Phalangeal osteosonogrammetry was introduced as a method for bone tissue investigation in 1992. It is based on the measure of the velocity of ultrasound (amplitude-dependent speed of sound [AD-SoS]) and on the interpretation of the characteristics of the ultrasound signal. In this study we have collected a database of 10,115 subjects to evaluate the performance of AD-SoS and to develop a parameter that is able to quantify the signal characteristics: ultrasound bone profile index (UBPI). The database only includes females of which 4.5% had documented vertebral osteoporotic fractures, 16% lumbar spine dual X-ray absorptiometry (DXA), and 6% hip DXA. The analysis of the ultrasound signal has shown that with aging the UBPI, first wave amplitude (FWA), and signal dynamics (SDy) follow a trend that is different from the one observed for AD-SoS; that is, there is no increase during childhood. In the whole population, the risk of fracture per SD decrease for AD-SOS was odds ratio (OR) 1.71 (CI, 1.58-1.84). The AD-SoS in fractured subjects was significantly lower than in a group of age-matched nonfractured subjects (p < 0.0001). In a small cohort of hip-fractured patients UBPI proved to be lower than in a control age-matched group (p < 0.0001). When the World Health Organization (WHO) working group criteria were applied to this population to identify the T score value for osteoporosis, for AD-SoS we found a T score of -3.2 and for UBPI we found a T score of -3.14. Sixty-six percent of vertebral fractures were below the AD-SoS -3.2 T score and 62% were below UBPI -3.14. We observed the highest incidence of fractures (63.6%) among subjects with AD-SoS who had both DXA T score values below the threshold. We conclude from this study that ultrasound investigation at the hand phalanges is a valid methodology for osteoporosis assessment. It has been possible to quantify signal changes by means of UBPI, a parameter that will improve the possibility of investigating bone structure.