The aim of this prospective study was to evaluate changes in bone mineral density (BMD) of the mandible (m-BMD) compared with hip BMD and ultrasound parameters of the calcaneus and hand phalanges over 28 months. The study group consisted of 18 post-menopausal edentulous women with no reasons known to affect bone metabolism, such as disease or medication. Each woman had undergone natural menopause. No previous fractures were noted. Measurements were performed at baseline and repeated after 28 months. Bone status was assessed by measuring BMD using dual energy X-ray absorptiometry (DXA) at the mandible and hip and by measuring speed of sound (SOS), broadband ultrasound attenuation (BUA), stiffness index (SI) and amplitude-dependent SOS (Ad-SOS) using quantitative ultrasound at the calcaneus and phalanges of the hand. The coefficient of variation for mandibular measurements was 2.06%. BMD of the mandible, femoral neck and Ward's triangle decreased significantly (-7.54%, -1.2%, -1.97% per year, respectively, p<0.05), whilst BUA, SI and Ad-SOS decreased, but not significantly (-1.1%, -0.47%, -0.08% per year, respectively). Both SOS and BMD of the trochanter had almost the same value without significant differences. The least significant change (LSC), denoting the minimum difference between two successive results in an individual that can be considered to reflect a real change, was calculated. With the exception of changes in m-BMD, no significant changes were observed at any of the sites for the majority of the women (39-89%). 67% of women had a decrease in m-BMD greater than the LSC and 22% had an increase in m-BMD greater than the LSC. Apart from the mandible, other sites showing a large percentage of women with a decrease in BMD greater than the LSC were the Ward's triangle (39%) and the femoral neck (28%). In conclusion, a 28-month longitudinal study of post-menopausal women revealed mandibular bone loss assessed by DXA to be much higher than in other skeletal sites.