Individuals with Down syndrome (DS), the result of trisomy of human chromosome Hsa21 (Ts21), present with an array of skeletal abnormalities typified by altered craniofacial features, short stature and low bone mineral density (BMD). While bone deficits progress with age in both sexes, low bone mass is more pronounced in DS men than women and osteopenia appears earlier. In the current study, the reproductive hormone status (FSH, LH, testosterone) of 17 DS patients (males, ages range 19–52 years) was measured. Although testosterone was consistently low, the hypothalamic-pituitary-gonadal axis was intact with corresponding rises in FSH and LH. To provide further insight into the heterogeneity of the bone mass in DS, the skeletal phenotypes of three of the most used murine DS models, Ts65Dn (Ts65), TC1, and Dp16(Yey1) (Dp16) were characterized and contrasted. Evaluation of the bone phenotype of both male and female 3-month-old Dp16 mice demonstrated sexual dimorphism, with low bone mass apparent in males, as it is in Ts65, but not in female Dp16. In contrast, male TC1 mice had no apparent bone phenotype. To determine whether low bone mass in DS impacted fracture healing, fractures of the middle phalanx (P2) digits were generated in both male and female Dp16 mice at 15 weeks of age, an age where the sexually dimorphic low BMD persisted. Fracture healing was assessed via in vivo microCT over (13 weeks) 93 days post fracture (DPF). At 93 DPF, 0 % of DS male (n = 12) or female (n = 8) fractures healed, compared to 50 % of the male (n = 28) or female (n = 8) WT littermate fractures. MicroCT revealed periosteal unbridged mineralized callus formation across the fracture gap in Dp16 mice, which was confirmed by subsequent histology. These studies provide the first direct evidence of significantly impaired fracture healing in the setting of DS.