Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis

Both a decrease in bone formation and an increase in bone resorption have b een implicated in the pathogenesis of age-related (type II) femoral neck os teoporosis. While the increase in the bone resorption rate has been shown t o be partially related to secondary hyperparathyroidism, the mechanisms und erlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation de ficit associated with type II osteoporosis might be due to secondary hyperp arathyroidism and/or to a deficiency of the insulin-like growth factor (IGF ) system. Circulating concentrations of IGF-I, IGF-TI, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D-3), and int act parathyroid hormone (PTH) were measured in 50 elderly women after susta ining a hip fracture and in 50 healthy age-matched controls. In addition, s erum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-termi nal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP -4 serum levels in the two groups studied, while mean levels of IGF-I, IGF- II, IGFBP-3, IGFBP-5, 25(OH)D-3, and markers of bone formation were signifi cantly lower (p < 0.006) in patients as compared with healthy subjects. Ser um PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of s erum OC (R-2 = 19%,p < 0.001) and BMD of femoral neck (R-2 = 49%,p < 0.0001 ), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D-3 and PTH, however, were s tatistically unrelated to OC, To address further the potential impact of tr auma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in s erum level of any of the IGF system components between the two groups. Alth ough limited by its cross-sectional design, the present study suggests that , in addition to bone resorption resulting from secondary hyperparathyroidi sm, impaired bone formation associated with deficiency of the IGF system mi ght predispose elderly women to fragility fracture of the proximal femur.