Serum Levels of Insulin-Like Growth Factor (IGF); IGF-Binding Proteins-3, -4, and -5; and Their Relationships to Bone Mineral Density and the Risk of Vertebral Fractures in Postmenopausal Women

Abstract

We previously found that serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP)-3, but not IFGBP-2, were associated with bone mineral density (BMD) and the risk of vertebral fractures. The aim of the present study was to investigate the roles of IGFBP-4 and -5 in age-dependent bone loss and vertebral fracture risk in postmenopausal Japanese women and to compare them with those of IGF-I and IGFBP-3. One hundred and ninety-three Japanese women aged 46-88 years (mean 62.5) were enrolled in the cross-sectional study. BMD was measured at the lumbar spine, femoral neck, ultradistal radius (UDR), and total body by dual-energy X-ray absorptiometry. Serum levels of IGFBP-4 and -5 as well as IGF-I and IGFBP-3 were measured by radioimmunoassay. Serum levels of IGF-I, IGFBP-3, and IGFBP-5 declined with age, while serum IGFBP-4 increased with age. Multiple regression analysis was performed between BMD at each skeletal site and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, and serum creatinine. BMD at the UDR was significantly and positively correlated with all serum levels of IGF-I and IGFBPs measured (P < 0.01), while BMD at the femoral neck was correlated with none of them. Serum IGF-I level was significantly and positively correlated with BMD at all sites except the femoral neck (P < 0.01), while serum IGFBP-3 and -4 levels were significantly and positively correlated with only radial BMD (P < 0.01). Serum IGFBP-5 level was positively correlated with UDR BMD (P < 0.001) and negatively correlated with total BMD (P < 0.05). Serum IGF-I, IGFBP-3, and IFGBP-5 levels were significantly lower in women with vertebral fractures than in those without fractures (mean +/- SD: 97.1 +/- 32.1 vs. 143.9 +/- 40.9 ng/dl, P < 0.0001; 2.18 +/- 1.02 vs. 3.23 +/- 1.07 microg/ml, P < 0.0001; 223.6 +/- 63.3 vs. 246.5 +/- 71.5 ng/ml, P = 0.0330, respectively). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, serum creatinine, and serum alubumin as independent variables, IGF-I and IGFBP-3 were selected as indices affecting the presence of vertebral fractures [odds ratio (OR) = 0.29, 95% confidential interval (CI) 0.15-0.57 per SD increase, P = 0.0003 and OR = 0.31, 95% CI 0.16-0.61 per SD increase, P = 0.0007, respectively]. To compare the significance values, IGF-I, IGFBP-3, and age were simultaneously added as independent variables in the analysis. IGFBP-3 was more strongly associated with the presence of vertebral fractures than IGF-I and age (P = 0.0006, P = 0.0148, and P = 0.0013, respectively). Thus, after comprehensive measurements of serum levels of IGF-I and IGFBPs, it seems that serum IGF-I level is most efficiently associated with bone mass and that serum IGFBP-3 level is most strongly associated with the presence of vertebral fractures in postmenopausal women among the IGF system components examined.

Diabetic Patients Have an Increased Risk of Vertebral Fractures Independent of BMD or Diabetic Complications

“…(25) The anabolic effects of these hormones on bone may explain the relatively maintained BMD in T2DM compared with T1DM. In clinical studies, we and others showed that serum IGF-I levels were positively correlated with BMD in non-DM populations (26)(27)(28)(29) and that the hormone level was associated with reduced risk of VFs in postmenopausal women. (26) In T2DM women, however, we previously showed that serum IGF-1 level was not significantly correlated with BMD, whereas its increase was associated with reduced VF risk.…”

Insulin-like growth factor binding proteins-2 and -4 enhance the migration of human CD34−/CD133+ hematopoietic stem and progenitor cells

“…Although lung epithelial cancer cells and fibroblasts express IGFBP-6, the IGFBP-6 did not influence the migration of CD34 -/CD133 + cells. The IGFBP-3, which is the major IGFBP in peripheral blood (8,35), had no influence on the migration of CD34 -/CD133 + HSPCs. In contrast to CD34 -/ CD133 + cells, the migration of CD34 + /CD133 -HSPCs was not influenced by the IGFBP-2 and -4.…”

“…According to the range of concentration in human plasma or serum (8,34,35), 100-500 ng/ml rh IGF-I, 100-900 ng/ml rh IGFBP-2, 2,000-3,000 ng/ml rh IGFBP-3, 250-750 ng/ml rh IGFBP-4 or 100-500 ng/ml rh IGFBP-6 were applied. Because these rh IGF compounds are stored in 0.1% bovine serum albumin (BSA) solution, each control experiment was performed with the same amount of BSA.…”

“…concentrations of each factor were chosen according to the concentration range detected in human plasma or serum (8,34,35). For these experiments we used the transwell membrane with 3-μm pores for 24 h because of the more selective effect on cell migration in co-culture as compared to experiments with 8-μm pores membrane for 2 h (Fig.…”

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

“…Prospective analysis confirmed a similar association in women (van Varsseveld et al, 2015). Low IGF-1 level has been linked to increased risk of future fracture in men and women, although not all studies have shown consistent sex-specific effects (Ohlsson et al, 2011; van Varsseveld et al, 2015; Yamaguchi et al, 2006). …”