGFBP-3 complex to promote the bone formation process at various bone sites in osteoporotic rat skeleton.