insulin - like growth factor-1 ( igf-1 ) is a key mediator of the growth - promoting effects of growth hormone ( gh ) . it is produced in virtually every tissue of the body , including bone , with the liver being the principal source of igf-1 in the blood . igf-1 is considered to be essential for longitudinal bone growth , skeletal maturation , and bone mass acquisition during growth and the maintenance of bone mass in adults ( giustina et al . , 2008 ; ohlsson et al . , osteoporosis - related fractures constitute an important public health issue , not only in women but also in men . besides high social and economic costs associated with fractures , mortality is increased in patients with hip and vertebral fractures , even more so in men than in women ( center et al . , 1999b ) . in this mini - review , we will shortly summarize the role of igf-1 for bone growth and maintenance using animal knockout ( ko ) models . in addition , our latest findings from population - based cohorts regarding the predictive role of serum igf-1 for fractures are discussed . systemic as well as locally produced igf-1 can affect the skeleton . to investigate the relative contribution of systemic versus local igf-1 , transgenic mouse models were developed using the cre - loxp system . mouse models with specific inactivation of the igf-1 gene in the liver showed an approximately 75% reduction in serum igf-1 levels , confirming that hepatic igf-1 is the major contributor to circulating igf-1 levels ( sjgren et al . despite these decreases in serum igf-1 , postnatal body growth was preserved and bone length was largely unaffected . serum igf-1 levels were even more reduced in ko mouse models of liver - derived igf-1 combined with acid - labile subunit and/or total igf binding protein 3 ( removing endocrine igf-1 ) . these mice displayed a modest but significant reduction in total body length ( yakar et al . when looking on the bone phenotype in more detail using computed tomography and histomorphometry , the liver - specific igf-1 ko mice showed a significant reduction in cortical bone mass . cortical thickness and periosteal circumference were decreased ( sjgren et al . , 2002 ; yakar et al . , 2002 ) , which was associated with reduced bone strength in adult mice ( sjgren et al . , 2002 ) . these models indicate a role for endocrine igf-1 in the regulation of normal longitudinal bone growth and cortical bone size . the role of local bone - derived igf-1 was examined in mouse models with osteoblast- or chondrocyte - specific inactivation of igf-1 ( govoni et al . these mice displayed reduced femur length ( 7% in the chondrocyte ko and 15% in the osteoblast ko ) while serum igf-1 levels were unaffected , indicating that igf-1 from both chondrocytes and osteoblasts participates in the regulation of bone growth . cortical bone was also affected in these mice , showing reduced bone width and bone mass in both models ( govoni et al . thus , local igf-1 from chondrocytes and osteoblasts seems essential for both normal bone length and width . taken together , these models indicate that both circulating ( endocrine ) igf-1 and bone - derived igf-1 are required for normal longitudinal bone growth and optimal accrual of cortical bone . since both sources of igf-1 have , to some extent , overlapping growth - promoting effects , they may partly but not completely be redundant for normal longitudinal bone growth ( ohlsson et al . , 2009 ) . patients with igf deficiency as a result of deletion or mutation of the igf1 gene display osteopenia , indicating a role for igf-1 in bone metabolism ( woods et al . , 1996 ; evaluation of the relationship between serum igf-1 levels and bone mineral density ( bmd ) yielded conflicting results , with a positive association being found in some studies ( barrett - connor and goodman - gruen , 1998 ; janssen et al . , 1998 ; langlois et al . , 1998 ) whereas no association was found in others ( bennett et al . , 1984 ; center et al . , 1999a ) . moreover , the rancho bernardo study ( barrett - connor and goodman - gruen , 1998 ) and the framingham study ( langlois et al . , 1998 ) found positive associations between serum igf-1 levels and bmd in women but not in men , whereas the same correlation was found in men but not in women in the rotterdam study ( janssen et al . , 1998 ) . the various experimental mouse models described above suggest that serum igf-1 levels contribute to bone growth and the accrual of an optimal cortical bone size . since the resistance of bone to bending or torsional forces is related exponentially