Characterization of the bone phenotype of 24-week-old female transgenic sickle cell disease (SCD), sickle cell trait (SCT) revealed significant reductions in bone mineral density and bone mineral content relative to control with a further significant decreased in SCD compared with SCT. By microcomputed tomography, femur middiaphyseal cortical area was significantly reduced in SCT and SCD. Cortical thickness was significantly decreased in SCD vs control. Diaphysis structural stiffness and strength were significantly reduced in SCT and SCD. Histomorphometry showed a significant increase in osteoclast perimeter in SCD and significantly decreased bone formation in SCD and SCT compared with control with a further significant decrease in SCD compared with SCT. Collagen-I mRNA was significantly decreased in tibiae from SCT and SCD and osterix, Runx2, osteoclacin, and Dmp-1 mRNA were significantly decreased in tibiae of SCD compared with control. Serum osteocalcin was significantly decreased and ferritin was significantly increased in SCD compared with control. Igf1 mRNA and serum IGF1 were significantly decreased in SCD and SCT. IGF1 protein was decreased in bone marrow stromal cells from SCT and SCD cultured in osteogenic media. Crystal violet staining revealed fewer cells and significantly reduced alkaline phosphatase positive mineralized nodules in SCT and SCD that was rescued by IGF1 treatment. We conclude that reduced bone mass in SCD and SCT mice carries architectural consequences that are detrimental to the mechanical integrity of femoral diaphysis. Furthermore reduced IGF1 and osteoblast terminal differentiation contributed to reduced bone formation in SCT and SCD mice.