Serum IGF‐1 Determines Skeletal Strength by Regulating Subperiosteal Expansion and Trait Interactions

Strong correlations between serum IGF‐1 levels and fracture risk indicate that IGF‐1 plays a critical role in regulating bone strength. However, the mechanism by which serum IGF‐1 regulates bone structure and fracture resistance remains obscure and cannot be determined using conventional approaches. Previous analysis of adult liver‐specific IGF‐1–deficient (LID) mice, which exhibit 75% reductions in serum IGF‐1 levels, showed reductions in periosteal circumference, femoral cross‐sectional area, cortical thickness, and total volumetric BMD. Understanding the developmental sequences and the resultant anatomical changes that led to this adult phenotype is the key for understanding the complex relationship between serum IGF‐1 levels and fracture risk. Here, we identified a unique developmental pattern of morphological and compositional traits that contribute to bone strength. We show that reduced bone strength associated with low levels of IGF‐1 in serum (LID mice) result in impaired subperiosteal expansion combined with impaired endosteal apposition and lack of compensatory changes in mineralization throughout growth and aging. We show that serum IGF‐1 affects cellular activity differently depending on the cortical surface. Last, we show that chronic reductions in serum IGF‐1 indirectly affect bone strength through its effect on the marrow myeloid progenitor cell population. We conclude that serum IGF‐1 not only regulates bone size, shape, and composition during ontogeny, but it plays a more fundamental role—that of regulating an individual's ability to adapt its bone structure to mechanical loads during growth and development.