A longitudinal study was conducted to investigate the relation between a polymorphism in the vitamin D receptor (VDR) gene and changes in bone mineral density (BMD) and quantitative ultrasound of the phalanges (QUS) over a five-year period. The subjects were 456 postmenopausal women with osteoporosis undergoing treatment, aged 59.95±7.97 years (mean±standard deviation [SD]) at baseline. BMD was measured at the hips and lumbar spine by dual-energy X-ray absorptiometry, and QUS was measured by means of amplitude-dependent speed of sound (Ad-SoS) at the phalanges. Lifestyle information was obtained via a questionnaire. The genotype frequencies of the BsmI (rs1544410) gene polymorphism were 29.4%, 47.1%, and 23.5% for bb, Bb, and BB, respectively. After five years, BMD (annual change in %/year) at the femoral neck (FN) showed a significant modification based on the rs1544410 genotype (BB vs Bb); there was an overall decrease in bone mass (-0.70±2.79%/year; P = 0.025). An analysis of covariance with adjustments for age, weight, height, percentage of weight change per year, baseline BMD and calcium intake showed that the observed associations were no longer significant (P = 0.429). No significant associations were found between the QUS measurements and the rs1544410 genotype after the five-year period. Our study limitations includes lack of information about type and length of duration of the osteoporosis treatment. Our results indicate that rs1544410 polymorphisms do not account significantly for the changes in bone mass in Spanish women with osteoporosis undergoing treatment.