Treatment of ovariectomized rats with the complex of rhIGF-I/IGFBP-3 Increases cortical and cancellous bone mass and improves structure in the femoral neck

Abstract

Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocortico-trabecular connectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias.

The −202 A Allele of Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Promoter Polymorphism Is Associated with Higher IGFBP-3 Serum Levels and Better Growth Response to Growth Hormone Treatment in Patients with Severe Growth Hormone Deficiency

“…First, IGFBP-3 prolongs the half-life of IGF-I, thus modulating its endocrine actions (11,13). Moreover, IGFBP-3 can potentiate IGF-I autocrine and paracrine actions, as demonstrated by many in vitro (30 -37) and in vivo studies (38,39). Indeed, IGF-I complexed to IGFBP-3 appears to be more potent than free IGF-I under many conditions (36, 38 -40).…”

Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system

“…This model would predict that null ALS mice with limited retention of liver-derived IGF-I would not respond as well to GH therapy or would have greater muscle wasting after endotoxin exposure (34,35). In support of this hypothesis, IGF-I therapies are more effective when ternary complex formation is improved by co-administration of GH or IGFBP-3 (36,37).…”

Contrasting bone effects of temporary versus permanent IGFBP administration in rodents

“…Systemic overexpression of IGFBP-3 in transgenic mice revealed inhibitory effects of IGFBP-3 on osteoblast proliferation and bone formation but stimulatory effects on osteoclast numbers and bone resorption, indicating inhibitory effects of long term exposure for bone growth on different levels [15]. In a series of experiments, the benefit of the rhIGF-I/IGFBP-3 complex on bone growth or bone density has been provided in rats but also in monkeys and humans [16][17][18][19][20]. The role of IGFBP-3 was proposed to safely allow for higher doses of IGF-I, which is thus gaining an improved therapeutic potential (reviewed in [21]).…”