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High serum levels of IGFBP-1 are related both to low body mass index (BMI) and to low insulin-like growth factor 1 (IGF-I), which both in turn are related to low bone mineral density (BMD) and to increased fracture risk. However, we have found no previous prospective studies on IGFBP-1 and fracture risk. Despite its name, IGFBP-1 is not only just a binding protein but also has its own IGF-independent effects, e.g., stimulating osteoclast differentiation. IGFBP-1 might have an IGF-related and/or an IGF-independent association to fracture risk. This is a population-based prospective cohort study with a ten-year follow-up of 351 women aged 69-79 at inclusion. Fracture and mortality data were collected from national health care registers. IGFBP-1 had a positive linear relation to the risk of both hip fractures and "major osteoporotic fractures" including fractures of the hip, spine, shoulder, and wrist. The age-adjusted hazard ratio (HR) for a hip fracture was 1.46 (95 % CI 1.08-1.99) for one SD increase in IGFBP-1. The corresponding age-adjusted HR for major osteoporotic fractures was 1.33 (95 % CI 1.05-1.69). The relation between IGFBP-1 and fracture risk was not confounded by either IGF-I or BMI. Femoral neck BMD, however, mediated 56 % of the total "effect" of IGFBP-1 on hip fracture risk. In conclusion, IGFBP-1 had a positive linear relation to fracture risk, partly mediated by BMD but not related to IGF-I or BMD. This implies that IGFBP-1 might be an important factor in bone turnover and that further studies on this would be valuable.

The aim of this study was to determine the influence of insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3, and IGF-I on calcaneal ultrasound parameters in middle-aged and elderly European men. Men aged 40-79 years were recruited from population registers for participation in the European Male Ageing Study (EMAS). Subjects were invited by letter to complete a postal questionnaire and to attend for an interviewer-assisted questionnaire, quantitative ultrasound (QUS) of the calcaneus, and a fasting blood sample from which serum levels of IGFBP-1, IGFBP-3, IGF-I, estradiol (E(2)), and SHBG were assayed. The questionnaires included the Physical Activity Scale for the Elderly (PASE) and questions about smoking and alcohol consumption. Estimated bone mineral density (eBMD) was derived as a function of the QUS parameters speed of sound and broadband ultrasound attenuation. Height and weight were measured in all subjects. 3057 men, mean age 59.7 years (standard deviation 11.0) were included in the analysis. After adjusting for age, center, and BMI, higher levels of IGFBP-1 were associated with lower eBMD. Higher levels of both IGFBP-3 and IGF-I were associated with higher eBMD. After further adjustment for PASE score, current smoking, alcohol consumption, free E(2), and SHBG, IGFBP-3 and IGF-I, though not IGFBP-1, remained significantly associated with eBMD. IGFBP-1 was associated with bone health, though the effect could be explained by other factors. IGFBP-3 and IGF-I were independent determinants of bone health in middle-aged and elderly European men.