to its diameter , the bone size is an important contributor to bone strength , and ultimately fracture risk ( orwoll , 2003 ) . therefore , we assessed the available evidence for a predictive value of serum igf-1 levels for risk of fracture . several studies reported lower serum igf-1 levels in women with prevalent fractures compared with women without fractures ( sugimoto et al . , 1997 ; munoz - torres et al . , 2001 ; kanazawa et al . , 2007 ) . ( 2000 ) found an association between low baseline igf-1 levels and increased risk of fractures . women with serum igf-1 concentrations below the median ( 212  ng / ml ) had a relative risk of fracture of 3.1 compared with women with concentrations above the median . since the study included 435 postmenopausal women of whom only 55 sustained a fracture , it had limited statistical power and was unable to evaluate the association between serum igf - i and fracture type . to determine the predictive value of serum igf-1 for fracture risk in men , we followed older men ( n  =  2902 ) participating in the prospective osteoporotic fractures in men ( mros ) sweden study for a mean of 3.3  years ( ohlsson et al . , 2011 ) . low serum igf-1 levels were associated with increased risk of all fractures , hip fractures , and vertebral fractures in these men . the risk of hip and vertebral fractures increased by 45 and 40% per sd decrease in serum igf-1 , respectively . serum levels of igf-1 below but not above the median ( 112  ng / ml ) were inversely related to the yearly incidence of fractures ( figure 1 ) . the highest risk of fractures was seen for the 25% of the subjects with serum igf-1 levels below 85  ng / ml . in addition , the population - attributable risk proportion was 7.5% for all fractures and 22.9% for hip fractures . in this cohort , low levels of serum igf-1 associated not only with increased fracture risk but also with low bmd . therefore , adjustment for bmd was performed which attenuated the predictive role of serum igf-1 for hip fractures and vertebral fractures , suggesting that at least part of the association between serum igf-1 and fracture risk is mediated via bmd . however , our data argue against a mediating role of neuromuscular function in the association between serum igf-1 and fracture risk , since this association was not affected by adjustment for grip strength , total body lean mass , or falls . in conclusion , this well - powered study was the first to show that older men with low serum igf-1 levels have an increased risk of fractures , especially for the two most important fracture types , hip and vertebral fractures ( ohlsson et al . , 2011 ) . poisson regression models were used to determine the relation between serum igf-1 levels and risk of fractures . the quartile limits ( 25 , 50 , and 75% ) are indicated by vertical lines in the figure . both systemic and bone - derived igf-1 play a critical role in normal longitudinal bone growth , bone development , and cortical bone mass accrual , as evidenced by various ko mouse models . future studies are needed to determine the mechanisms by which endocrine and local igf-1 regulate skeletal growth and bone size . findings from our mros sweden cohort show that in older men , serum igf-1 is a predictor of incident fractures , more specifically , of the two most important fractures types , hip and vertebral fractures , in older men . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
growth hormone and insulin - like growth factor-1 ( igf-1 ) are essential for the achievement of normal longitudinal bone growth and bone mass . preclinical studies using various knockout models have shown that both endocrine ( mostly liver - derived ) igf-1 and bone - derived igf-1 contribute to normal longitudinal skeletal growth and cortical bone size . since bone size is an important determinant of bone strength , and hence fracture risk , we evaluated the predictive role of serum igf-1 for fracture risk . the population - based osteoporotic fractures in men sweden cohort recently showed for the first time that older men with low serum igf-1 levels have an increased fracture risk , especially for the two most important fracture types , hip and vertebral fractures . 
 this association between serum igf-1 and incident fracture risk is partly mediated via bone mineral density . 
 future studies are required to identify the mechanisms by which endocrine and local igf-1 regulate skeletal growth and bone size . 
 in addition , possible mediators affecting the impact of igf-1 on fractures in men remain to be elucidated .