The complex of recombinant human insulin like growth factor-I (rhIGF-I) and its binding protein-5 (IGFBP-5) induces local bone formation in murine calvariae and in rat cortical bone after local or systemic administration

The influence of recombinant human insulin-like growth factor-I (rhlGF-I), its binding protein-5 (IGFBP-5) or their equimolar complexes on calvarial o steogenesis was investigated by quantitative radiography and histomorphomet ry after local administration to adult mice or mature rats. The systemic ef fects of these proteins were investigated in aged Sprague-Dawley rats with regard to their ability to prevent or restore bone mass in ovariectomy indu ced osteopenia as assessed by radiography, dual-energy X-ray absorptiometry (DEXA) analyses, peripheral computerized tomography (pQCT) and mineral ana lyses after daily s.c. administration for 3 or 8 weeks following a bone dep letion period of 8 weeks. Bone mass of murine calvariae was significantly i ncreased in a dose-dependent manner by the complex 7 days after discontinua tion of local administration for 19 days in mice, whereas IGF-I alone expre ssed only weak effects. IGFBP-5 alone was ineffective in this respect. In t he same model, only the complex had a weak osteogenetic potential in 7 week or 5 month old rats. Systemic long-term treatment with the complex of rhlG F-I/IGFBP-5 (2.0/7.6 mg/kg/day, s.c.) for 8 weeks resulted in significantly increased cortical thickness, area and mineral density in femoral midshaft or tibial metaphysis suggesting periosteal bone formation. This was obviou sly related to increased muscle strength since these effects were parallell ed by increased body weight. No effect on trabecular bone occurred as demon strated by site-specific analyses (vertebrae, proximal tibia) using DEXA, p QCT and radiography. This selective action of rhlGF-I/IGFBP-5 on periosteal bone formation is unique for an IGFBP. Femoral ash and calcium content, bo th corrected for tissue volume, increased slightly. However, when the incre ase in cortical thickness and bone mass was corrected for bone size, the ef fects are nearly abolished, suggesting an additional effect of bone growth. This potential deserves further evaluation in order to differentiate betwe en effects on cortical bone via muscle strength and lack of efficacy on tra becular bone balance. (C) 2001 Harcourt Publishers Ltd.