Osteoporosis has reached epidemic proportions. This situation has stimulated the development of biochemical markers to assist in assessing osteoporotic risk and monitoring treatment efficacy. Biochemical markers for assessing the level of bone resorption have been developed during the last few decades. One of the most widely used bone resorption markers is cross-linked N-terminal telopeptides (NTX). Measurements of urinary and serum NTX provide indications of the level of bone resorption during osteoporosis treatment. However, it remains unclear whether urinary or serum NTX measurements show better efficacy for assessing osteoporosis treatment effects during the early phase of treatment. Therefore, the primary aim of the present study was to compare the efficacies of urinary and serum NTX measurements for assessing the level of bone resorption during the early stage of osteoporosis treatment. We enrolled 43 postmenopausal Japanese women in an open-label randomized placebo-controlled trial. Overall, 21 women in the osteoporosis treatment group and 19 women in the placebo group completed the study. There was a significant reduction in urinary NTX in the treatment group, which was detectable as early as 4 weeks and maintained until 16 weeks, compared with the placebo group. On the other hand, serum NTX did not show a significant reduction in the treatment group compared with the placebo group until 16 weeks. These results indicate that urinary NTX measurements are more sensitive and show higher efficacy than serum NTX measurements for assessing treatment effect during the early phase of osteoporosis treatment in postmenopausal women.